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Find video protocols related to scientific articles indexed in Pubmed.
Apoptosis Pathways in HIV-1-Infected Patients Before and After Highly Active Antiretroviral Therapy: Relevance to Immune Recovery.
AIDS Res. Hum. Retroviruses
PUBLISHED: 11-12-2014
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Abstract Investigations into apoptotic pathways, intrinsic and extrinsic, and the effects of highly active antiretroviral therapy (HAART) on T cell death via those pathways may provide insight into the mechanisms of and barriers to immune recovery. HIV-1-infected patients were enrolled into a randomized, controlled study of the immune effects of a lopinavir/ritonavir (LPV/r)-based versus an efavirenz (EFV)-based HAART regimen in antiretroviral-naive subjects with CD4(+) counts <350 cells/mm(3). Patients were randomized to receive TDF/FTC/EFZ or TDF/FTC plus LPV/r. Fourteen patients were enrolled and 10 patients completed 6 months of therapy as per the protocol. CD4(+) counts were measured before and during HAART therapy. We isolated T cell subsets to measure ex vivo apoptosis by propidium iodide staining. We also assessed caspase activation for the intrinsic and extrinsic pathways of apoptosis, as well as effector caspase activation. We also measured mitochondrial membrane potential. Cells were analyzed by flow cytometry. All patients had increased activation of caspase 8 (extrinsic pathway), caspase 9 (intrinsic pathway), effector caspases 3/7, and low mitochondrial membrane potential at baseline compared to controls. By 4 weeks, there was a decrease in activation of all caspases, but little further decrease by week 24. T cell mitochondrial membrane potential did not increase until week 12, but continued to increase until week 24. The only predictor of CD4(+) count increase was the increase in mitochondrial membrane potential of naive cells at 6 months (r=0.66, p=0.038). This suggests that positive selection of naive CD4(+) T cells in the thymus is the major determinant of CD4(+) recovery.
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Glucose Transporter 1-Expressing Proinflammatory Monocytes Are Elevated in Combination Antiretroviral Therapy-Treated and Untreated HIV+ Subjects.
J. Immunol.
PUBLISHED: 11-03-2014
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Monocyte activation during HIV-1 infection is associated with increased plasma levels of inflammatory markers and increased risk for premature development of age-related diseases. Because activated monocytes primarily use glucose to support cellular metabolism, we hypothesized that chronic monocyte activation during HIV-1 infection induces a hypermetabolic response with increased glucose uptake. To test this hypothesis, we evaluated glucose transporter 1 (Glut1) expression and glucose uptake by monocyte subpopulations in HIV-seropositive (HIV(+)) treatment-naive individuals (n = 17), HIV(+) individuals on combination antiretroviral therapy with viral loads below detection (n = 11), and HIV-seronegative (HIV(-)) individuals (n = 16). Surface expression of Glut1 and cellular uptake of the fluorescent glucose analog 2-(N-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl) amino)-2 deoxyglucose were analyzed by flow cytometry on monocyte subpopulations. Irrespective of treatment status, monocytes from HIV(+) persons had significantly increased surface expression of Glut1 compared with those from HIV(-) controls. Nonclassical (CD14(+)CD16(++)) and intermediate (CD14(++)CD16(+)) monocyte subpopulations showed higher Glut1 expression than did classical (CD14(++)CD16(-)) monocytes. Intermediate monocytes from treatment-naive HIV(+) individuals also showed increased uptake of 2-(N-(7-nitrobenz-2-oxa-1, 3-diazol-4-yl) amino)-2 deoxyglucose compared with those from HIV(-) controls. Our results show that HIV infection is associated with increased glucose metabolism in monocytes and that Glut1 expression by proinflammatory monocytes is a potential marker of inflammation in HIV-infected subjects. However, the possibility exists whereby other Gluts such as Glut3 and Glut4 may also support the influx of glucose into activated and inflammatory monocyte populations.
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Association of Chronic Hepatitis C Infection With T-Cell Phenotypes in HIV-Negative and HIV-Positive Women.
J. Acquir. Immune Defic. Syndr.
PUBLISHED: 10-15-2014
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Hepatitis C virus (HCV) viremia is thought to have broad systemic effects on the cellular immune system that go beyond its impact on just those T cells that are HCV specific. However, previous studies of chronic HCV and circulating T-cell subsets (activation and differentiation phenotypes) in HIV negatives used general population controls, rather than a risk-appropriate comparison group. Studies in HIV positives did not address overall immune status (total CD4 count).
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Rifaximin has a Marginal Impact on Microbial Translocation, T-cell Activation and Inflammation in HIV-Positive Immune Non-responders to Antiretroviral Therapy - ACTG A5286.
J. Infect. Dis.
PUBLISHED: 09-11-2014
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?Rifaximin, a nonabsorbable antibiotic that decreases lipopolysaccharide (LPS) in cirrhotics, may decrease the elevated levels of microbial translocation, T-cell activation and inflammation in human immunodeficiency virus (HIV)-positive immune nonresponders to antiretroviral therapy (ART).
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Sevelamer Does Not Decrease Lipopolysaccharide or Soluble CD14 Levels But Decreases Soluble Tissue Factor, Low-Density Lipoprotein (LDL) Cholesterol, and Oxidized LDL Cholesterol Levels in Individuals With Untreated HIV Infection.
J. Infect. Dis.
PUBLISHED: 05-26-2014
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Abnormal levels of inflammation are associated with cardiovascular disease and mortality in human immunodeficiency virus (HIV)-infected patients. Microbial translocation, which may cause inflammation, is decreased by sevelamer in patients undergoing hemodialysis. In this single-arm study, we evaluated the effects of 8 weeks of sevelamer therapy on 36 HIV-infected subjects who were not receiving antiretroviral therapy. Sevelamer did not significantly change markers of microbial translocation, inflammation, or T-cell activation. During sevelamer treatment, however, levels of soluble tissue factor, low-density lipoprotein (LDL) cholesterol, and oxidized LDL cholesterol decreased significantly, whereas D-dimer levels increased. Thus, in this study population, sevelamer did not reduce microbial translocation but may have yielded cardiovascular benefits.
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In vitro evaluation of intestinal epithelial TLR activation in preventing food allergic responses.
Clin. Immunol.
PUBLISHED: 05-19-2014
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Alterations in the gut microbiota composition are associated with food allergy. Toll-like receptors (TLRs) respond to microbial stimuli. We studied the effects of the ligation of TLRs on intestinal epithelial cells (IECs) in preventing an allergic effector response. IEC monolayers (T84 cells) were co-cultured with CD3/28-activated PBMCs from healthy controls or atopic patients and simultaneously apically exposed to TLR2, TLR4 or TLR9 ligands. The barrier integrity of T84 cell monolayers was significantly reduced upon co-culture with PBMCs of food allergic subjects compared to healthy subjects. Apical exposure of IECs to a TLR9 ligand prevented PBMC-induced epithelial barrier disruption. Using PBMCs from food allergic subjects, apical TLR9 activation on IECs increased the IFN-?/IL-13 and IL-10/IL-13 ratio, while suppressing pro-inflammatory IL-6, IL-8 and TNF-? production in an IEC-dependent manner. Hence, the activation of apical TLR9 on IECs, potentially by microbiota-derived signals, may play an important role in the prevention of allergic inflammation.
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A randomized controlled trial of palifermin (recombinant human keratinocyte growth factor) for the treatment of inadequate CD4+ T-lymphocyte recovery in patients with HIV-1 infection on antiretroviral therapy.
J. Acquir. Immune Defic. Syndr.
PUBLISHED: 05-13-2014
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Poor CD4 lymphocyte recovery on antiretroviral therapy (ART) is associated with reduced function of the thymus. Palifermin (keratinocyte growth factor), by providing support to the thymic epithelium, promotes lymphopoiesis in animal models of bone marrow transplantation and graft-versus-host disease.
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Soluble markers of inflammation and coagulation but not T-cell activation predict non-AIDS-defining morbid events during suppressive antiretroviral treatment.
J. Infect. Dis.
PUBLISHED: 05-01-2014
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Defining the association of non-AIDS-defining events with inflammation and immune activation among human immunodeficiency virus (HIV)-infected persons with antiretroviral therapy (ART)-associated virological suppression is critical to identifying interventions to decrease the occurrence of these events.
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Human ?-amylase present in lower-genital-tract mucosal fluid processes glycogen to support vaginal colonization by Lactobacillus.
J. Infect. Dis.
PUBLISHED: 04-15-2014
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Lactobacillus colonization of the lower female genital tract provides protection from the acquisition of sexually transmitted diseases, including human immunodeficiency virus, and from adverse pregnancy outcomes. While glycogen in vaginal epithelium is thought to support Lactobacillus colonization in vivo, many Lactobacillus isolates cannot utilize glycogen in vitro. This study investigated how glycogen could be utilized by vaginal lactobacilli in the genital tract. Several Lactobacillus isolates were confirmed to not grow in glycogen, but did grow in glycogen-breakdown products, including maltose, maltotriose, maltopentaose, maltodextrins, and glycogen treated with salivary ?-amylase. A temperature-dependent glycogen-degrading activity was detected in genital fluids that correlated with levels of ?-amylase. Treatment of glycogen with genital fluids resulted in production of maltose, maltotriose, and maltotetraose, the major products of ?-amylase digestion. These studies show that human ?-amylase is present in the female lower genital tract and elucidates how epithelial glycogen can support Lactobacillus colonization in the genital tract.
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Macrophage inflammatory markers are associated with subclinical carotid artery disease in women with human immunodeficiency virus or hepatitis C virus infection.
Arterioscler. Thromb. Vasc. Biol.
PUBLISHED: 03-20-2014
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Infection with hepatitis C virus (HCV) or human immunodeficiency virus (HIV) may be associated with atherosclerosis and vascular disease. Macrophages are a major component of atherosclerotic plaque, and classically activated (M1) macrophages contribute to plaque instability. Our goal was to identify plasma biomarkers that reflect macrophage inflammation and are associated with subclinical atherosclerosis.
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The relation of plasmacytoid dendritic cells (pDCs) and regulatory T-cells (Tregs) with HPV persistence in HIV-infected and HIV-uninfected women.
Viral Immunol.
PUBLISHED: 02-06-2014
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Other than CD4+ count, the immunologic factors that underlie the relationship of HIV/AIDS with persistent oncogenic HPV (oncHPV) and cervical cancer are not well understood. Plasmacytoid dendritic cells (pDCs) and regulatory T-cells (Tregs) are of particular interest. pDCs have both effector and antigen presenting activity and, in HIV-positive patients, low pDC levels are associated with opportunistic infections. Tregs downregulate immune responses, and are present at high levels in HIV-positives. The current pilot study shows for the first time that low pDC and high Treg levels may be significantly associated with oncHPV persistence in both HIV-positive and HIV-negative women. Larger studies are now warranted.
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A compositional look at the human gastrointestinal microbiome and immune activation parameters in HIV infected subjects.
PLoS Pathog.
PUBLISHED: 02-01-2014
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HIV progression is characterized by immune activation and microbial translocation. One factor that may be contributing to HIV progression could be a dysbiotic microbiome. We therefore hypothesized that the GI mucosal microbiome is altered in HIV patients and this alteration correlates with immune activation in HIV. 121 specimens were collected from 21 HIV positive and 22 control human subjects during colonoscopy. The composition of the lower gastrointestinal tract mucosal and luminal bacterial microbiome was characterized using 16S rDNA pyrosequencing and was correlated to clinical parameters as well as immune activation and circulating bacterial products in HIV patients on ART. The composition of the HIV microbiome was significantly different than that of controls; it was less diverse in the right colon and terminal ileum, and was characterized by loss of bacterial taxa that are typically considered commensals. In HIV samples, there was a gain of some pathogenic bacterial taxa. This is the first report characterizing the terminal ileal and colonic mucosal microbiome in HIV patients with next generation sequencing. Limitations include use of HIV-infected subjects on HAART therapy.
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Early microbial translocation blockade reduces SIV-mediated inflammation and viral replication.
J. Clin. Invest.
PUBLISHED: 01-08-2014
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Damage to the intestinal mucosa results in the translocation of microbes from the intestinal lumen into the circulation. Microbial translocation has been proposed to trigger immune activation, inflammation, and coagulopathy, all of which are key factors that drive HIV disease progression and non-HIV comorbidities; however, direct proof of a causal link is still lacking. Here, we have demonstrated that treatment of acutely SIV-infected pigtailed macaques with the drug sevelamer, which binds microbial lipopolysaccharide in the gut, dramatically reduces immune activation and inflammation and slightly reduces viral replication. Furthermore, sevelamer administration reduced coagulation biomarkers, confirming the contribution of microbial translocation in the development of cardiovascular comorbidities in SIV-infected nonhuman primates. Together, our data suggest that early control of microbial translocation may improve the outcome of HIV infection and limit noninfectious comorbidities associated with AIDS.
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Older age is associated with peripheral blood expansion of naïve B cells in HIV-infected subjects on antiretroviral therapy.
PLoS ONE
PUBLISHED: 01-01-2014
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Older HIV infected subjects were previously found to have significant B cell expansion during initial antiretroviral therapy in a prospective age-differentiated cohort of older and younger (?45 vs. ?30 years) HIV-infected subjects initiating antiretroviral therapy (ART) through the AIDS Clinical Trials Group. Here to further describe this expansion, using a subset of subjects from the same cohort, we characterized B cell phenotypes at baseline and after 192 weeks of ART in both older and younger HIV-infected groups and compared them to uninfected age-matched controls. We also examined whether phenotypes at baseline associated with response to tetanus and hepatitis A vaccine at 12 weeks. Forty six subjects were analyzed in the HIV infected group (21 older, 25 younger) and 30 in the control group (15 per age group). We observed naïve B cells to normalize in younger subjects after 192 weeks of ART, while in older subjects naïve B cells increased to greater levels than those of controls (p?=?0.045). Absolute resting memory (RM) cell count was significantly lower in the older HIV infected group at baseline compared to controls and numbers normalized after 192 weeks of ART (p<0.001). Baseline RM cell count positively correlated with week 12 increase in antibody to tetanus vaccine among both younger and older HIV-infected subjects combined (p?=?0.01), but not in controls. The age-associated naïve B cell expansion is a novel finding and we discuss several possible explanations for this observation. Relationship between RM cells at baseline and tetanus responses may lead to insights about the effects of HIV infection on B cell memory function and vaccine responses.
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Free glycogen in vaginal fluids is associated with Lactobacillus colonization and low vaginal pH.
PLoS ONE
PUBLISHED: 01-01-2014
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Lactobacillus dominates the lower genital tract microbiota of many women, producing a low vaginal pH, and is important for healthy pregnancy outcomes and protection against several sexually transmitted pathogens. Yet, factors that promote Lactobacillus remain poorly understood. We hypothesized that the amount of free glycogen in the lumen of the lower genital tract is an important determinant of Lactobacillus colonization and a low vaginal pH.
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Comparison of lower genital tract microbiota in HIV-infected and uninfected women from Rwanda and the US.
PLoS ONE
PUBLISHED: 01-01-2014
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Previous studies have shown that alterations of the bacterial microbiota in the lower female genital tract influence susceptibility to HIV infection and shedding. We assessed geographic differences in types of genital microbiota between HIV-infected and uninfected women from Rwanda and the United States.
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Regulatory B cells inhibit cytotoxic T lymphocyte (CTL) activity and elimination of infected CD4 T cells after in vitro reactivation of HIV latent reservoirs.
PLoS ONE
PUBLISHED: 01-01-2014
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During HIV infection, IL-10/IL-10 receptor and programmed death-1 (PD-1)/programmed death-1-ligand (PD-L1) interactions have been implicated in the impairment of cytotoxic T lymphocyte (CTL) activity. Despite antiretroviral therapy (ART), attenuated anti-HIV CTL functions present a major hurdle towards curative measures requiring viral eradication. Therefore, deeper understanding of the mechanisms underlying impaired CTL is crucial before HIV viral eradication is viable. The generation of robust CTL activity necessitates interactions between antigen-presenting cells (APC), CD4+ and CD8+ T cells. We have shown that in vitro, IL-10hiPD-L1hi regulatory B cells (Bregs) directly attenuate HIV-specific CD8+-mediated CTL activity. Bregs also modulate APC and CD4+ T cell function; herein we characterize the Breg compartment in uninfected (HIVNEG), HIV-infected "elite controllers" (HIVEC), ART-treated (HIVART), and viremic (HIVvir), subjects, and in vitro, assess the impact of Bregs on anti-HIV CTL generation and activity after reactivation of HIV latent reservoirs using suberoylanilide hydroxamic acid (SAHA). We find that Bregs from HIVEC and HIVART subjects exhibit comparable IL-10 expression levels significantly higher than HIVNEG subjects, but significantly lower than HIVVIR subjects. Bregs from HIVEC and HIVART subjects exhibit comparable PD-L1 expression, significantly higher than in HIVVIR and HIVNEG subjects. SAHA-treated Breg-depleted PBMC from HIVEC and HIVART subjects, displayed enhanced CD4+ T-cell proliferation, significant upregulation of antigen-presentation molecules, increased frequency of CD107a+ and HIV-specific CD8+ T cells, associated with efficient elimination of infected CD4+ T cells, and reduction in integrated viral DNA. Finally, IL-10-R and PD-1 antibody blockade partially reversed Breg-mediated inhibition of CD4+ T-cell proliferation. Our data suggest that, possibly, via an IL-10 and PD-L1 synergistic mechanism; Bregs likely inhibit APC function and CD4+ T-cell proliferation, leading to anti-HIV CTL attenuation, hindering viral eradication.
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Systematic review of the use of dried blood spots for monitoring HIV viral load and for early infant diagnosis.
PLoS ONE
PUBLISHED: 01-01-2014
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Dried blood spots (DBS) have been used as alternative specimens to plasma to increase access to HIV viral load (VL) monitoring and early infant diagnosis (EID) in remote settings. We systematically reviewed evidence on the performance of DBS compared to plasma for VL monitoring and EID.
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Regulation of Intestinal Immune Responses through TLR Activation: Implications for Pro- and Prebiotics.
Front Immunol
PUBLISHED: 01-01-2014
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The intestinal mucosa is constantly facing a high load of antigens including bacterial antigens derived from the microbiota and food. Despite this, the immune cells present in the gastrointestinal tract do not initiate a pro-inflammatory immune response. Toll-like receptors (TLRs) are pattern recognition receptors expressed by various cells in the gastrointestinal tract, including intestinal epithelial cells (IEC) and resident immune cells in the lamina propria. Many diseases, including chronic intestinal inflammation (e.g., inflammatory bowel disease), irritable bowel syndrome (IBS), allergic gastroenteritis (e.g., eosinophilic gastroenteritis and allergic IBS), and infections are nowadays associated with a deregulated microbiota. The microbiota may directly interact with TLR. In addition, differences in intestinal TLR expression in health and disease may suggest that TLRs play an essential role in disease pathogenesis and may be novel targets for therapy. TLR signaling in the gut is involved in either maintaining intestinal homeostasis or the induction of an inflammatory response. This mini review provides an overview of the current knowledge regarding the contribution of intestinal epithelial TLR signaling in both tolerance induction or promoting intestinal inflammation, with a focus on food allergy. We will also highlight a potential role of the microbiota in regulating gut immune responses, especially through TLR activation.
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Systematic review of the performance of HIV viral load technologies on plasma samples.
PLoS ONE
PUBLISHED: 01-01-2014
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Viral load (VL) monitoring is the standard of care in developing country settings for detecting HIV treatment failure. Since 2010 the World Health Organization has recommended a phase-in approach to VL monitoring in resource-limited settings. We conducted a systematic review of the accuracy and precision of HIV VL technologies for treatment monitoring.
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Optimizing viable leukocyte sampling from the female genital tract for clinical trials: an international multi-site study.
PLoS ONE
PUBLISHED: 01-01-2014
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Functional analysis of mononuclear leukocytes in the female genital mucosa is essential for understanding the immunologic effects of HIV vaccines and microbicides at the site of HIV exposure. However, the best female genital tract sampling technique is unclear.
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Transient Increase of Interferon-Stimulated Genes and No Clinical Benefit by Chloroquine Treatment During Acute Simian Immunodeficiency Virus Infection of Macaques.
AIDS Res. Hum. Retroviruses
PUBLISHED: 12-24-2013
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Abstract Simian immunodeficiency virus (SIV) infection leads to AIDS in experimentally infected Rhesus macaques similarly to HIV-infected humans. In contrast, SIV infection of natural hosts is characterized by a down-regulation of innate acute responses to the virus within a few weeks of infection and results in limited pathology. Chloroquine (CQ) has been used in the treatment or prevention of malaria and has recently been shown to cause a decrease of immune activation and CD4 cell loss in HIV-infected individuals treated with antiretroviral therapy. Here, we treated Rhesus macaques with CQ during the acute phase of SIVmac251 infection with the intent to decrease viral-induced immune activation and possibly limit disease progression. Contrary to what was expected, CQ treatment resulted in a temporary increased expression of interferon (IFN)-stimulating genes and it worsened the recovery of CD4(+) T cells in the blood. Our findings confirm recent results observed in asymptomatic HIV-infected patients and suggest that CQ does not provide an obvious benefit in the absence of antiretroviral therapy.
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Is HIV a Model of Accelerated or Accentuated Aging?
J. Gerontol. A Biol. Sci. Med. Sci.
PUBLISHED: 10-24-2013
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Antiretroviral therapy has reduced the incidence of adverse events and early mortality in HIV-infected persons. Despite these benefits, important comorbidities that increase with age (eg, diabetes, cardiovascular disease, cancer, liver disease, and neurocognitive impairment) are more prevalent in HIV-infected persons than in HIV-uninfected persons at every age, and geriatric syndromes such as falls and frailty occur earlier in HIV-infected persons. This raises a critical research question: Does HIV accelerate aging through pathways and mechanisms common to the aging process or is HIV simply an additional risk factor for a wide number of chronic conditions, thus accentuating aging?
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Characterization of CD4? T-cell immune activation and interleukin 10 levels among HIV, hepatitis C virus, and HIV/HCV-coinfected patients.
J. Acquir. Immune Defic. Syndr.
PUBLISHED: 10-18-2013
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HIV/hepatitis C virus (HCV)-coinfected patients have accelerated liver disease compared with HCV monoinfection. In HIV-positive patients with viral suppression, data comparing inflammatory cytokines and immune activation between HIV/HCV coinfection with chronic hepatitis C (CHC) to HIV/HCV-seropositive patients with cleared HCV are limited.
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Association of HIV clinical disease progression with profiles of early immune activation: results from a cluster analysis approach.
AIDS
PUBLISHED: 08-16-2013
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CD4 and CD8 T-cell activation are independent predictors of AIDS. The complete activation profile of both T-cell subtypes and their predictive value for AIDS risk is largely unknown.
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A role for TLR signaling during B cell activation in antiretroviral-treated HIV individuals.
AIDS Res. Hum. Retroviruses
PUBLISHED: 08-16-2013
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The mechanisms underlying B cell activation that persists during antiretroviral therapy (ART) are unknown. Toll-like receptor (TLR) signaling is a critical mediator of innate cell activation and though B cells express TLRs, few studies have investigated a role for TLR signaling in B cell activation during HIV infection. We addressed this question by assessing the activated phenotype and TLR expression/responsiveness of B cells from ART-treated HIV-infected subjects (HIVART(+)). We evaluated activation markers implicated in B cell-mediated T cell trans infection during HIV pathogenesis. We found no significant difference in TLR expression between B cells of HIVART(+) and HIV(-) subjects. However, B cells of HIVART(+) subjects exhibited heightened endogenous expression levels of IL-6 (p=0.0051), T cell cognate ligands CD40 (p=0.0475), CD54 (p=0.0229), and phosphorylated p38 (p<0.0001), a marker of TLR signaling. In vitro, B cells of HIVART(+) individuals were less responsive to TLR stimulation compared to B cells of HIV(-) subjects. The activated phenotype of in vitro TLR-stimulated B cells of HIV(-) subjects was similar to ex vivo B cells from HIVART(+) individuals. TLR2 stimulation was a potent mediator of B cell activation, whereas B cells were least responsive to TLR4 stimulation. Compared to HIV(-) subjects, the serum level of lipoteichoic acid (TLR2 ligand) in HIVART(+) subjects was significantly higher (p=0.0207), correlating positively with viral load (p=0.0127, r=0.6453). Our data suggest that during HIV infection TLR-activated B cells may exert a pathogenic role and B cells from HIVART(+) subjects respond to in vitro TLR stimulation, yet exhibit a TLR tolerant phenotype suggesting prior in vivo TLR stimulation.
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GB virus C infection and B-cell, natural killer cell, and monocyte activation markers in HIV-infected individuals.
AIDS
PUBLISHED: 06-29-2013
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GB virus C (GBV-C), a pan-lymphotropic flavivirus capable of persistent infection, is associated with prolonged survival and reduced T-cell activation in HIV-infected patients. GBV-C was associated with reduced CD56brt/CD16- natural killer cell and monocyte activation, and a trend toward reduced B-cell activation by measuring cell surface activation markers or HIV entry coreceptors. The GBV-C association was independent of HIV viral load. Thus, GBV-C may influence non-T-cell immune activation in individuals with HIV infection.
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TLR2-activated B cells are phenotypically similar to the abnormal circulating B cells seen preceding the diagnosis of AIDS-related NHL diagnosis.
J. Acquir. Immune Defic. Syndr.
PUBLISHED: 06-01-2013
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AIDS-related non-Hodgkin lymphoma (AIDS-NHL) is a common AIDS-defining cancer. Prior studies suggest that chronic B-cell activation precedes AIDS-NHL diagnosis. Activation of B cells by multiple factors, including Toll-like receptor (TLR) signaling, leads to the expression of activation-induced cytidine deaminase (AID), a DNA mutating molecule that can contribute to oncogene translocations/mutations, leading to NHL. The goal of this study was to determine whether surface markers expressed on activated and/or germinal center B cells, and AID expression, were elevated on circulating B cells preceding AIDS-NHL and to determine if TLR signaling contributes to this activated B-cell phenotype.
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Microbial translocation and liver disease progression in women coinfected with HIV and hepatitis C virus.
J. Infect. Dis.
PUBLISHED: 05-17-2013
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Microbial translocation has been implicated in the pathogenesis of liver fibrosis and cirrhosis. We sought to determine whether markers of microbial translocation are associated with liver disease progression during coinfection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV).
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GB virus C particles inhibit T cell activation via envelope E2 protein-mediated inhibition of TCR signaling.
J. Immunol.
PUBLISHED: 05-17-2013
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Viruses enter into complex interactions within human hosts, leading to facilitation or suppression of each others replication. Upon coinfection, GB virus C (GBV-C) suppresses HIV-1 replication in vivo and in vitro, and GBV-C coinfection is associated with prolonged survival in HIV-infected people. GBV-C is a lymphotropic virus capable of persistent infection. GBV-C infection is associated with reduced T cell activation in HIV-infected humans, and immune activation is a critical component of HIV disease pathogenesis. We demonstrate that serum GBV-C particles inhibited activation of primary human T cells. T cell activation inhibition was mediated by the envelope glycoprotein E2, because expression of E2 inhibited TCR-mediated activation of Lck. The region on the E2 protein was characterized and revealed a highly conserved peptide motif sufficient to inhibit TCR-mediated signaling. The E2 region contained a predicted Lck substrate site, and substitution of an alanine or histidine for the tyrosine reversed TCR-signaling inhibition. GBV-C E2 protein and a synthetic peptide representing the inhibitory amino acid sequence were phosphorylated by Lck in vitro. The synthetic peptide also inhibited TCR-mediated activation of primary human CD4(+) and CD8(+) T cells. Extracellular microvesicles from GBV-C E2-expressing cells contained E2 protein and inhibited TCR signaling in bystander T cells not expressing E2. Thus, GBV-C reduced global T cell activation via competition between its envelope protein E2 and Lck following TCR engagement. This novel inhibitory mechanism of T cell activation may provide new approaches for HIV and immunoactivation therapy.
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Virological and immunological characteristics of human cytomegalovirus infection associated with Alzheimer disease.
J. Infect. Dis.
PUBLISHED: 05-09-2013
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Serum, cerebrospinal fluid (CSF), and cryopreserved lymphocytes from subjects in the Rush Alzheimers Disease Center Religious Orders Study were analyzed for associations between cytomegalovirus (CMV) infection and clinical and pathological markers of Alzheimer disease. CMV antibody levels were associated with neurofibrillary tangles (NFTs). CSF interferon ? was only detected in seropositive subjects and was significantly associated with NFTs. The percentage of senescent T cells (CD4+ or CD8+CD28-CD57+) was significantly higher for CMV-seropositive as compared to CMV-seronegative subjects and was marginally associated with the pathologic diagnosis of Alzheimer disease (CD4+) or amyloid-? (CD8+). Immunocytochemical analysis showed induction of amyloid-? in human foreskin fibroblasts (HFFs) infected with each of 3 clinical CMV strains. In the same subjects, there was no association of herpes simplex virus type 1 (HSV-1) antibody levels with CMV antibody levels or clinical or pathological markers of Alzheimer disease. HSV-1 infection of HFFs did not induce amyloid-?. These data support an association between CMV and the development of Alzheimer disease.
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The immunologic effects of maraviroc intensification in treated HIV-infected individuals with incomplete CD4+ T-cell recovery: a randomized trial.
Blood
PUBLISHED: 04-15-2013
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The CCR5 inhibitor maraviroc has been hypothesized to decrease T-cell activation in HIV-infected individuals, but its independent immunologic effects have not been established in a placebo-controlled trial. We randomized 45 HIV-infected subjects with CD4 counts <350 cells per mm(3) and plasma HIV RNA levels <48 copies per mL on antiretroviral therapy (ART) to add maraviroc vs placebo to their regimen for 24 weeks followed by 12 weeks on ART alone. Compared with placebo-treated subjects, maraviroc-treated subjects unexpectedly experienced a greater median increase in % CD38+HLA-DR+ peripheral blood CD8+ T cells at week 24 (+2.2% vs -0.7%, P = .014), and less of a decline in activated CD4+ T cells (P < .001). The % CD38+HLA-DR+ CD4+ and CD8+ T cells increased nearly twofold in rectal tissue (both P < .001), and plasma CC chemokine receptor type 5 (CCR5) ligand (macrophage-inflammatory protein 1?) levels increased 2.4-fold during maraviroc intensification (P < .001). During maraviroc intensification, plasma lipopolysaccharide declined, whereas sCD14 levels and neutrophils tended to increase in blood and rectal tissue. Although the mechanisms explaining these findings remain unclear, CCR5 ligand-mediated activation of T cells, macrophages, and neutrophils via alternative chemokine receptors should be explored. These results may have relevance for trials of maraviroc for HIV preexposure prophylaxis and graft-versus-host disease. This trial was registered at www.clinicaltrials.gov as #NCT00735072.
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Treatment-related changes in serum lipids and inflammation: clinical relevance remains unclear. Analyses from the Womens Interagency HIV study.
AIDS
PUBLISHED: 02-26-2013
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Among 127 HIV-infected women, the magnitude of high-density lipoprotein cholesterol (HDLc) increases after HAART initiation predicted the magnitude of concurrent decreases in inflammation biomarkers. After HAART initiation, changes in low-density lipoprotein cholesterol (LDLc) and inflammation were unrelated. In the same population, predicted risk of coronary heart disease, based upon levels of standard clinical risk factors, was similar before and after HAART. Thus, it remains unknown whether short-term treatment-related changes in standard risk factors may appreciably change risk of cardiovascular disease (CVD).
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Regulatory B cell frequency correlates with markers of HIV disease progression and attenuates anti-HIV CD8? T cell function in vitro.
J. Leukoc. Biol.
PUBLISHED: 02-22-2013
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HIV infection is associated with elevated expression of IL-10 and PD-L1, contributing to impairment of T cell effector functions. In autoimmunity, tumor immunology, and some viral infections, Bregs modulate T cell function via IL-10 production. In this study, we tested the hypothesis that during HIV infection, Bregs attenuate CD8(+) T cell effector function, contributing to immune dysfunction. We determined that in vitro, TLR2-, TLR9-, and CD40L-costimulated Bregs from HIV(-) individuals exhibited a high frequency of cells expressing IL-10 and PD-L1. Compared with Bregs from HIV(-) individuals, a significantly higher percentage of Bregs from HIV(+) individuals spontaneously expressed IL-10 (P=0.0218). After in vitro stimulation with HIV peptides, Breg-depleted PBMCs from HIV(+) individuals exhibited a heightened frequency of cytotoxic (CD107a(+); P=0.0171) and HIV-specific CD8(+) T cells compared with total PBMCs. Furthermore, Breg depletion led to enhanced proliferation of total CD8(+) and CD107a(+)CD8(+) T cells (P=0.0280, and P=0.0102, respectively). In addition, augmented CD8(+) T cell effector function in vitro was reflected in a 67% increased clearance of infected CD4(+) T cells. The observed Breg suppression of CD8(+) T cell proliferation was IL-10-dependent. In HIV(+) individuals, Breg frequency correlated positively with viral load (r=0.4324; P=0.0095), immune activation (r=0.5978; P=0.0005), and CD8(+) T cell exhaustion (CD8(+)PD-1(+); r=0.5893; P=0.0101). Finally, the frequency of PD-L1-expressing Bregs correlated positively with CD8(+)PD-1(+) T cells (r=0.4791; P=0.0443). Our data indicate that Bregs contribute to HIV-infection associated immune dysfunction by T cell impairment, via IL-10 and possibly PD-L1 expression.
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IL-22 levels are associated with Trichomonas vaginalis infection in the lower genital tract.
Am. J. Reprod. Immunol.
PUBLISHED: 01-25-2013
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IL-22 has important functions at mucosal surfaces, including the induction of antimicrobial peptides and maintenance of epithelium. However, IL-22 has not been investigated in the genital tract during TV infection.
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Age-associated changes in monocyte and innate immune activation markers occur more rapidly in HIV infected women.
PLoS ONE
PUBLISHED: 01-24-2013
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Aging is associated with immune dysfunction and the related development of conditions with an inflammatory pathogenesis. Some of these immune changes are also observed in HIV infection, but the interaction between immune changes with aging and HIV infection are unknown. Whilst sex differences in innate immunity are recognized, little research into innate immune aging has been performed on women.
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Hepatitis C viremia is associated with cytomegalovirus IgG antibody levels in HIV-infected women.
PLoS ONE
PUBLISHED: 01-01-2013
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Individuals with HIV infection exhibit high cytomegalovirus (CMV) IgG levels, but there are few data regarding the association of hepatitis C virus (HCV) with the immune response against CMV.
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Short-chain fatty acids induce pro-inflammatory cytokine production alone and in combination with toll-like receptor ligands.
Am. J. Reprod. Immunol.
PUBLISHED: 11-08-2011
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Short-chain fatty acids (SCFAs), produced at relatively high levels by anaerobic bacteria in bacterial vaginosis (BV), are believed to be anti-inflammatory. BV, a common alteration in the genital microbiota associated with increased susceptibility to HIV infection, is characterized by increased levels of both pro-inflammatory cytokines and SCFAs. We investigated how SCFAs alone or together with Toll-like receptor (TLR) ligands affected pro-inflammatory cytokine secretion.
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Multisite comparison of high-sensitivity multiplex cytokine assays.
Clin. Vaccine Immunol.
PUBLISHED: 06-22-2011
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The concentrations of cytokines in human serum and plasma can provide valuable information about in vivo immune status, but low concentrations often require high-sensitivity assays to permit detection. The recent development of multiplex assays, which can measure multiple cytokines in one small sample, holds great promise, especially for studies in which limited volumes of stored serum or plasma are available. Four high-sensitivity cytokine multiplex assays on a Luminex (Bio-Rad, BioSource, Linco) or electrochemiluminescence (Meso Scale Discovery) platform were evaluated for their ability to detect circulating concentrations of 13 cytokines, as well as for laboratory and lot variability. Assays were performed in six different laboratories utilizing archived serum from HIV-uninfected and -infected subjects from the Multicenter AIDS Cohort Study (MACS) and the Womens Interagency HIV Study (WIHS) and commercial plasma samples spanning initial HIV viremia. In a majority of serum samples, interleukin-6 (IL-6), IL-8, IL-10, and tumor necrosis factor alpha were detectable with at least three kits, while IL-1? was clearly detected with only one kit. No single multiplex panel detected all cytokines, and there were highly significant differences (P < 0.001) between laboratories and/or lots with all kits. Nevertheless, the kits generally detected similar patterns of cytokine perturbation during primary HIV viremia. This multisite comparison suggests that current multiplex assays vary in their ability to measure serum and/or plasma concentrations of cytokines and may not be sufficiently reproducible for repeated determinations over a long-term study or in multiple laboratories but may be useful for longitudinal studies in which relative, rather than absolute, changes in cytokines are important.
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The effect of HIV infection and HAART on inflammatory biomarkers in a population-based cohort of women.
AIDS
PUBLISHED: 05-17-2011
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HIV causes inflammation that can be at least partially corrected by HAART. To determine the qualitative and quantitative nature of cytokine perturbation, we compared cytokine patterns in three HIV clinical groups, including HAART responders (HAART), untreated HIV noncontrollers, and HIV-uninfected (NEG).
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HIV-1 viruses detected during episodic blips following interleukin-7 administration are similar to the viruses present before and after interleukin-7 therapy.
AIDS
PUBLISHED: 05-07-2011
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administration of recombinant human interleukin (IL)-7 leads to CD4 and CD8 T-cell expansions in HIV-infected individuals, demonstrating promising capacity for immune reconstitution. However, a proportion of patients treated with recombinant human IL-7 experience transient increases in plasma HIV-RNA (blips), possibly reflecting purging of a quiescent reservoir that provides a barrier to viral eradication.
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Resumption of HIV replication is associated with monocyte/macrophage derived cytokine and chemokine changes: results from a large international clinical trial.
AIDS
PUBLISHED: 04-21-2011
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There is increasing interest in the role of immune activation and inflammation in HIV disease, but data on direct effects of HIV replication on immune cell activation are limited.
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Multiplex immunoassay of lower genital tract mucosal fluid from women attending an urban STD clinic shows broadly increased IL1ß and lactoferrin.
PLoS ONE
PUBLISHED: 04-09-2011
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More than one million new cases of sexually transmitted diseases (STDs) occur each day. The immune responses and inflammation induced by STDs and other frequent non-STD microbial colonizations (i.e. Candida and bacterial vaginosis) can have serious pathologic consequences in women including adverse pregnancy outcomes, infertility and increased susceptibility to infection by other pathogens. Understanding the types of immune mediators that are elicited in the lower genital tract by these infections/colonizations can give important insights into the innate and adaptive immune pathways that are activated and lead to strategies for preventing pathologic effects.
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HIV infection and aging of the innate immune system.
Sex Health
PUBLISHED: 02-22-2011
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The increased life expectancy of HIV-infected individuals due to improved treatment has revealed an unexpected increase in non-AIDS comorbidities that are typically associated with older age including cardiovascular disease, dementia and frailty. The majority of these diseases arise as the result of dysregulated systemic inflammation, and both the aged and HIV-infected individuals exhibit elevated basal levels of inflammation. In the elderly, increased inflammation and age-related diseases are associated with a state of impaired immunity called immunosenescence, which is thought to result from a lifetime of immune stimulation. It is now apparent that HIV induces premature immunosenescence within T-cells; however, the impact of HIV on aging of cells of the innate arm of the immune system is unknown. Innate immune cells play a central role in inflammation and are thus critical for the pathogenesis of inflammatory diseases. Limited evidence suggests HIV infection mimics age-related changes to innate immune cells; however, the extent of this effect and the mechanism underlying these changes remain to be defined. This review focuses on the impact of HIV infection on the function and aging of innate immune cells and discusses potential drivers of premature immunosenescence including chronic endotoxaemia, residual viraemia, telomere attrition and altered cellular signalling.
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A randomized trial of interleukin-2 during withdrawal of antiretroviral treatment.
J. Interferon Cytokine Res.
PUBLISHED: 02-03-2011
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In HIV-infected individuals on antiretroviral treatment with viral suppression, structured treatment interruptions are designed to allow exposure to endogenous HIV antigens and to thereby boost HIV-specific immunity. AIDS Clinical Trials Group A5132 was an exploratory 2-arm randomized trial that evaluated two 4-week treatment interruptions in combination with 2 strategies for administering interleukin-2 (IL-2): 2.0 million international units of IL-2 subcutaneously daily during the final 2 weeks of treatment interruption and the first week of treatment reinitiation (arm A), or 4.5 million international units of IL-2 subcutaneously twice a day during the first 5 days of treatment reinitiation (arm B). Twenty-one subjects with HIV-1 RNA <50 copies/mL and CD4+ T cell counts ?300 (median 615) cells/mm(3) were randomized. The primary endpoint was the viral setpoint measured 11-12 weeks after a third treatment interruption (observed for 7 Arm A and 9 Arm B). The median HIV-1 RNA setpoints were 4.3 and 4.5 log(10) copies/mL for Arm A and Arm B, respectively; there was no evidence of a difference between arms (P = 0.50, rank-sum test, worst rank for unobserved viral setpoint). The current study, the first to evaluate IL-2 during repeated short-term treatment interruptions, revealed no evidence for augmentation of HIV immunity. Viral setpoints were similar to historical controls, emphasizing the need for new strategies to enhance HIV-specific immunity.
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A low T regulatory cell response may contribute to both viral control and generalized immune activation in HIV controllers.
PLoS ONE
PUBLISHED: 01-31-2011
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HIV-infected individuals maintaining undetectable viremia in the absence of therapy (HIV controllers) often maintain high HIV-specific T cell responses, which has spurred the development of vaccines eliciting HIV-specific T cell responses. However, controllers also often have abnormally high T cell activation levels, potentially contributing to T cell dysfunction, CD4+ T cell depletion, and non-AIDS morbidity. We hypothesized that a weak T regulatory cell (Treg) response might contribute to the control of viral replication in HIV controllers, but might also contribute to generalized immune activation, contributing to CD4+ T cell loss. To address these hypotheses, we measured frequencies of activated (CD38+ HLA-DR+), regulatory (CD4+CD25+CD127(dim)), HIV-specific, and CMV-specific T cells among HIV controllers and 3 control populations: HIV-infected individuals with treatment-mediated viral suppression (ART-suppressed), untreated HIV-infected "non-controllers" with high levels of viremia, and HIV-uninfected individuals. Despite abnormally high T cell activation levels, controllers had lower Treg frequencies than HIV-uninfected controls (P = 0.014). Supporting the propensity for an unusually low Treg response to viral infection in HIV controllers, we observed unusually high CMV-specific CD4+ T cell frequencies and a strong correlation between HIV-specific CD4+ T cell responses and generalized CD8+ T cell activation levels in HIV controllers (P ? 0.001). These data support a model in which low frequencies of Tregs in HIV controllers may contribute to an effective adaptive immune response, but may also contribute to generalized immune activation, potentially contributing to CD4 depletion.
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T cell activation predicts carotid artery stiffness among HIV-infected women.
Atherosclerosis
PUBLISHED: 01-11-2011
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HIV disease is associated with increased arterial stiffness, which may be related to inflammation provoked by HIV-related immune perturbation. We assessed the association of T cell markers of immune activation and immunosenescence with carotid artery stiffness among HIV-infected women.
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T cell activation and senescence predict subclinical carotid artery disease in HIV-infected women.
J. Infect. Dis.
PUBLISHED: 01-10-2011
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Individuals infected with human immunodeficiency virus (HIV) have increased risk of cardiovascular events. It is unknown whether T cell activation and senescence, 2 immunologic sequelae of HIV infection, are associated with vascular disease among HIV-infected adults.
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The effects of commensal bacteria on innate immune responses in the female genital tract.
Am. J. Reprod. Immunol.
PUBLISHED: 12-09-2010
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The innate and adaptive immune systems are important mechanisms for resistance to pathogens in the female lower genital tract. Lactobacilli at this site help maintain a healthy vagina by producing several factors including lactic acid. Indeed, bacterial vaginosis, a condition in which the genital microbiota is altered, is strongly associated with increased rates of a number of infections including HIV. However, the precise factors that contribute to increased rates of microbial and viral infections in bacterial vaginosis remain to be elucidated. We have studied the effects of bacterial microbiota in the lower genital tract on innate immunity and have found that Toll-like receptor ligands and short chain fatty acids, produced by bacterial microbiota, have dramatic effects on immune function. In this review, we will discuss these results, in addition to some recent articles that we believe will enhance our understanding of how microbes might interact with the immune system.
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Pyrosequencing of the genital microbiotas of HIV-seropositive and -seronegative women reveals Lactobacillus iners as the predominant Lactobacillus Species.
Appl. Environ. Microbiol.
PUBLISHED: 11-12-2010
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The species of vaginal lactobacilli in HIV-seropositive and -seronegative women were determined by 16S gene pyrosequencing. Lactobacillus iners sequences were the predominant lactobacillus sequences in 66% of HIV(+) women and 90% of HIV(-) women. This has implications for resistance of HIV(+) and HIV(-) women to genital colonization by pathogenic organisms.
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Biomarkers of immune dysfunction in HIV.
Curr Opin HIV AIDS
PUBLISHED: 10-28-2010
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HIV infection is characterized by chronic immune system activation and inflammatory cytokine production. This review will highlight recent developments using plasma and cellular biomarkers of immune system activation and dysfunction to predict mortality and opportunistic disease in HIV-infected individuals.
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Comparison of immunologic assays for detecting immune responses in HIV immunotherapeutic studies: AIDS Clinical Trials Group Trial A5181.
Clin. Vaccine Immunol.
PUBLISHED: 07-14-2010
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This study was designed to evaluate which of several T-cell-specific, immune response assays are the most relevant in measuring the key characteristics of an effective immune response to HIV-1. Using 5 HIV-1 antigens as stimulants, we assessed lymphocyte proliferation, supernatant gamma interferon (IFN-gamma) cytokine production (CP), single-cell IFN-gamma production by enzyme-linked immunospot (ELISPOT) assay, with and without Epstein-Barr virus-transformed B-lymphoblastoid cell lines (B-LCLs), and intracellular cytokine production (ICC) for IFN-gamma and interleukin 2 (IL-2) by flow cytometry. We used these to compare specimens from HIV-1-infected subjects who were virally suppressed with a stable antiretroviral therapy (ART) regimen (group A) with specimens from subjects not on ART but with HIV-1 viremia of <3,000 copies/ml (group B). The lymphocyte proliferation assay (LPA) did not significantly differentiate between the two groups. Using fresh peripheral blood mononuclear cells (PBMCs), the CP and ELISPOT assays for IFN-gamma detected the greatest differences between the two groups, specific for three of the five HIV-1 antigens, whereas significant differences were seen only in response to one antigen when cryopreserved cells were used. The strongest correlations were seen between the CP and ELISPOT assays. The ELISPOT B-LCL assay showed a cell concentration-dependent increase in IFN-gamma production compared to that shown by the standard ELISPOT assay but did not differentiate between the groups. In the ICC assay, greater numbers of IFN-gamma-producing T cells were seen in group B, and little or no detectable IL-2 production was seen in both groups. These studies highlight complexities of immunologic monitoring of T-cell responses in multisite clinical trials in HIV infection and outline considerations for optimizing these efforts.
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Intracellular Casp8p41 content is inversely associated with CD4 T cell count.
J. Infect. Dis.
PUBLISHED: 06-23-2010
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Casp8p41 is a protein fragment generated by cleavage of procaspase 8 by human immunodeficiency virus (HIV) protease. We measured Casp8p41 content in memory CD4 T cells and analyzed the association of Casp8p41 content with CD4 T cell count, cross-sectionally and longitudinally. Casp8p41 content was inversely correlated with CD4 T cell count, and change in Casp8p41 content was associated with absolute CD4 T cell count with change over time. Casp8p41 change was a better predictor of CD4 T cell count change than activated CD8 T cell percentage or viral load and was comparable to bacterial 16s DNA levels. This suggests that Casp8p41 is a relevant mediator of CD4 T cell death during HIV infection.
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Age-related changes in plasma concentrations of the HIV protease inhibitor lopinavir.
AIDS Res. Hum. Retroviruses
PUBLISHED: 06-22-2010
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The advent of highly active antiretroviral therapy in the treatment of HIV disease has substantially extended the lifespan of individuals infected with HIV resulting in a growing population of older HIV-infected individuals. The efficacy and safety of antiretroviral agents in the population are important concerns. There have been relatively few studies assessing antiretroviral pharmacokinetics in older patients. Thirty-seven subjects aged 18-30 years and 40 subjects aged 45-79 years, naive to antiretroviral therapy, received lopinavir/ritonavir (400/100) bid, emtricitibine 200 mg qd, and stavudine 40 mg bid. Trough lopinavir concentrations were available for 44 subjects, collected at 24, 36, and 96 weeks. At week 24, older age was associated with higher lopinavir trough concentrations, and a trend was observed toward older age being associated with higher lopinavir trough concentrations when all time points were evaluated. In the young cohort, among subjects with two or more measurements, there was a trend toward increasing intrasubject trough lopinavir concentrations over time. Using a nonlinear, mixed-effects population pharmacokinetic model, age was negatively associated with lopinavir clearance after adjusting for adherence. Adherence was assessed by patient self-reports; older patients missed fewer doses than younger patients (p = 0.02). No difference in grade 3-4 toxicities was observed between the two age group. Older patients have higher trough lopinavir concentrations and likely decreased lopinavir clearance. Age-related changes in the pharmacokinetics of antiretroviral drugs may be of increasing importance as the HIV-infected population ages and as older individuals comprise an increasing proportion of new diagnoses.
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Pretreatment levels of soluble cellular receptors and interleukin-6 are associated with HIV disease progression in subjects treated with highly active antiretroviral therapy.
J. Infect. Dis.
PUBLISHED: 05-08-2010
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To identify inflammatory pathways that may contribute to the pathogenesis of human immunodeficiency virus (HIV) disease, we explored associations between AIDS or death and different inflammatory markers, including selected soluble tumor necrosis factor superfamily receptors (sTNFRs) and ligands, interleukin (IL)-6, and CD8 T cell activation, in individuals treated with highly active antiretroviral therapy (HAART).
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Early immune senescence in HIV disease.
Curr HIV/AIDS Rep
PUBLISHED: 04-29-2010
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Non-AIDS-defining co-morbidities that occur despite viral suppression and immune reconstitution using antiretroviral therapy depict early aging process in HIV-infected individuals. During aging, a reduction in T-cell renewal, together with a progressive enrichment of terminally differentiated T cells, translates into a general decline of the immune system, gradually leading to immunosenescence. Inflammation is a hallmark of age-associated comorbidities, and immune activation is a hallmark of HIV disease. Constant stimulation of the immune system by HIV or due to co-infections activates the innate and adaptive immune system, resulting in release of mediators of inflammation. Immune activation coupled with lack of anti-inflammatory responses likely results in accelerated aging in HIV disease. Dysfunctional thymic output, along with HIV-mediated disruption of the gastrointestinal barrier leading to microbial translocation, contributes to the circulating antigenic load driving early senescence in HIV disease.
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Continuing or adding IL-2 in patients treated with antiretroviral therapy (ACTG Protocol A5051, a rollover trial of ACTG Protocol A328).
AIDS Res Ther
PUBLISHED: 03-26-2010
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Effective antiretroviral therapy reduces HIV-1 RNA levels, improves CD4 T-cell counts, and lowers the risk of opportunistic infections and malignancies. Interleukin-2 (IL-2) has been shown to increase CD4 T-cell numbers mainly by expanding CD4 cells and by prolonging their half-lives. HIV-infected patients previously enrolled into A328 had been randomized to antiretroviral therapy (ART) alone or ART followed by IL-2. In A5051, 53 patients from A328 who had previously received IL-2 were allowed to continue IL-2 for an additional 80 weeks; 27 patients who had received ART alone received IL-2 for 80 weeks.
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Identification of rhesus macaque genital microbiota by 16S pyrosequencing shows similarities to human bacterial vaginosis: implications for use as an animal model for HIV vaginal infection.
AIDS Res. Hum. Retroviruses
PUBLISHED: 02-17-2010
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The composition of the lower genital tract microbiota in women is believed to affect the risk of sexually acquiring HIV. Since macaque genital microbiota could similarly impact vaginal infection with SIV we identified microbiota in 11 rhesus macaques using multitag pyrosequencing of the 16S rRNA gene. The microbiota was polymicrobial with a median of nine distinct bacterial taxa per macaque (range 3-16 taxa, each constituting 1% or more of the sequences). Taxa frequently found included Peptoniphilus, Sneathia, Porphyromonas, Mobiluncus, Atopobacter, Dialister, Thioreductor, Prevotella, and Streptococcus, many of which are also frequently found in women with bacterial vaginosis. Lactobacillus sequences (mostly L. johnsonii) were found in only four macaques but were not predominant in any (median of 0% of sequences, range 0-39%). All macaques were resampled 6 months after the first time point to determine the stability of the microbiota. The microbiota remained polymicrobial with a median of 10 taxa (range 6-18). Microbial patterns remained similar for six of the macaques, changed substantially in two, and had a mixed pattern in three. Significant sialidase enzyme activity, a marker of bacteria vaginosis in women, was detected in genital fluid from 9/11 and 8/11 macaques from the first and second time points, respectively. These results show that the macaque lower genital microbiota resembled a bacteria vaginosis-type microbiota in women and suggest that the microbiota of macaques in captivity promote rather than protect against vaginal infection with SIV. These results also suggest macaques could be used as an animal model to study some aspects of bacterial vaginosis.
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Activation of CD8 T cells predicts progression of HIV infection in women coinfected with hepatitis C virus.
J. Infect. Dis.
PUBLISHED: 02-16-2010
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Because activation of T cells is associated with human immunodeficiency virus (HIV) pathogenesis, CD4 and CD8 activation levels in patients coinfected with HIV and hepatitis C virus (HCV) may explain conflicting reports regarding effects of HCV on HIV disease progression.
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Innate immunity and chronic immune activation in HCV/HIV-1 co-infection.
Clin. Immunol.
PUBLISHED: 01-25-2010
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Innate immune responses are critical in the defense against viral infections. NK cells, myeloid and plasmacytoid dendritic cells, and invariant CD1d-restricted NKT cells mediate both effector and regulatory functions in this early immune response. In chronic uncontrolled viral infections such as HCV and HIV-1, these essential immune functions are compromised and can become a double edged sword contributing to the immunopathogenesis of viral disease. In particular, recent findings indicate that innate immune responses play a central role in the chronic immune activation which is a primary driver of HIV-1 disease progression. HCV/HIV-1 co-infection is affecting millions of people and is associated with faster viral disease progression. Here, we review the role of innate immunity and chronic immune activation in HCV and HIV-1 infection, and discuss how mechanisms of innate immunity may influence protection as well as immunopathogenesis in the HCV/HIV-1 co-infected human host.
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Chloroquine modulates HIV-1-induced plasmacytoid dendritic cell alpha interferon: implication for T-cell activation.
Antimicrob. Agents Chemother.
PUBLISHED: 11-30-2009
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Plasmacytoid dendritic cells (pDC) contribute to antiviral immunity mainly through recognition of microbial products and viruses via intracellular Toll-like receptor 7 (TLR7) or TLR9, resulting in the production of type I interferons (IFNs). Although interferons reduce the viral burden in the acute phase of infection, their role in the chronic phase is unclear. The presence of elevated plasma IFN-alpha levels in advanced HIV disease and its association with microbial translocation in chronic HIV infection lead us to hypothesize that IFN-alpha could contribute to immune activation. Blocking of IFN-alpha production using chloroquine, an endosomal inhibitor, was tested in a novel in vitro model system with the aim of characterizing the effects of chloroquine on HIV-1-mediated TLR signaling, IFN-alpha production, and T-cell activation. Our results indicate that chloroquine blocks TLR-mediated activation of pDC and MyD88 signaling, as shown by decreases in the levels of the downstream signaling molecules IRAK-4 and IRF-7 and by inhibition of IFN-alpha synthesis. Chloroquine decreased CD8 T-cell activation induced by aldrithiol-2-treated HIV-1 in peripheral blood mononuclear cell cultures. In addition to blocking pDC activation, chloroquine also blocked negative modulators of the T-cell response, such as indoleamine 2,3-dioxygenase (IDO) and programmed death ligand 1 (PDL-1). Our results indicate that TLR stimulation and production of IFN-alpha by pDC contribute to immune activation and that blocking of these pathways using chloroquine may interfere with events contributing to HIV pathogenesis. Our results suggests that a safe, well-tolerated drug such as chloroquine can be proposed as an adjuvant therapeutic candidate along with highly active antiretroviral therapy to control immune activation in HIV-1 infection.
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Serum immune activation markers are persistently increased in patients with HIV infection after 6 years of antiretroviral therapy despite suppression of viral replication and reconstitution of CD4+ T cells.
J. Infect. Dis.
PUBLISHED: 09-05-2009
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The effect of long-term antiretroviral therapy on serum immune activation markers was assessed in a cohort of 63 patients before and after 6 years of boosted lopinavir-based antiretroviral therapy. High levels of most markers were associated with lower CD4(+) T cell counts at baseline and at year 6, with the exception of soluble cytotoxic T lymphocyte antigen-4 (sCTLA-4); high levels of sCTLA-4 were associated with higher CD4(+) T cell counts at year 6. Abnormalities of serum immune activation markers persisted after 6 years of ART but probably had different causes. Further investigation of the clinical usefulness of assaying immunoglobulin A, neopterin, and sCTLA-4 levels to assess the effectiveness of treatments for human immunodeficiency virus (HIV) disease are warranted.
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IL-7 administration drives T cell-cycle entry and expansion in HIV-1 infection.
Blood
PUBLISHED: 04-20-2009
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Interleukin 7 (IL-7) is a common gamma chain receptor cytokine implicated in thymopoiesis and in peripheral expansion and survival of T lymphocytes. The safety and activity of recombinant human IL-7 (rhIL-7) administration were therefore examined in HIV-infected persons. In this prospective randomized placebo-controlled study, a single subcutaneous dose of rhIL-7 was well tolerated with biologic activity demonstrable at 3 microg/kg and a maximum tolerated dose of 30 microg/kg. Injection site reactions and transient elevations of liver function tests were the most notable side effects. Transient increases in plasma HIV-RNA levels were observed in 6 of 11 IL-7-treated patients. Recombinant hIL-7 induced CD4 and CD8 T cells to enter cell cycle; cell-cycle entry was also confirmed in antigen-specific CD8 T cells. Administration of rhIL-7 led to transient down-regulation of the IL-7 receptor alpha chain (CD127) in both CD4(+) and CD8(+) T cells. Single-dose rhIL-7 increased the numbers of circulating CD4(+) and CD8(+) T cells, predominantly of central memory phenotype. The frequency of CD4(+) T cells with a regulatory T-cell phenotype (CD25(high) CD127(low)) did not change after rhIL-7 administration. Thus, rhIL-7 has a biologic and toxicity profile suggesting a potential for therapeutic trials in HIV infection and other settings of lymphopenia. This clinical trial has been registered at http://www.clinicaltrials.gov under NCT0099671.
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Plasma levels of bacterial DNA correlate with immune activation and the magnitude of immune restoration in persons with antiretroviral-treated HIV infection.
J. Infect. Dis.
PUBLISHED: 03-07-2009
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The significance of elevated plasma levels of bacterial lipopolysaccharide (LPS) in persons with chronic HIV infection remains undefined. We measured LPS levels by use of limulus lysate assay, and DNA sequences encoding bacterial ribosomal 16S RNA (16S rDNA) were assessed by quantitative polymerase chain reactions in plasma samples obtained from 242 donors. Plasma levels of 16S rDNA were significantly higher in human immunodeficiency virus (HIV)-infected subjects than in uninfected subjects, and they correlated with LPS levels. Higher levels of 16S rDNA were associated with higher levels of T cell activation and with lower levels of CD4 T cell restoration during antiretroviral therapy. Antiretroviral therapy reduces but does not fully normalize plasma levels of bacterial 16S rDNA, an index of microbial translocation from the gastrointestinal tract. High levels of 16S rDNA during therapy are strongly associated with reduced increases in the CD4(+) T lymphocyte count, irrespective of plasma HIV RNA levels. These findings are consistent with the importance of microbial translocation in immunodeficiency and T cell homeostasis in chronic HIV infection.
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The effect of aging on T-regulatory cell frequency in HIV infection.
Clin. Immunol.
PUBLISHED: 03-04-2009
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T-regulatory cell (T-reg) frequency is increased in HIV infection and with aging. We evaluated the effect of age on total, memory and naïve T-reg percentages in untreated HIV infection. Older HIV(+) subjects had a total T-reg percent that is 2.8% (p=0.02) higher than among younger HIV(+), older HIV(-) and younger HIV(-) subjects. In HIV(+) subjects, the total T-reg percentage is inversely correlated with the lymphocyte proliferative responses to tetanus (r=-0.45, p=0.002) and Candida (r=-0.43, p=0.003) antigens. Similar correlations were seen between memory T-reg percentages and the lymphocyte proliferative response to tetanus and Candida in HIV(+) subjects. T-reg percentages did not correlate consistently with markers of immune activation. T-reg percentages are increased in the older HIV(+) population and may play a role in the accelerated disease progression seen in older HIV-infected persons.
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Delaying a treatment switch in antiretroviral-treated HIV type 1-infected patients with detectable drug-resistant viremia does not have a profound effect on immune parameters: AIDS Clinical Trials Group Study A5115.
AIDS Res. Hum. Retroviruses
PUBLISHED: 02-26-2009
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Some patients are unable to achieve and maintain an undetectable plasma HIV-1 RNA level with combination antiretroviral therapy (ART) and are therefore maintained on a partially suppressive regimen. To determine the immune consequences of continuing ART despite persistent viremia, we randomized 47 ART-treated individuals with low to moderate plasma HIV-1 RNA levels (200-9999 copies/ml) to either an immediate switch in therapy or a delayed switch (when plasma HIV-1 RNA became > or =10,000 copies/ml). After 48 weeks of follow-up, naive and memory CD4+ T cell percents were comparable in the two groups. The proportion of subjects with a lymphocyte proliferative response to Candida, Mycobacterium avium-intracellulare complex, or HIV-gag was also not significantly different at week 48. Delaying a treatment switch in patients with partial virologic suppression and stable CD4+ T cells does not have profound effects on immune parameters.
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Enhanced antibody responses elicited by a CpG adjuvant do not improve the protective effect of an aldrithiol-2-inactivated simian immunodeficiency virus therapeutic AIDS vaccine.
Clin. Vaccine Immunol.
PUBLISHED: 02-18-2009
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The potential benefit of using unmethylated CpG oligoribodeoxynucleotides (ODN) as an adjuvant in a therapeutic simian immunodeficiency virus (SIV) vaccine consisting of AT2-inactivated SIVmac239 was evaluated in SIV-infected rhesus macaques receiving antiretroviral therapy (ART). We hypothesized that using CpG ODN as an adjuvant in therapeutic vaccination would enhance SIV-specific immune responses and suppress SIV replication after ART was stopped. To test our hypothesis, we immunized chronically SIV-infected rhesus macaques receiving ART with one of the following therapeutic vaccines: (i) AT2-inactivated SIVmac239, (ii) CpG10103 plus AT2-inactivated SIVmac239, (iii) CpG10103, and (iv) saline. While immunization with CpG plus AT2-SIVmac239 significantly increased SIV-specific immunoglobulin G (IgG) antibody titers, the mean plasma viral RNA (vRNA) level in these animals after ART did not differ from those of saline-treated animals. The AT2-inactivated SIVmac239-immunized animal group had a significantly higher mean SIV-specific gamma interferon T-cell response after three immunizations and lower plasma vRNA levels for 6 weeks after ART was withdrawn compared to the saline-treated animal group. Compared to the saline control group, the animal group treated with CpG alone had a significantly higher mean SIV-specific lymphocyte proliferation index and a higher rate of plasma vRNA rebound after ART. These results demonstrate that while the use of CpG as an adjuvant enhances SIV-specific antibody responses, this does not improve the control of SIV replication after ART is stopped. The lack of benefit may be related to the high levels of SIV-specific lymphocyte proliferation in the CpG adjuvant group.
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