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Find video protocols related to scientific articles indexed in Pubmed.
The HIV-1 gp120 CD4-bound conformation is preferentially targeted by ADCC-mediating antibodies in sera from HIV-1-infected individuals.
J. Virol.
PUBLISHED: 10-24-2014
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Recent studies have linked antibody Fc-mediated effector functions with protection or control of HIV-1 and SIV infections. Interestingly, the presence of antibodies with potent antibody-dependent cellular cytotoxicity (ADCC) activity in the Thai RV144 vaccine trial was suggested to correlate with a decreased HIV-1 acquisition risk. These antibodies were recently found to recognize HIV envelope (Env) epitopes exposed upon Env - CD4 interaction. CD4 downregulation by Nef and Vpu, as well as Vpu-mediated BST-2 antagonism, were reported to modulate exposure of those CD4-induced HIV-1 Env epitopes and therefore were proposed to play a role in reducing the susceptibility of infected cells to ADCC mediated by this class of antibodies. Here we report a high prevalence of antibodies recognizing CD4-induced HIV-1 Env epitopes in sera from HIV-1 infected individuals, which correlated with their ability to mediate ADCC responses against HIV-1 infected cells exposing these Env epitopes at the cell surface. Furthermore, our results indicate that Env variable regions V1, V2, V3 and V5 do not represent a major determinant for ADCC responses mediated by sera from HIV-1-infected individuals. Altogether, these findings suggest that HIV-1 tightly controls the exposure of certain Env epitopes at the surface of infected cells in order to prevent elimination by Fc-effector functions.
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Synergistic Combinations of the CCR5 Inhibitor VCH-286 with Other Classes of HIV-1 Inhibitors.
Antimicrob. Agents Chemother.
PUBLISHED: 09-29-2014
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Here, we evaluated the in vitro anti-HIV-1 activity of the experimental CCR5 inhibitor VCH-286 as a single agent or in combination with various classes of HIV-1 inhibitors. Although VCH-286 used alone had highly inhibitory activity, paired combinations with different drug classes led to synergistic or additive interactions. However, combinations with other CCR5 inhibitors led to effects ranging from synergy to antagonism. We suggest that caution should be exercised when combining CCR5 inhibitors in vivo.
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Flow cytometry-based assay to study HIV-1 gp120 specific antibody-dependent cellular cytotoxicity responses.
J. Virol. Methods
PUBLISHED: 08-12-2014
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Increased attention on the role of Fc-mediated effector functions against HIV-1 has led to renewed interest into the role that antibody-dependent cellular cytotoxicity (ADCC) could play in controlling viral transmission and/or the rate of disease progression. While (51)Chromium release assays have traditionally been used to study ADCC responses against HIV-1, a number of alternative flow-cytometry-based assays were recently developed. In this study, an alternative flow-cytometry-based assay was established to allow non-radioactive measurement of ADCC-mediated elimination of HIV-1 gp120 envelope glycoprotein (Env)-coated target cells. This assay relies on staining target and effector cells with different dyes, which allows precise gating and permits the calculation of the number of surviving target cells by normalization to flow-cytometry particles. By using small concentrations of recombinant gp120 Env, suitable targets cells that recapitulate the ADCC response mediated against HIV-1-infected cells were generated. Finally, this method was applied successfully to screen human sera for ADCC activity directed against HIV-1 gp120 Env.
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Genomic characterization of a large outbreak of Legionella pneumophila serogroup 1 strains in Quebec City, 2012.
PLoS ONE
PUBLISHED: 08-08-2014
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During the summer of 2012, a major Legionella pneumophila serogroup 1 outbreak occurred in Quebec City, Canada, which caused 182 declared cases of Legionnaire's disease and included 13 fatalities. Legionella pneumophila serogroup 1 isolates from 23 patients as well as from 32 cooling towers located in the vicinity of the outbreak were recovered for analysis. In addition, 6 isolates from the 1996 Quebec City outbreak and 4 isolates from patients unrelated to both outbreaks were added to allow comparison. We characterized the isolates using pulsed-field gel electrophoresis, sequence-based typing, and whole genome sequencing. The comparison of patients-isolated strains to cooling tower isolates allowed the identification of the tower that was the source of the outbreak. Legionella pneumophila strain Quebec 2012 was identified as a ST-62 by sequence-based typing methodology. Two new Legionellaceae plasmids were found only in the epidemic strain. The LVH type IV secretion system was found in the 2012 outbreak isolates but not in the ones from the 1996 outbreak and only in half of the contemporary human isolates. The epidemic strains replicated more efficiently and were more cytotoxic to human macrophages than the environmental strains tested. At least four Icm/Dot effectors in the epidemic strains were absent in the environmental strains suggesting that some effectors could impact the intracellular replication in human macrophages. Sequence-based typing and pulsed-field gel electrophoresis combined with whole genome sequencing allowed the identification and the analysis of the causative strain including its likely environmental source.
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First documented case of human infection with ovine Shiga-toxin-producing Escherichia coli serotype O52:H45.
Can. J. Microbiol.
PUBLISHED: 04-26-2014
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We report a concurrent case of infection with non-O157 Shiga-toxin-producing Escherichia coli (STEC) strain in an 8-month-old child. Laboratory and epidemiological investigations indicated child exposure to contaminated sheep meat following the Muslim feast of sacrifice (Eid al-Adha). Microbiological and molecular typing confirmed that the ovine strain O52:H45 (stx1+, eae-, hlyA-) was the causal agent. This is the first documented case of human infection to this STEC serotype.
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Performance of a clonal-based HIV-1 tropism phenotypic assay.
J. Virol. Methods
PUBLISHED: 03-31-2014
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Adequate determination of HIV-1 tropism is important in clinical and research settings. Genotypic and phenotypic approaches to evaluate tropism have been described. Phenotypic assays are widely used to determine HIV-1 tropism because of their sensitivity to detect minor CXCR4-using variants (X4). However they cannot differentiate mixed quasi-species of R5 and X4 viruses from dual-tropic viruses. We describe here a clonal-based HIV-1 tropism phenotypic assay. Env-pseudo-typed viruses were produced by co-transfection of the env expression plasmid pcDNA3.1/V5HisTOPO and a backbone vector pNL4-3.Luc.E-R- that expresses the entire HIV-1 genome except for env and vpr in 293T cell cultures. Co-receptor use was tested by infecting U87.CD4.CCR5+ and U87.CD4.CXCR4+ cells in the presence or absence of co-receptor inhibitors, using 10 clones from each sample. The ability of the assay to detect minor variants in a viral population was assessed by mixing X4 and R5 clones using different ratios. Both R5 and X4 minority variants were detected when present at greater than 0.4% in a mixture of envelope populations. This assay can be useful in both clinical and research laboratories.
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Psychosocial Profile and Lived Experience of HIV-infected Long-term Nonprogressors: A Mixed Method Study.
J Assoc Nurses AIDS Care
PUBLISHED: 02-22-2014
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The goal of this mixed method study was to describe the psychosocial profile of HIV-infected persons identified as long-term nonprogressors (LTNP), and their experiences of nonprogression. Data were collected from 24 participants with a mean age of 48 years and a mean duration of infection of 14 years. Results show rather moderate levels of anxiety and depression symptoms and a modest mean score of social support. Participants adapted by using acceptance, positive restructuring, and active coping strategies. Seven themes marked the experience: (a) reacting to announcement and dealing with diagnosis, (b) valuing interpersonal relations and well-being, (c) making changes in life, (d) coping with stress, (e) dealing with health care, (f) beliefs about reasons for nonprogression, and (g) living positively while dreading progression. The findings enrich a field of knowledge that has had little attention so far and shed light on the psychosocial profile of LTNP and their experiences of nonprogression.
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A Significant Reduction in the Frequency of HIV-1 Drug Resistance in Québec from 2001 to 2011 Is Associated with a Decrease in the Monitored Viral Load.
PLoS ONE
PUBLISHED: 01-01-2014
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HIV drug resistance represents a major threat for effective treatment. We assessed the trends in the frequency of drug resistance mutations and the monitored viral load (VL) in treatment-naïve (TN) and treatment-experienced (TE) individuals infected with HIV-1 in Québec, Canada, between 2001 and 2011.
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Distinct resistance patterns to etravirine and rilpivirine in viruses containing nonnucleoside reverse transcriptase inhibitor mutations at baseline.
AIDS
PUBLISHED: 10-25-2013
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The current in-vitro study examined HIV-1 drug resistance patterns following etravirine (ETR) and rilpivirine (RPV) drug pressure in viruses containing baseline nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations.
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Clinical prediction and diagnosis of neurosyphilis in HIV-infected patients with early Syphilis.
J. Clin. Microbiol.
PUBLISHED: 10-02-2013
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The diagnosis of neurosyphilis (NS) is a challenge, especially in HIV-infected patients, and the criteria for deciding when to perform a lumbar puncture (LP) in HIV-infected patients with syphilis are controversial. We retrospectively reviewed demographic, clinical, and laboratory data from 122 cases of HIV-infected patients with documented early syphilis who underwent an LP to rule out NS, and we evaluated 3 laboratory-developed validated real-time PCR assays, the Treponema pallidum particle agglutination (TPPA) assay, the fluorescent treponemal antibody absorption (FTA-ABS) assay, and the line immunoassay INNO-LIA Syphilis, for the diagnosis of NS from cerebrospinal fluid (CSF) samples of these patients. NS was defined by a reactive CSF-VDRL test result and/or a CSF white blood cell (WBC) count of >20 cells/?l. Thirty of the 122 patients (24.6%) had early NS. Headache, visual symptoms, a CD4 cell count of <500 cells/?l, and viremia, as defined by an HIV-1 RNA count of ?50 copies/ml, were associated with NS in multivariate analysis (P = <0.001 for each factor). Blood serum rapid plasma reagin (RPR) titers were not associated with early NS (P = 0.575). For the diagnosis of NS, the PCR, FTA-ABS, TPPA, and INNO-LIA assays had sensitivities of 58%, 100%, 68%, and 100%, specificities of 67%, 12%, 49%, and 13%, and negative predictive values of 85%, 100%, 84%, and 100%, respectively. Visual disturbances, headache, uncontrolled HIV-1 viremia, and a CD4 cell count of <500 cells/?l were predictors of NS in HIV-infected patients with early syphilis, while blood serum RPR titers were not; therefore, RPR titers should not be used as the sole criterion for deciding whether to perform an LP in early syphilis. When applied to CSF samples, the INNO-LIA Syphilis assay easily helped rule out NS.
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Mutations in variable domains of the HIV-1 envelope gene can have a significant impact on maraviroc and vicriviroc resistance.
AIDS Res Ther
PUBLISHED: 04-04-2013
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Resistance to CCR5 inhibitors, such as maraviroc and vicriviroc is characterized by reduction of maximal percent inhibition which indicates the use of an inhibitor-bound conformation of CCR5 for human immunodeficiency virus-1(HIV-1) entry. It is accompanied by substitutions in gp120 and gp41. Variable domain 3 (V3) plays the most important role, but substitutions outside V3 could also be involved in phenotype resistance. In this work, we investigated how mutations in variable regions of the viral envelope protein gp120 can contribute to CCR5 inhibitor resistance.
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Sexual behaviour after antiretroviral therapy initiation in female sex workers and HIV-positive patients from the general population, Cotonou, Benin.
AIDS Care
PUBLISHED: 02-25-2013
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From September 2008 to December 2011, we enrolled and followed-up 247 HIV-negative, 88 untreated and 32 treated HIV-positive female sex workers (FSWs), as well as 238 untreated and 115 treated HIV-positive patients from the general population (GP) of Cotonou, Benin. We wanted to assess the effect of antiretroviral therapy (ART) on sexual risk-taking in FSWs and patients from the GP. We used multivariate log binomial regression models for repeated measures to compare risky behaviours reported during pre-ART and post-ART visits and we performed linear time-trend analyses to assess changes in condom use in all five groups. At 58.8% of pre-ART and 45.3% of post-ART visits (adjusted p-value=0.293), treated FSWs have reported ?16 clients during the last week of work. Inconsistent condom use with clients over the same period decreased by more than 50% (from 20.7 to 10.0%, adjusted p-value=0.082). In treated patients from the GP, inconsistent condom use with regular partners during the last four months was reported at 52.8% of pre-ART and 53.5% of post-ART visits (p=0.778). Reported casual sex was stable (36.8% versus 38.7%, adjusted p-value=0.924). In linear time-trend analyses, there was a significant downward trend in inconsistent condom use at the early stage of the study and stability thereafter in all HIV-negative and HIV-positive FSWs. There was no negative alteration in sexual behaviour following ART initiation either inpatients from the GP or in FSWs. The results underscore the key role of concomitant sexual risk-reduction strategies.
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Short communication: antibody responses to human immunodeficiency virus envelope from infections with multiple subtypes utilize the 1F7-idiotypic repertoire.
AIDS Res. Hum. Retroviruses
PUBLISHED: 01-29-2013
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A common idiotype of anti-HIV antibodies (Abs), designated as 1F7, was recently observed on anti-HIV broadly neutralizing Abs (BnAbs). The presence of the 1F7-idiotype on BnAbs suggests that continuous selection of 1F7-idiotypic Abs may allow these clones to achieve the somatic hypermutation necessary for broad neutralization. As the selection of type-specific BnAbs occurs in the setting of infections with a wide array of HIV subtypes, we investigated Abs from subjects infected with diverse subtypes for the selection of 1F7-idiotypic Abs. We observed the 1F7-idiotype on antiviral Abs in infections with various HIV subtypes. Furthermore, gp140-specific 1F7-idiotypic Abs recognized the gp140 antigens from several HIV subtypes. These results demonstrate that the 1F7-idiotype is a common characteristic of Abs from infections with diverse HIV subtypes, and suggests that early cross-reactivity of 1F7-idiotypic clones may act in conjunction with somatic hypermutation to produce BnAbs.
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Distinct tryptophan catabolism and Th17/Treg balance in HIV progressors and elite controllers.
PLoS ONE
PUBLISHED: 01-01-2013
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Tryptophan (Trp) catabolism into immunosuppressive kynurenine (Kyn) by indoleamine 2,3-dioxygenase (IDO) was previously linked to Th17/Treg differentiation and immune activation. Here we examined Trp catabolism and its impact on Th17/Treg balance in uninfected healthy subjects (HS) and a large cohort of HIV-infected patients with different clinical outcomes: ART-naïve, Successfully Treated (ST), and elite controllers (EC). In ART-naïve patients, increased IDO activity/expression, together with elevated levels of TNF-? and sCD40L, were associated with Treg expansion and an altered Th17/Treg balance. These alterations were normalized under ART. In contrast, Trp 2,3-dioxegenase (TDO) expression was dramatically lower in EC when compared to all other groups. Interestingly, EC displayed a distinctive Trp metabolism characterized by low Trp plasma levels similar to ART-naïve patients without accumulating immunosuppressive Kyn levels which was accompanied by a preserved Th17/Treg balance. These results suggest a distinctive Trp catabolism and Th17/Treg balance in HIV progressors and EC. Thus, IDO-induced immune-metabolism may be considered as a new inflammation-related marker for HIV-1 disease progression.
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Serotyping of Streptococcus pneumoniae Based on Capsular Genes Polymorphisms.
PLoS ONE
PUBLISHED: 01-01-2013
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Streptococcus pneumoniae serotype epidemiology is essential since serotype replacement is a concern when introducing new polysaccharide-conjugate vaccines. A novel PCR-based automated microarray assay was developed to assist in the tracking of the serotypes. Autolysin, pneumolysin and eight genes located in the capsular operon were amplified using multiplex PCR. This step was followed by a tagged fluorescent primer extension step targeting serotype-specific polymorphisms. The tagged primers were then hybridized to a microarray. Results were exported to an expert system to identify capsular serotypes. The assay was validated on 166 cultured S. pneumoniae samples from 63 different serotypes as determined by the Quellung method. We show that typing only 12 polymorphisms located in the capsular operon allows the identification at the serotype level of 22 serotypes and the assignation of 24 other serotypes to a subgroup of serotypes. Overall, 126 samples (75.9%) were correctly serotyped, 14 were assigned to a member of the same serogroup, 8 rare serotypes were erroneously serotyped, and 18 gave negative serotyping results. Most of the discrepancies involved rare serotypes or serotypes that are difficult to discriminate using a DNA-based approach, for example 6A and 6B. The assay was also tested on clinical specimens including 43 cerebrospinal fluid samples from patients with meningitis and 59 nasopharyngeal aspirates from bacterial pneumonia patients. Overall, 89% of specimens positive for pneumolysin were serotyped, demonstrating that this method does not require culture to serotype clinical specimens. The assay showed no cross-reactivity for 24 relevant bacterial species found in these types of samples. The limit of detection for serotyping and S. pneumoniae detection was 100 genome equivalent per reaction. This automated assay is amenable to clinical testing and does not require any culturing of the samples. The assay will be useful for the evaluation of serotype prevalence changes after new conjugate vaccines introduction.
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Loss of the signaling adaptor TRAF1 causes CD8+ T cell dysregulation during human and murine chronic infection.
J. Exp. Med.
PUBLISHED: 12-19-2011
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The signaling adaptor TNFR-associated factor 1 (TRAF1) is specifically lost from virus-specific CD8 T cells during the chronic phase of infection with HIV in humans or lymphocytic choriomeningitis virus (LCMV) clone 13 in mice. In contrast, TRAF1 is maintained at higher levels in virus-specific T cells of HIV controllers or after acute LCMV infection. TRAF1 expression negatively correlates with programmed death 1 expression and HIV load and knockdown of TRAF1 in CD8 T cells from viral controllers results in decreased HIV suppression ex vivo. Consistent with the desensitization of the TRAF1-binding co-stimulatory receptor 4-1BB, 4-1BBL-deficient mice have defects in viral control early, but not late, in chronic infection. TGF? induces the posttranslational loss of TRAF1, whereas IL-7 restores TRAF1 levels. A combination treatment with IL-7 and agonist anti-4-1BB antibody at 3 wk after LCMV clone 13 infection expands T cells and reduces viral load in a TRAF1-dependent manner. Moreover, transfer of TRAF1(+) but not TRAF1(-) memory T cells at the chronic stage of infection reduces viral load. These findings identify TRAF1 as a potential biomarker of HIV-specific CD8 T cell fitness during the chronic phase of disease and a target for therapy.
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Transmission of HIV-1 drug resistance in Benin could jeopardise future treatment options.
Sex Transm Infect
PUBLISHED: 12-12-2011
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As access to antiretrovirals (ARV) increases in developing countries, the identification of optimal therapeutic regimens and prevention strategies requires the identification of resistance pathways in non-B subtypes as well as the surveillance of drug mutation resistance (SDMR) including the trafficking of viral strains between high-risk groups such as commercial sex workers (CSW) and the general population (GP). In this study, the authors evaluated the rate of primary resistance mutations and the epidemiological link between isolates from GP and CSW from Bénin.
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Relative contribution of HIV-specific functional lymphocyte subsets restricted by protective and non-protective HLA alleles.
Viral Immunol.
PUBLISHED: 06-15-2011
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Expression of major histocompatibility complex (MHC) class I alleles such as B*57 and B*27 are associated with slow HIV disease progression. HIV-specific immune responses in slow progressors (SP) are characterized by a poly-functional profile. We previously observed within infected subjects that HIV peptide-specific responses could differ from each other in their functional composition. We investigate here whether responses restricted by MHC class I alleles associated with slow disease progression have a more poly-functional profile than responses restricted by other alleles. We stimulated peripheral blood mononuclear cells (PBMCs) isolated from 36 chronically HIV-infected individuals with a panel of optimal peptides restricted by the HLA alleles expressed by each subject, and assessed the contribution of single IL-2-, single IFN-?-, and IFN-?/IL-2-secreting lymphocytes to the total response measured using a dual color ELISPOT assay. The contribution of functional subsets to responses restricted by HLA B*57/B*27 was similar in SP and progressors. For responses restricted by other MHC class I alleles, dual IFN-?/IL-2-secreting lymphocytes contributed significantly more to the total response in SP than progressors. Within SP subjects, peptides restricted by both B*57/B*27 and other alleles stimulated responses with similar functional profiles. In progressors, peptides restricted by B*57/B*27 stimulated responses composed of a significantly greater proportion of IFN-?/IL-2-secreting cells than peptides restricted by other alleles. Within progressors, the contribution of IFN-?/IL-2-secreting lymphocytes was greater to epitopes restricted by protective HLA alleles compared with responses restricted by other alleles. HLA haplotypes influence the relative functional composition of HIV-specific responses.
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Loss of memory B cells during chronic HIV infection is driven by Foxo3a- and TRAIL-mediated apoptosis.
J. Clin. Invest.
PUBLISHED: 05-27-2011
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Loss of memory B cells occurs from the onset of HIV-1 infection and persists into the chronic stages of infection. Lack of survival of these cells, even in subjects being treated, could primarily be the consequence of an altered local microenvironment induced by HIV infection. In this study we showed that memory B cell survival was significantly decreased in aviremic successfully treated (ST) subjects compared with subjects who control viral load as a result of natural immunity (elite controller [EC]) or with uninfected control (HIV-) subjects. The lower survival levels observed in memory B cells from ST subjects were the result of disrupted IL-2 signaling that led to increased transcriptional activity of Foxo3a and increased expression of its proapoptotic target TRAIL. Notably, memory B cell survival in ST subjects was significantly enhanced by the addition of exogenous IL-2 in a Foxo3a-dependent manner. We further showed that Foxo3a silencing by siRNA resulted in decreased expression of TRAIL and apoptosis levels in memory B cells from ST subjects. Our results thus establish a direct role for Foxo3a/TRAIL signaling in the persistence of memory B cells and provide a mechanism for the reduced survival of memory B cells during HIV infection. This knowledge could be exploited for the development of therapeutic and preventative HIV vaccines.
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Association between HIV infection, antiretroviral therapy, and risk of acute myocardial infarction: a cohort and nested case-control study using Québecs public health insurance database.
J. Acquir. Immune Defic. Syndr.
PUBLISHED: 04-19-2011
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Morbidity associated with cardiovascular disease is increasing in the HIV-infected population. We aimed to study the impact of HIV and of antiretrovirals on acute myocardial infarction (AMI).
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T cell Activation does not drive CD4 decline in longitudinally followed HIV-infected Elite Controllers.
AIDS Res Ther
PUBLISHED: 04-18-2011
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Elite controllers (EC) are a rare subset of HIV infected individuals who control viral load below 50 copies/ml of plasma without treatment.
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Receptor-ligand requirements for increased NK cell polyfunctional potential in slow progressors infected with HIV-1 coexpressing KIR3DL1*h/*y and HLA-B*57.
J. Virol.
PUBLISHED: 04-06-2011
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Carriage of the natural killer (NK) receptor genotype KIR3DL1*h/*y with its HLA-B*57 ligand (*h/*y+B*57) is associated with slow time to AIDS and low viral load (VL). To provide a functional basis for these epidemiological observations, we assessed whether HIV-1-infected slow progressors (SP) carrying the *h/*y+B*57 compound genotype would have increased NK cell polyfunctional potential in comparison to SP with other killer immunoglobulin-like receptor (KIR)/HLA compound genotypes and whether this enhanced polyfunctionality was dependent upon the coexpression of both KIR3DL1*h/*y and HLA-B*57. The functional potential of NK cells was investigated by stimulating peripheral blood mononuclear cells with HLA-devoid targets or single HLA transfectants. Multiparametric flow cytometry was used to detect NK cells with seven functional profiles representing all permutations of CD107a expression and gamma interferon (IFN-?) and tumor necrosis factor alpha (TNF-?) secretion. NK cells from individuals carrying KIR3DL1 receptor-HLA-Bw4 ligand pairs had greater trifunctional responses than those from KIR3DL1 homozygotes (hmz), who were Bw6 homozygotes. NK cells from subjects carrying the *h/*y+B*57 genotypes exhibited the highest trifunctional potential, and this was dependent on cocarriage of the NK receptor and its ligand. Trifunctional cells secreted more of each function tested on a per-cell basis than each corresponding monofunctional NK subset. Although VL influenced NK functionality, individuals with defined KIR/HLA genotypes exhibited differences in NK cell polyfunctionality that could not be accounted for by VL alone. The protective effect of HLA-B*57 on slow progression to AIDS and low VL may be mediated through its interaction with KIR3DL1 alleles to educate NK cells for potent activity upon stimulation.
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Management and treatment of hepatitis B virus in patients with HIV infection: A practical guide for health care professionals.
Can J Infect Dis Med Microbiol
PUBLISHED: 03-10-2011
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The management and treatment of HIV and hepatitis B virus (HBV)-coinfected patients present specific challenges for clinicians. The morbidity and mortality related to these concomitant infections are growing concerns, while the use of antiviral drugs effective against both viruses complicates therapeutic decision making. The present document provides guidelines for physicians regarding care and treatment of patients coinfected with HIV and HBV. Primary prevention of HBV in HIV-positive patients is achieved through appropriate vaccination schedules. Follow-up before treatment of HBV may include liver biopsy, screening for hepatocellular carcinoma and testing for esophageal varicies in cases of cirrhosis. In HBV-infected patients requiring treatment, recommendations regarding initiation, duration and choice of first-line drugs are made. Finally, in the case of resistance, appropriate alternative therapies are necessary.
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A randomized controlled trial of HIV therapeutic vaccination using ALVAC with or without Remune.
AIDS
PUBLISHED: 02-19-2011
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Therapeutic HIV vaccination during the time of virologic suppression may delay or blunt viral load rebound after interruption of antiretroviral therapy (ART). The use of ALVAC, to enhance cytotoxic T-lymphocyte responses, with Remune, which provides CD4 T-cell help, may induce anti-HIV responses capable of controlling viral replication.
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Characterization of the E138K resistance mutation in HIV-1 reverse transcriptase conferring susceptibility to etravirine in B and non-B HIV-1 subtypes.
Antimicrob. Agents Chemother.
PUBLISHED: 12-06-2010
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We have selected for resistance to etravirine (ETR) and efavirenz (EFV) in tissue culture using three subtype B, three subtype C, and two CRF02_AG clinical isolates, grown in cord blood mononuclear cells. Genotypic analysis was performed at baseline and at various weeks of selection. Phenotypic resistance in regard to ETR, EFV, and nevirapine (NVP) was evaluated at weeks 25 to 30 for all ETR-selected viruses and in viral clones that contained specific resistance mutations that were inserted by site-directed mutagenesis into pNL-4.3 and AG plasmids. The results show that ETR selected mutations at positions V90I, K101Q, E138K, V179D/E/F, Y181C, V189I, G190E, H221H/Y, and M230L and that E138K was the first of these to emerge in most instances. The time to the emergence of resistance was longer in the case of ETR (18 weeks) compared to EFV (11 weeks), and no differences in the patterns of emergent mutations could be documented between the B and non-B subtypes. Viral clones containing E138K displayed low-level phenotypic resistance to ETR (3.8-fold) and modestly impaired replication capacity (2-fold) compared to wild-type virus. ETR-selected virus showed a high degree of cross-resistance to NVP but not to EFV. We identified K101Q, E138K, V179E, V189I, G190E, and H221Y as mutations not included among the 17 currently recognized resistance-associated mutations for ETR.
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The major genetic determinants of HIV-1 control affect HLA class I peptide presentation.
, Florencia Pereyra, Xiaoming Jia, Paul J McLaren, Amalio Telenti, Paul I W de Bakker, Bruce D Walker, Stephan Ripke, Chanson J Brumme, Sara L Pulit, Mary Carrington, Carl M Kadie, Jonathan M Carlson, David Heckerman, Robert R Graham, Robert M Plenge, Steven G Deeks, Lauren Gianniny, Gabriel Crawford, Jordan Sullivan, Elena González, Leela Davies, Amy Camargo, Jamie M Moore, Nicole Beattie, Supriya Gupta, Andrew Crenshaw, Noel P Burtt, Candace Guiducci, Namrata Gupta, Xiaojiang Gao, Ying Qi, Yuko Yuki, Alicja Piechocka-Trocha, Emily Cutrell, Rachel Rosenberg, Kristin L Moss, Paul Lemay, Jessica O'Leary, Todd Schaefer, Pranshu Verma, Ildikó Tóth, Brian Block, Brett Baker, Alissa Rothchild, Jeffrey Lian, Jacqueline Proudfoot, Donna Marie L Alvino, Seanna Vine, Marylyn M Addo, Todd M Allen, Marcus Altfeld, Matthew R Henn, Sylvie Le Gall, Hendrik Streeck, David W Haas, Daniel R Kuritzkes, Gregory K Robbins, Robert W Shafer, Roy M Gulick, Cecilia M Shikuma, Richard Haubrich, Sharon Riddler, Paul E Sax, Eric S Daar, Heather J Ribaudo, Brian Agan, Shanu Agarwal, Richard L Ahern, Brady L Allen, Sherly Altidor, Eric L Altschuler, Sujata Ambardar, Kathryn Anastos, Ben Anderson, Val Anderson, Ushan Andrady, Diana Antoniskis, David Bangsberg, Daniel Barbaro, William Barrie, J Bartczak, Simon Barton, Patricia Basden, Nesli Basgoz, Suzane Bazner, Nicholaos C Bellos, Anne M Benson, Judith Berger, Nicole F Bernard, Annette M Bernard, Christopher Birch, Stanley J Bodner, Robert K Bolan, Emilie T Boudreaux, Meg Bradley, James F Braun, Jon E Brndjar, Stephen J Brown, Katherine Brown, Sheldon T Brown, Jedidiah Burack, Larry M Bush, Virginia Cafaro, Omobolaji Campbell, John Campbell, Robert H Carlson, J Kevin Carmichael, Kathleen K Casey, Chris Cavacuiti, Gregory Celestin, Steven T Chambers, Nancy Chez, Lisa M Chirch, Paul J Cimoch, Daniel Cohen, Lillian E Cohn, Brian Conway, David A Cooper, Brian Cornelson, David T Cox, Michael V Cristofano, George Cuchural, Julie L Czartoski, Joseph M Dahman, Jennifer S Daly, Benjamin T Davis, Kristine Davis, Sheila M Davod, Edwin DeJesus, Craig A Dietz, Eleanor Dunham, Michael E Dunn, Todd B Ellerin, Joseph J Eron, John J W Fangman, Claire E Farel, Helen Ferlazzo, Sarah Fidler, Anita Fleenor-Ford, Renee Frankel, Kenneth A Freedberg, Neel K French, Jonathan D Fuchs, Jon D Fuller, Jonna Gaberman, Joel E Gallant, Rajesh T Gandhi, Efrain Garcia, Donald Garmon, Joseph C Gathe, Cyril R Gaultier, Wondwoosen Gebre, Frank D Gilman, Ian Gilson, Paul A Goepfert, Michael S Gottlieb, Claudia Goulston, Richard K Groger, T Douglas Gurley, Stuart Haber, Robin Hardwicke, W David Hardy, P Richard Harrigan, Trevor N Hawkins, Sonya Heath, Frederick M Hecht, W Keith Henry, Melissa Hladek, Robert P Hoffman, James M Horton, Ricky K Hsu, Gregory D Huhn, Peter Hunt, Mark J Hupert, Mark L Illeman, Hans Jaeger, Robert M Jellinger, Mina John, Jennifer A Johnson, Kristin L Johnson, Heather Johnson, Kay Johnson, Jennifer Joly, Wilbert C Jordan, Carol A Kauffman, Homayoon Khanlou, Robert K Killian, Arthur Y Kim, David D Kim, Clifford A Kinder, Jeffrey T Kirchner, Laura Kogelman, Erna Milunka Kojic, P Todd Korthuis, Wayne Kurisu, Douglas S Kwon, Melissa Lamar, Harry Lampiris, Massimiliano Lanzafame, Michael M Lederman, David M Lee, Jean M L Lee, Marah J Lee, Edward T Y Lee, Janice Lemoine, Jay A Levy, Josep M Llibre, Michael A Liguori, Susan J Little, Anne Y Liu, Alvaro J Lopez, Mono R Loutfy, Dawn Loy, Debbie Y Mohammed, Alan Man, Michael K Mansour, Vincent C Marconi, Martin Markowitz, Rui Marques, Jeffrey N Martin, Harold L Martin, Kenneth Hugh Mayer, M Juliana McElrath, Theresa A McGhee, Barbara H McGovern, Katherine McGowan, Dawn McIntyre, Gavin X Mcleod, Prema Menezes, Greg Mesa, Craig E Metroka, Dirk Meyer-Olson, Andy O Miller, Kate Montgomery, Karam C Mounzer, Ellen H Nagami, Iris Nagin, Ronald G Nahass, Margret O Nelson, Craig Nielsen, David L Norene, David H O'Connor, Bisola O Ojikutu, Jason Okulicz, Olakunle O Oladehin, Edward C Oldfield, Susan A Olender, Mario Ostrowski, William F Owen, Eunice Pae, Jeffrey Parsonnet, Andrew M Pavlatos, Aaron M Perlmutter, Michael N Pierce, Jonathan M Pincus, Leandro Pisani, Lawrence Jay Price, Laurie Proia, Richard C Prokesch, Heather Calderon Pujet, Moti Ramgopal, Almas Rathod, Michael Rausch, J Ravishankar, Frank S Rhame, Constance Shamuyarira Richards, Douglas D Richman, Berta Rodés, Milagros Rodriguez, Richard C Rose, Eric S Rosenberg, Daniel Rosenthal, Polly E Ross, David S Rubin, Elease Rumbaugh, Luis Saenz, Michelle R Salvaggio, William C Sanchez, Veeraf M Sanjana, Steven Santiago, Wolfgang Schmidt, Hanneke Schuitemaker, Philip M Sestak, Peter Shalit, William Shay, Vivian N Shirvani, Vanessa I Silebi, James M Sizemore, Paul R Skolnik, Marcia Sokol-Anderson, James M Sosman, Paul Stabile, Jack T Stapleton, Sheree Starrett, Francine Stein, Hans-Jürgen Stellbrink, F Lisa Sterman, Valerie E Stone, David R Stone, Giuseppe Tambussi, Randy A Taplitz, Ellen M Tedaldi, William Theisen, Richard Torres, Lorraine Tosiello, Cécile Tremblay, Marc A Tribble, Phuong D Trinh, Alice Tsao, Peggy Ueda, Anthony Vaccaro, Emília Valadas, Thanes J Vanig, Isabel Vecino, Vilma M Vega, Wenoah Veikley, Barbara H Wade, Charles Walworth, Chingchai Wanidworanun, Douglas J Ward, Daniel A Warner, Robert D Weber, Duncan Webster, Steve Weis, David A Wheeler, David J White, Ed Wilkins, Alan Winston, Clifford G Wlodaver, Angelique van't Wout, David P Wright, Otto O Yang, David L Yurdin, Brandon W Zabukovic, Kimon C Zachary, Beth Zeeman, Meng Zhao.
Science
PUBLISHED: 11-04-2010
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Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified >300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alleles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection.
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Altruism motivates participation in a therapeutic HIV vaccine trial (CTN 173).
AIDS Care
PUBLISHED: 10-12-2010
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This is the first study examining motivation to participate in an HIV therapeutic vaccine trial of Remune and ALVAC. Trial participants (N=49) completed psychological measures at baseline. While 69% reported some personal risk in participating, 100% felt hopeful for societal benefits. Trial participants also reported high levels of existential well-being (e.g., "I believe there is some real purpose for my life"). Results suggest that HIV therapeutic vaccine trial participants are highly motivated by altruism and that participating in research may contribute meaning to living with HIV. Fostering altruism and responsibly promoting the societal benefits of research may facilitate trial participation.
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Immunogenicity and tolerability of an inactivated and adjuvanted pandemic H1N1 influenza vaccine, in HIV-1-infected patients.
Vaccine
PUBLISHED: 06-25-2010
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We evaluated the efficacy and tolerability of a single dose of the split virion AS03-adjuvanted pandemic H1N1 influenza vaccine (A/California/7/2009) in 84 HIV-1 infected individuals. Antibody titers were determined by hemagglutination inhibition assay and by microneutralization. Vaccine was well tolerated. At 21 days post vaccination, 56 (67%) patients had seroconverted. There was no correlation between baseline CD4 cell count (p=0.539) or HIV viral load (p=0.381) and immune response. Other vaccine strategies should be evaluated in this HIV population, to improve response rates.
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Changes in function of HIV-specific T-cell responses with increasing time from infection.
Viral Immunol.
PUBLISHED: 04-09-2010
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Recently HIV-infected individuals have virus-specific responses characterized by IFN-gamma/IL-2 secretion and proliferation rarely seen in chronic infection. To investigate the timing of loss of HIV-specific T-cell function, we screened cells from 59 treatment-naïve HIV-infected individuals with known dates of infection for proteome-wide responses secreting IFN-gamma/IL-2 and IFN-gamma alone by ELISPOT. HIV peptide-specific proliferation was assessed by carboxyfluorescein diacetate succinimidyl ester (CFSE) dilution. The contribution of IFN-gamma/IL-2 and IFN-gamma-only secretion to the total HIV-specific response was compared in subjects infected <6, 6-12, and 12-36 mo earlier. The frequency of IFN-gamma/IL-2-secreting cells fell, while that of IFN-gamma-only secretion rose with time from infection. HIV peptide-specific proliferative responses were almost exclusively mediated by CD8(+) T cells, and were significantly lower in cells obtained from the 12-36 mo versus < 6 mo post-infection groups. By the second year of infection there was a significant difference in these functions compared to those assessed within 6 mo.
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Characterization of emergent HIV resistance in treatment-naive subjects enrolled in a vicriviroc phase 2 trial.
J. Infect. Dis.
PUBLISHED: 04-09-2010
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Vicriviroc is a C-C motif chemokine receptor 5 (CCR5) antagonist that is in clinical development for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. This study explored the molecular basis for the development of phenotypically resistant virus.
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Wide variation in the multiplicity of HIV-1 infection among injection drug users.
J. Virol.
PUBLISHED: 04-07-2010
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Recent studies indicate that sexual transmission of human immunodeficiency virus type 1 (HIV-1) generally results from productive infection by only one virus, a finding attributable to the mucosal barrier. Surprisingly, a recent study of injection drug users (IDUs) from St. Petersburg, Russia, also found most subjects to be acutely infected by a single virus. Here, we show by single-genome amplification and sequencing in a different IDU cohort that 60% of IDU subjects were infected by more than one virus, including one subject who was acutely infected by at least 16 viruses. Multivariant transmission was more common in IDUs than in heterosexuals (60% versus 19%; odds ratio, 6.14; 95% confidence interval [CI], 1.37 to 31.27; P = 0.008). These findings highlight the diversity in HIV-1 infection risks among different IDU cohorts and the challenges faced by vaccines in protecting against this mode of infection.
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Challenges in initiating antiretroviral therapy in 2010.
Can J Infect Dis Med Microbiol
PUBLISHED: 03-23-2010
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Many clinical trials have shown that initiating antiretroviral therapy (ART) at higher rather than lower CD4 T cell-positive counts results in survival benefit. Early treatment can help prevent end-organ damage associated with HIV replication and can decrease infectivity. The mainstay of treatment is either a non-nucleoside reverse transcriptase inhibitor or a ritonavir-boosted protease inhibitor in combination with two nucleoside reverse transcriptase inhibitors. While effective at combating HIV, ART can produce adverse alterations of lipid parameters, with some studies suggesting a relationship between some anti-retroviral agents and cardiovascular disease. As the HIV-positive population ages, issues such as hypertension and diabetes must be taken into account when initiating ART. Adhering to ART can be difficult; however, nonoptimal adherence to ART can result in the development of resistance; thus, drug characteristics and the patients preparedness to begin therapy must be considered. Reducing the pill burden through the use of fixed-dose antiretroviral drug combinations can facilitate adherence.
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Tissue culture drug resistance analysis of a novel HIV-1 protease inhibitor termed PL-100 in non-B HIV-1 subtypes.
Antiviral Res.
PUBLISHED: 03-05-2010
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PL-100 is a novel HIV-1 protease inhibitor (PI) that maintains activity against viruses that are resistant to other PIs. To further characterize this compound, we used it to select for drug resistance in tissue culture, using two non-B HIV-1 subtypes, viz. subtype C and a CRF01_AE recombinant virus. PL-100 selected for both minor and major PI resistance mutations along either of two distinct pathways. One of these involved the V82A and L90M resistance mutations while the other involved a mutation at position T80I, with other mutations being observed at positions M46I/L, I54M, K55R, L76F, P81S and I85V. The resistance patterns in both subtype C and CRF01_AE were similar and an accumulation of at least three mutations in the flap and active sites were required in each case for high-level resistance to occur, demonstrating that PL-100 has a high genetic barrier against the development of drug resistance.
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IL-21 enhances NK cell functions and survival in healthy and HIV-infected patients with minimal stimulation of viral replication.
J. Leukoc. Biol.
PUBLISHED: 01-26-2010
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IL-21 plays an important role in regulating immune response and controlling chronic viral infections. Recently, we reported its decreased serum concentrations and their immunological consequences in HIV-infected persons. In this study, we have investigated how exogenous IL-21 enhances NK cell responses in these persons. We show that the cytokine receptors are expressed equally on all NK cell subsets defined by expression of CD16 and CD56; the cytokine activates STAT-3, MAPK, and Akt to enhance NK cell functions; the STAT-3 activation plays a key role in constitutive and IL-21-mediated enhancement of NK cell functions; the cytokine increases expression of antiapoptotic proteins Bcl-2 and Bcl-X(L) and enhances viability of NK cells but has no effect on their proliferation; the cytokine enhances HIV-specific ADCC, secretory, and cytotoxic functions, as well as viability of NK cells from HIV-infected persons; it exerts its biological effects on NK cells with minimal stimulation of HIV-1 replication; and the cytokine-activated NK cells inhibit viral replication in cocultured, HIV-infected, autologous CD4(+) T cells in a perforin- and LFA-1-dependent manner. These data suggest that IL-21 may serve as a valuable therapeutic tool for enhancing NK cell responses and inhibiting viral replication in HIV-infected patients.
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HIV-1 causes an imbalance in the production of interleukin-18 and its natural antagonist in HIV-infected individuals: implications for enhanced viral replication.
J. Infect. Dis.
PUBLISHED: 01-19-2010
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Concentrations of interleukin (IL)-18 increase in the circulation of human immunodeficiency virus (HIV)-infected persons. However, nothing is known concerning the regulation of IL-18-binding protein (IL-18BP), which neutralizes IL-18 in vivo. This issue is addressed in the present study.
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Dynamics and consequences of IL-21 production in HIV-infected individuals: a longitudinal and cross-sectional study.
J. Immunol.
PUBLISHED: 11-30-2009
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IL-21 is a relatively newly discovered immune-enhancing cytokine that plays an essential role in controlling chronic viral infections. It is produced mainly by CD4(+) T cells, which are also the main targets of HIV-1 and are often depleted in HIV-infected individuals. Therefore, we sought to determine the dynamics of IL-21 production and its potential consequences for the survival of CD4(+) T cells and frequencies of HIV-specific CTL. For this purpose, we conducted a series of cross-sectional and longitudinal studies on different groups of HIV-infected patients and show in this study that the cytokine production is compromised early in the course of the infection. The serum cytokine concentrations correlate with CD4(+) T cell counts in the infected persons. Among different groups of HIV-infected individuals, only elite controllers maintain normal production of the cytokine. Highly active antiretroviral therapy only partially restores the production of this cytokine. Interestingly, HIV infection of human CD4(+) T cells inhibits cytokine production by decreasing the expression of c-Maf in virus-infected cells, not in uninfected bystander cells. We also show that the frequencies of IL-21-producing HIV-specific, but not human CMV-specific, Ag-experienced CD4(+) T cells are decreased in HIV-infected viremic patients. Furthermore, we demonstrate in this study that recombinant human IL-21 prevents enhanced spontaneous ex vivo death of CD4(+) T cells from HIV-infected patients. Together, our results suggest that serum IL-21 concentrations may serve as a useful biomarker for monitoring HIV disease progression and the cytokine may be considered for immunotherapy in HIV-infected patients.
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Role of interleukin-18 in the development and pathogenesis of AIDS.
AIDS Rev
PUBLISHED: 08-06-2009
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Interleukin-18 is a proinflammatory, proapoptotic, and proatherogenic cytokine belonging to the interleukin-1 family of cytokines. The cytokine exerts many unique immunologic and biological effects. It is produced as a biologically inactive and leaderless precursor protein, which must be cleaved into its mature form by caspase-1. The caspase-1 also exists in an inactive precursor in the cytosol and needs proteolytic auto-cleavage, which is catalyzed by the assembly of a multi-protein complex called inflammasome. Inside the circulation, interleukin-18 is bound to its naturally occurring antagonist called interleukin-18 binding protein. The antagonist is induced as a negative feedback to increased interleukin-18 production. It protects body cells and tissues from the potentially destructive and harmful proinflammatory effects of the cytokine. Several researchers have reported that the concentrations and biological activities of the cytokine are increased in the circulation of HIV-infected patients. Unlike interleukin-18, the concentrations of its antagonist, interleukin-18 binding protein, are decreased in these persons. The cytokine may play a major role in the development and pathogenesis of AIDS in HIV-infected persons. Insufficient/lack of interleukin-12 and related cytokines may compromise the ability of interleukin-18 to induce interferon-gamma production from natural killer and T-cells. By inducing production of T-helper 2-type cytokines like interleukin-4, -5, -9, and -13 from basophils and mast cells, interleukin-18 promotes the development and differentiation of CD4+ naive T-cells into T-helper 2-type effector cells, which blunt anti-HIV immunity. The effect may be more pronounced in HIV-infected persons with compromised production of interleukin-12. Interleukin-18 also directly enhances viral replication. Because of its proapoptotic effects, the cytokine decreases survivability and promotes the death of various immune and nonimmune cells. It has also been documented to play a role in the depletion and wasting of subcutaneous fat from the limbs and face. The wasting is a characteristic feature of HIV-associated lipodystrophy. The cytokine is also likely to be involved in the higher incidence of atherosclerotic plaques and systemic insulin resistance in these patients. Finally, increased production of the cytokine in the brain may lead to motor and cognitive dysfunctions, leading to the development of HIV-associated dementia. In conclusion, increased interleukin-18 concentrations in HIV-infected persons are likely to play an important role in the development and progression of the infection toward AIDS and associated clinical conditions. Therefore, its neutralization may represent an appropriate and useful immunotherapeutic strategy in these patients. It may delay AIDS progression and improve the immune status of infected persons. The best way to achieve this goal may be using exogenous interleukin-18 binding protein.
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Optimal use of raltegravir (Isentress(R)) in the treatment of HIV-infected adults - Canadian consensus guidelines.
Can J Infect Dis Med Microbiol
PUBLISHED: 07-13-2009
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A meeting of a Canadian group with significant experience and knowledge in HIV management, consisting of five physicians, a pharmacist and an AIDS researcher, was convened. Their goal was to develop guidance for Canadian HIV-treating physicians on the appropriate use of raltegravir (MK-0518, Isentress(R), Merck Frosst Canada Inc) in HIV-infected adults.
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Persistence of high levels of blood soluble human leukocyte antigen-G is associated with rapid progression of HIV infection.
AIDS
PUBLISHED: 05-23-2009
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Human leukocyte antigen-G is an important suppressor of the immune response, and HIV can modulate its expression. Longitudinal monitoring of soluble human leukocyte antigen-G plasma levels in patients with primary HIV infection undergoing different rates of disease progression showed that levels were elevated in the early phases of infection and remained high throughout follow-up in rapid progressors who responded to antiretroviral therapy but were restored to normal levels in the chronic phase of infection in both untreated normal progressors and long-term nonprogressors.
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Potential role of interleukin-18 in the immunopathogenesis of AIDS: involvement in fratricidal killing of NK cells.
J. Virol.
PUBLISHED: 04-01-2009
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We had shown earlier that the concentrations of circulating interleukin-18 (IL-18) are increased significantly in human immunodeficiency virus (HIV)-infected persons compared to HIV-seronegative healthy subjects. In the present study, we investigated the consequences of these elevated levels of IL-18 on natural killer (NK) cells and the immunopathogenesis of AIDS. We show here an inverse correlation between IL-18 concentrations and absolute numbers of various subsets of NK cells in infected persons. Recombinant human IL-18 caused increased death of a human NK cell line, as well as of primary human NK cells in vitro. The IL-18-mediated cell death was dependent upon Fas-FasL interactions and tumor necrosis factor alpha. IL-18 induced the expression of FasL on NK cells, increased the transcription from the human FasL promoter, reduced the expression of Bcl-X(L) in NK cells, and increased their sensitivity to FasL-mediated cell death. These results suggest that increased IL-18 concentrations present in the circulation of HIV-infected persons contribute to the immunopathogenesis of AIDS by altering NK cell homeostasis.
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HIV infection affects blood myeloid dendritic cells after successful therapy and despite nonprogressing clinical disease.
J. Infect. Dis.
PUBLISHED: 02-24-2009
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We assessed the longitudinal changes in blood myeloid dendritic cell (mDC) and plasmacytoid dendritic cell (pDC) populations in subjects with primary human immunodeficiency virus (HIV) infection undergoing different rates of disease progression. The relative level and degree of maturation of all cell populations decreased significantly in untreated individuals with acute infection. The most dramatic changes were observed in the rapid progressor group, correlating with their rate of clinical progression. Levels of mDCs remained lower than normal throughout follow-up for both rapid progressors who responded to antiretroviral therapy (ART) and untreated normal progressors. In contrast, mDC precursors were restored to normal levels during subsequent phases of infection in both rapid and normal progressors, and these levels were increased in long-term nonprogressors. pDC levels followed the pattern of CD4+ T cell fluctuations. These findings provide evidence for an ongoing process affecting mDCs after successful ART and despite nonprogressing clinical disease following HIV infection.
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HIV Gag p24 specific responses secreting IFN-gamma and/or IL-2 in treatment-naïve individuals in acute infection early disease (AIED) are associated with low viral load.
Clin. Immunol.
PUBLISHED: 01-08-2009
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HIV-specific immune responses in acute infection early disease (AIED) may be effective at controlling viral replication and in establishing viral load (VL) set point. However, evidence correlating the function and specificity of these responses with the VL set point is lacking. To address this issue, we screened cells from 59 treatment-naïve HIV infected individuals (33 in AIED and 26 progressors) for responses to the entire HIV proteome using a dual color ELISPOT assay detecting 3 functional lymphocyte populations: single IFN-gamma, dual IFN-gamma/IL-2 and single IL-2 secreting cells. Responses characterized by dual secreting cells contributed more to the HIV specific response in AIED versus chronic infection. Of responses directed to individual HIV gene products the magnitude and breadth of only Gag p24-specific responses for the 3 functional subsets were associated with lower concurrent or set point VL. Therefore the early appearance of broader and more intense Gag-p24-specific responses may be a determinant of subsequent VL.
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Carbapenem disks on MacConkey agar in screening methods for detection of carbapenem-resistant Gram-negative rods in stools.
J. Clin. Microbiol.
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Direct plating of simulated stool specimens on MacConkey agar (MCA) with 10-?g ertapenem, meropenem, and imipenem disks allowed the establishment of optimal zone diameters for the screening of carbapenem-resistant Gram-negative rods (CRGNR) of ? 24 mm (ertapenem), ? 34 mm (meropenem), and ? 32 mm (imipenem).
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Evaluation of a real-time virtual intervention to empower persons living with HIV to use therapy self-management: study protocol for an online randomized controlled trial.
Trials
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Living with HIV makes considerable demands on a person in terms of self-management, especially as regards adherence to treatment and coping with adverse side-effects. The online HIV Treatment, Virtual Nursing Assistance and Education (Virus de Iimmunodéficience Humaine-Traitement Assistance Virtuelle Infirmière et Enseignement; VIH-TAVIE™) intervention was developed to provide persons living with HIV (PLHIV) with personalized follow-up and real-time support in managing their medication intake on a daily basis. An online randomized controlled trial (RCT) will be conducted to evaluate the efficacy of this intervention primarily in optimizing adherence to combination anti-retroviral therapy (ART) among PLHIV.
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Acceptability and feasibility of a virtual intervention to help people living with HIV manage their daily therapies.
J Telemed Telecare
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We conducted a study of the acceptability and feasibility of a web application which was designed to empower people living with HIV to manage their daily antiretroviral therapies. The application (VIH-TAVIE) consists of four interactive computer sessions with a virtual nurse who guides the user through a learning process aimed at enhancing treatment management capacities. The information furnished and the strategies proposed by the nurse are tailored, based on the responses provided by the user. The application was evaluated in a hospital setting as an adjunct to usual care. The participants (n = 71) had a mean age of 47 years (SD = 7.6). There were 59 men and 12 women. They had been diagnosed with HIV some 15 years earlier and had been on antiretroviral medication for a mean duration of 11 years. Data were collected by acceptability questionnaires, field notes and observations. Most participants found the application easy to use. They learned tips for taking their medication, diminishing adverse side-effects and maintaining a positive attitude towards treatment. Many participants deemed their experience with the application highly satisfactory and felt that it met their needs with respect to strategies and proficiencies despite their long experience of medication use. The results of the study support the feasibility and acceptability of the intervention.
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In vitro and structural evaluation of PL-100 as a potential second-generation HIV-1 protease inhibitor.
J. Antimicrob. Chemother.
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HIV-1 protease inhibitors (PIs) are key components of HIV therapy. PL-100 is a novel lysine sulphonamide that demonstrates potent antiviral activity against multiresistant HIV-1 strains as well as a higher genetic barrier for development of resistance mutations compared with first-generation PIs. In the present study, we compared the antiviral activity of PL-100 against HIV-1 subtype B with that of darunavir.
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CD160 and PD-1 co-expression on HIV-specific CD8 T cells defines a subset with advanced dysfunction.
PLoS Pathog.
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Chronic viral infections lead to persistent CD8 T cell activation and functional exhaustion. Expression of programmed cell death-1 (PD-1) has been associated to CD8 T cell dysfunction in HIV infection. Herein we report that another negative regulator of T cell activation, CD160, was also upregulated on HIV-specific CD8 T lymphocytes mostly during the chronic phase of infection. CD8 T cells that expressed CD160 or PD-1 were still functional whereas co-expression of CD160 and PD-1 on CD8 T cells defined a novel subset with all the characteristics of functionally exhausted T cells. Blocking the interaction of CD160 with HVEM, its natural ligand, increased HIV-specific CD8 T cell proliferation and cytokine production. Transcriptional profiling showed that CD160(-)PD-1(+)CD8 T cells encompassed a subset of CD8(+) T cells with activated transcriptional programs, while CD160(+)PD-1(+) T cells encompassed primarily CD8(+) T cells with an exhausted phenotype. The transcriptional profile of CD160(+)PD-1(+) T cells showed the downregulation of the NF?B transcriptional node and the upregulation of several inhibitors of T cell survival and function. Overall, we show that CD160 and PD-1 expressing subsets allow differentiating between activated and exhausted CD8 T cells further reinforcing the notion that restoration of function will require multipronged approaches that target several negative regulators.
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Foxo3a: an integrator of immune dysfunction during HIV infection.
Cytokine Growth Factor Rev.
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Chronic HIV infection, which is primarily characterized by the progressive depletion of total CD4(+) T cells, also causes persistent inflammation and immune activation. This is followed by profound changes in cellular and tissue microenvironments that often lead to prolonged immune dysfunction. The global nature of this immune dysfunction suggests that factors that are involved in immune cell survival, proliferation, differentiation and maturation are all affected. Of particular interest is the transcriptional factor Foxo3a that regulates a number of genes that are critical in the development and the maintenance of T and B cells, dendritic cells (DCs) and macrophages. Alterations in the microenvironment mediated by HIV infection cause significant increase in the transcriptional activity of Foxo3a; this has major impact on T cell and B cell immunity. In fact, recent findings from HIV infected individuals highlight three important points: (1) the alteration of Foxo3a signaling during HIV infection deregulates innate and adaptive immune responses; (2) Foxo3a-mediated effects are reversible and could be restored by interfering with the Foxo3a pathway; and (3) down-regulation of Foxo3a transcriptional activity in elite controllers (ECs) represents a molecular signature, or a correlate of immunity, associated with natural protection and lack of disease progression. In this review, we will discuss how HIV-infection altered microenvironments could result in impaired immune responses via the Foxo3a signaling pathway. Defining precisely the molecular mechanisms of how persistent inflammation and immune activation are able to influence the Foxo3a pathway could ultimately help in the development of novel approaches to improve immune responses in HIV infected subjects.
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Antiviral drug resistance and the need for development of new HIV-1 reverse transcriptase inhibitors.
Antimicrob. Agents Chemother.
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Highly active antiretroviral therapy (HAART) consists of a combination of drugs to achieve maximal virological response and reduce the potential for the emergence of antiviral resistance. Despite being the first antivirals described to be effective against HIV, reverse transcriptase inhibitors remain the cornerstone of HAART. There are two broad classes of reverse transcriptase inhibitor, the nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). Since the first such compounds were developed, viral resistance to them has inevitably been described; this necessitates the continuous development of novel compounds within each class. In this review, we consider the NRTIs and NNRTIs currently in both preclinical and clinical development or approved for second-line therapy and describe the patterns of resistance associated with their use as well as the underlying mechanisms that have been described. Due to reasons of both affordability and availability, some reverse transcriptase inhibitors with a low genetic barrier are more commonly used in resource-limited settings. Their use results in the emergence of specific patterns of antiviral resistance and so may require specific actions to preserve therapeutic options for patients in such settings.
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Risk of spontaneous intracranial hemorrhage in HIV-infected individuals: a population-based cohort study.
J Stroke Cerebrovasc Dis
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We studied the association between HIV infection, antiretroviral medications, and the risk of spontaneous intracranial hemorrhage.
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The colocalization potential of HIV-specific CD8+ and CD4+ T-cells is mediated by integrin ?7 but not CCR6 and regulated by retinoic acid.
PLoS ONE
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CD4(+) T-cells from gut-associated lymphoid tissues (GALT) are major targets for HIV-1 infection. Recruitment of excess effector CD8(+) T-cells in the proximity of target cells is critical for the control of viral replication. Here, we investigated the colocalization potential of HIV-specific CD8(+) and CD4(+) T-cells into the GALT and explored the role of retinoic acid (RA) in regulating this process in a cohort of HIV-infected subjects with slow disease progression. The expression of the gut-homing molecules integrin ?7, CCR6, and CXCR3 was identified as a "signature" for HIV-specific but not CMV-specific CD4(+) T-cells thus providing a new explanation for their enhanced permissiveness to infection in vivo. HIV-specific CD8(+) T-cells also expressed high levels of integrin ?7 and CXCR3; however CCR6 was detected at superior levels on HIV-specific CD4(+) versus CD8(+) T-cells. All trans RA (ATRA) upregulated the expression of integrin ?7 but not CCR6 on HIV-specific T-cells. Together, these results suggest that HIV-specific CD8(+) T-cells may colocalize in excess with CD4(+) T-cells into the GALT via integrin ?7 and CXCR3, but not via CCR6. Considering our previous findings that CCR6(+)CD4(+) T-cells are major cellular targets for HIV-DNA integration in vivo, a limited ability of CD8(+) T-cells to migrate in the vicinity of CCR6(+)CD4(+) T-cells may facilitate HIV replication and dissemination at mucosal sites.
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Inhibitory Killer Immunoglobulin-like Receptors to self HLA-B and HLA-C ligands contribute differentially to Natural Killer cell functional potential in HIV infected slow progressors.
Clin. Immunol.
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Inhibitory Killer Immunoglobulin-like Receptors (iKIR) interact with their ligands, HLA molecules, to license Natural Killer (NK) cells for functional competence. Previous studies stimulating peripheral blood mononuclear cells (PBMCs) with the HLA-devoid K562 cell line revealed that NK cells from individuals with an iKIR encoded by the KIR3DL1 locus with self HLA-Bw4 as their ligands, had higher frequencies of tri-functional NK cells that expressed the degranulation marker CD107a and secreted Interferon-? and Tumor Necrosis Factor-? than those from individuals who were homozygous for HLA-Bw6 alleles, which are not ligands for these iKIR. To assess the effect of other iKIR to self-HLA (S-iKIR) on the NK cell response, we compared HIV-infected slow progressors (SP) carrying S-iKIR to HLA-C alleles with or without S-iKIR to HLA-Bw4. We show that S-iKIR to HLA-B and C alleles differ in their contribution to NK cell functional potential in HIV-infected SP upon stimulation with K562 targets.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.