Treatment Interruptions in HIV-infected Subjects

The Journal of Antimicrobial Chemotherapy. Sep, 2006  |  Pubmed ID: 16816398

Despite a high antiviral efficacy, the use of highly active antiretroviral therapy (HAART) in clinical practice is often impaired by the long-term toxicity of antiretroviral treatment, the increased rate of human immunodeficiency virus-1 (HIV-1) drug resistance in treated patients and the cost of therapies, so that possible interruption of HAART has to be considered as part of the current clinical practice. However, this strategy is usually followed by a rapid viral rebound with a substantial loss of CD4 T lymphocytes because the HIV suppression with HAART does not result in reconstitution of the HIV-specific immune response. Structured treatment interruption (STI) has already been investigated in HIV-infected subjects with well-controlled viral replication (initiating treatment during primary or chronic HIV infection) and in those with multiple treatment failures. A clear benefit of STI in patients with chronic infection remains controversial and these benefits are more often observed in patients starting treatment during primary HIV infection.

FoxP3 MRNA Expression in Regulatory T Cells from Patients with Tuberculosis

American Journal of Respiratory and Critical Care Medicine. Aug, 2006  |  Pubmed ID: 16864720

Bone Diseases Associated with Human Immunodeficiency Virus Infection: Pathogenesis, Risk Factors and Clinical Management

Current Molecular Medicine. Jun, 2006  |  Pubmed ID: 16900662

Bone disorders such as osteopenia and osteoporosis have been recently reported in patients infected with the human immunodeficiency virus (HIV), but their etiology remains still unknown. The prevalence estimates vary widely among the different studies and can be affected by concomitant factors such as the overlapping of other possible conditions inducing bone loss as lypodystrophy, advanced HIV-disease, advanced age, low body weight or concomitant use of other drugs. All the reports at the moment available in the literature showed a higher than expected prevalence of reduced bone mineral density (BMD) in HIV-infected subjects both naïve and receiving potent antiretroviral therapy compared to healthy controls. This controversial can suggest a double role played by both antiretroviral drugs and HIV itself due to immune activation and/or cytokines disregulation. An improved understanding of the pathogenesis of bone disorders can result in better preventative and therapeutic measures. However, the clinical relevance and the risk of fractures remains undefined in HIV-population. The clinical management of osteopenia and osteoporosis in HIV-infected subjects is still being evaluated. Addressing potential underlying bone disease risk factors (e.g., smoking and alcohol intake, use of corticosteroids, advanced age, low body weight), evaluating calcium and vitamin D intake, and performing dual x-ray absorptiometry in HIV-infected individuals who have risk factors for bone disease can be important strategies to prevent osteopenia and osteoporosis in this population. The administration of bisphosphonates (e.g., alendronate), with calcium and vitamin D supplementation, may be a reasonable and effective option to treat osteoporosis in these subjects.

Subclinical Hypothyroidism in HIV-infected Subjects

The Journal of Antimicrobial Chemotherapy. Nov, 2006  |  Pubmed ID: 16950823

The correlation between subclinical hypothyroidism [thyroid stimulating hormone (TSH)>4 mIU/L with normal free triiodothyroxine and free thyroxine levels], HIV infection and HAART is still unclear.

Early Impairment of Gut Function and Gut Flora Supporting a Role for Alteration of Gastrointestinal Mucosa in Human Immunodeficiency Virus Pathogenesis

Journal of Clinical Microbiology. Feb, 2008  |  Pubmed ID: 18094140

Our results show that impairment of the gastrointestinal tracts in human immunodeficiency virus (HIV)-positive patients is present in the early phases of HIV disease. This impairment is associated with alterations in gut microbiota and intestinal inflammatory parameters. These findings support the hypothesis that alterations at the gastrointestinal-tract level are a key factor in HIV pathogenesis.

Untangling the Immunological Implications of Nadir on CD4+ Cell Recovery During Suppressive Highly Active Antiretroviral Therapy

Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. Jan, 2008  |  Pubmed ID: 18171234

Insulin Resistance Affects Early Virologic Response in HIV-infected Subjects Treated for Hepatitis C Infection

Journal of Acquired Immune Deficiency Syndromes (1999). Feb, 2008  |  Pubmed ID: 18223362

The Challenge of IL-2 Immunotherapy in HIV Disease: "no Through Road" or Turning Point?

Current HIV Research. May, 2008  |  Pubmed ID: 18473782

The perception of HAART failure in achieving broadest immune reconstitution has further strengthened the rationale to widely explore new adjuvant immunotherapy. Most work has been performed on IL-2, given its potential to correct HIV-driven immune defects, possibly translating in enhanced immune competency. This is a literature review report reviewing different trials on IL-2 immunotherapy in HIV/AIDS in the past ten years through the Cochrane and NIH review database. IL-2 can benefit severely compromised patients, either HAART-naïve or lacking HAART-driven immune rescue. Furthermore, by sparing HAART-related toxicity, IL-2 is indicated within treatment interruptions or immunization protocols. Important clinical insights stem from the IL-2-mediated immune reconstitution, with a rise in long-term peripheral T-cell turnover, survival and functional markers. Furthermore, IL-2 immunotherapy proved to interfere with cytokine networks with specific regulatory functions over T-cell homeostasis and function. Despite the plethora of immunological findings exploring the intriguing hypothesis that IL-2 might contribute to amend the skewed T-cell immunophenotype and cytokine milieu in HIV/AIDS, major question on the actual clinical impact remain unanswered. This review is meant to thoroughly explore the possibility that the immunological advantages described during IL-2 immunotherapy might translate into actual clinical benefits in the treatment of HIV/AIDS disease.

Serum Alpha-fetoprotein Levels Predict Early Virologic Response in HIV-positive Subjects Treated for Chronic Hepatitis C

Journal of Acquired Immune Deficiency Syndromes (1999). Jul, 2008  |  Pubmed ID: 18580339

Microbial Translocation is Associated with Sustained Failure in CD4+ T-cell Reconstitution in HIV-infected Patients on Long-term Highly Active Antiretroviral Therapy

AIDS (London, England). Oct, 2008  |  Pubmed ID: 18784466

Patients with inefficient CD4+ T-cell recovery on virogically suppressive highly active antiretroviral therapy constitute a major clinical hurdle given the threat of HIV/AIDS disease progression. We show heightened circulating lipopolysaccharide associated with plasma enterobacterial DNA and highly activated Ki67+CD4+CD8+ in 24 immunologic-nonresponders (CD4+ T-cell < or = 200; HIV-RNA < or = 50) compared with 11 full responders (CD4+ T-cell > or= 400; HIV-RNA < or = 50). These data provide novel insight into INRs pathogenesis, since they correlate augmented systemic translocation of microbial bioproducts with T-cell hyperactivation.

Abacavir and Cardiovascular Risk in HIV-infected Patients: Does T Lymphocyte Hyperactivation Exert a Pathogenic Role?

Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. Dec, 2008  |  Pubmed ID: 18986270

Sudden Cardiac Death in a Young HIV-positive Man on Effective Antiretroviral Therapy

Current HIV Research. Nov, 2008  |  Pubmed ID: 18991622

We describe the case of a young HIV-positive man on effective HAART with excellent viro-immunological control who presented a massive cardiac infarction. Despite the presence of clinical risk factors for cardiovascular disease, the patient had normal arterial carotid IMT values, known to be strong predictors of atherosclerosis and stroke. Interestingly, parameters of T-cell activation (CD8+CD38+) were shown to increase just before the onset of myocardial infarction. As T-cell activation is known to mediate atherosclerosis, the authors suggest that surrogate immunologic markers should be identified to better assess cardiovascular risk in the setting of HIV infection.

The Absence of CD4+ T Cell Count Recovery Despite Receipt of Virologically Suppressive Highly Active Antiretroviral Therapy: Clinical Risk, Immunological Gaps, and Therapeutic Options

Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. Feb, 2009  |  Pubmed ID: 19123868

Up to 30% of human immunodeficiency virus (HIV)-infected patients who are receiving long-term highly active antiretroviral therapy do not exhibit a marked increase in the CD4(+) T cell count, despite achieving complete suppression of the HIV load. These patients are referred to as "immunological nonresponders." When treating immunological nonresponders, the practicing clinician has several questions, including questions about the clinical risk associated with persistent immunodeficiency and about possible approaches to treatment that would provide clinical and immunological benefits. However, tentative answers to these questions require investigations of the mechanisms that underlie the lack of immune recovery, because only the deepest comprehension of the immunological gaps underlying functional defects will allow administration of highly targeted and efficacious treatment strategies. The aim of our review is to provide a thorough assessment of the clinical implications of a lack of increase in the CD4(+) T cell count in immunological nonresponders, to examine the immunological gaps limiting recovery of the CD4(+) T cell count, and to note possible therapeutic avenues, which may offer clinicians guidance regarding how to most efficaciously treat these critical patients.

Early Initiation of Highly Active Antiretroviral Therapy Fails to Reverse Immunovirological Abnormalities in Gut-associated Lymphoid Tissue Induced by Acute HIV Infection

Antiviral Therapy. 2009  |  Pubmed ID: 19474466

During the acute phase of HIV infection, large CD4+ T-cell depletion occurs in the gastrointestinal tract. The kinetics of CD4+ T-cell decrease and highly active antiretroviral therapy (HAART)-mediated immune reconstitution were evaluated.

CD8+ Hyperactivation and Senescence Correlate with Early Carotid Intima-media Thickness in HIV+ Patients with No Cardiovascular Disease

Journal of Acquired Immune Deficiency Syndromes (1999). Aug, 2009  |  Pubmed ID: 19628982

IL-2 Immunotherapy to Recently HIV-1 Infected Adults Maintains the Numbers of IL-17 Expressing CD4+ T (T(H)17) Cells in the Periphery

Journal of Clinical Immunology. Sep, 2010  |  Pubmed ID: 20571894

Little is known about the manipulation of IL-17 producing CD4+ T cells (T(H)17) on a per-cell basis in humans in vivo. Previous studies on the effects of IL-2 on IL-17 secretion in non-HIV models have shown divergent results. We hypothesized that IL-2 would mediate changes in IL-17 levels among recently HIV-1-infected adults receiving anti-retroviral therapy. We measured cytokine T cell responses to CD3/CD28, HIV-1 Gag, and CMV pp65 stimulation, and changes in multiple CD4+ T cell subsets. Those who received IL-2 showed a robust expansion of naive and total CD4+ T cell counts and T-reg counts. However, after IL-2 treatment, the frequency of T(H)17 cells declined, while counts of T(H)17 cells did not change due to an expansion of the CD4+ naïve T cell population (CD27+CD45RA+). Counts of HIV-1 Gag-specific T cells declined modestly, but CMV pp65 and CD3/CD28 stimulated populations did not change. Hence, in contrast with recent studies, our results suggest IL-2 is not a potent in vivo regulator of T(H)17 cell populations in HIV-1 disease. However, IL-2-mediated T-reg expansions may selectively reduce responses to certain antigen-specific populations, such as HIV-1 Gag.

Reduced CD127 Expression on Peripheral CD4+ T Cells Impairs Immunological Recovery in Course of Suppressive Highly Active Antiretroviral Therapy

AIDS (London, England). Oct, 2010  |  Pubmed ID: 20935556

Inefficient immune recovery under highly active antiretroviral therapy (HAART) represents a clinical issue. Twenty-seven of 121 HIV+ naïve patients became immunological nonresponders (INRs) and 55 introduced therapy late [very late treated (VLT)]. INR displayed older age, lower CD4(+) cell counts, down-regulation of CD127(+)CD4(+) and higher apoptotic CD95(+)CD8(+). VLT also showed higher activated CD38(+)CD8(+)%. The only factor associated with INR status was CD127(+)CD4(+)%. INR showed lower baseline interleukin (IL)-7 levels and a reduced expression of IL-7R (CD127(+)) on naïve and memory T-cells, reaching significance in memory CD127(+)CD45(+)R0(+)CD4(+). These results suggest a possible role for the IL-7/IL-7R system in the pathogenesis of poor immunological recovery during HAART.

A Comprehensive Ex Vivo Functional Analysis of Human NKT Cells Reveals Production of MIP1-α and MIP1-β, a Lack of IL-17, and a Th1-bias in Males

PloS One. 2010  |  Pubmed ID: 21082024

NKT cells contribute to the modulation of immune responses and are believed to be important in the pathogenesis of autoimmune and infectious diseases, as well as cancer. Variations in the composite NKT cytokine response may determine individual disease susceptibility or severity. Due to low frequencies in peripheral blood, knowledge of the breadth of ex vivo human NKT cell functions has been limited. To bridge this gap, we studied highly purified NKT cells from PBMC of healthy donors and assessed the production of 27 effector functions using sensitive Elispot and multiplex bead assays. We found the ex vivo human NKT cell response is predominantly comprised of the chemokines MIP1-α, and MIP1-β as well as the Th1 cytokines IFN-γ and TNF-α. Although lower in magnitude, there was also significant production of IL-2, IL-4, and perforin after mitogen stimulation. Surprisingly, little/no IL-5, IL-6, IL-10, or IL-13 was detected, and no subjects' NKT cells produced IL-17. Comparison of the NKT functional profiles between age-matched male and female subjects revealed similar IL-4 responses, but higher frequencies of cells producing IFN-γ and MIP1-α, from males. There were no gender differences in the circulating NKT subset distribution. These findings implicate chemokines as a major mechanism by which NKT cells control responses in humans. In addition, the panoply of Th2 and Th17 cytokine secretion by NKT cells from healthy donors may not be as pronounced as previously believed. NKT cells may therefore contribute to the gender bias found in many diseases.

Evidence for Polymicrobic Flora Translocating in Peripheral Blood of HIV-infected Patients with Poor Immune Response to Antiretroviral Therapy

PloS One. 2011  |  Pubmed ID: 21494598

In advanced HIV infection, the homeostatic balance between gastrointestinal indigenous bacteria and gut immunity fails and microbes are able to overcome the intestinal barrier and gain the systemic circulation. Because microbial translocation is not fully controlled by antiviral therapy and is associated with inefficient CD4+ reconstitution, we investigated the profile of translocating bacteria in peripheral blood of 44 HIV-infected patients starting therapy with advanced CD4+ T-lymphopenia and displaying poor CD4+ recovery on virologically suppressive HAART. According to CD4+ reconstitution at 12-months HAART, patients were considered Partial Immunological Responders, PIRs (CD4+≥250/µl, n = 29) and Immunological non Responders, INRs (CD4+<200/µl, n = 15)). We show that PIRs and INRs present similarly elevated plasma levels of lipopolysaccharide (LPS) and its ligand sCD14 that were not lowered by virologically suppressive therapy. Bacterial 16S rRNA gene amplification and sequencing resulted in a highly polymicrobic peripheral blood microbiota both prior and after 12-month HAART. Several differences in bacterial composition were shown between patients' groups, mainly the lack of probiotic Lactobacillaceae both prior and after therapy in INRs. Failure to control microbial translocation on HAART is associated with a polymicrobic flora circulating in peripheral blood that is not substantially modified by therapy.

Reduced Central Memory CD4+ T Cells and Increased T-Cell Activation Characterise Treatment-Naive Patients Newly Diagnosed at Late Stage of HIV Infection

AIDS Research and Treatment. 2012  |  Pubmed ID: 22110905

Objectives. We investigated immune phenotypes of HIV+ patients who present late, considering late presenters (LPs, CD4+ < 350/μL and/or AIDS), advanced HIV disease (AHD, CD4+ < 200/μL and/or AIDS), and AIDS presenters (AIDS-defining condition at presentation, independently from CD4+). Methods. Patients newly diagnosed with HIV at our clinic between 2007-2011 were enrolled. Mann-Whitney/Chi-squared tests and logistic regression were used for statistics. Results. 275 patients were newly diagnosed with HIV between January/2007-March/2011. 130 (47%) were LPs, 79 (29%) showed AHD, and 49 (18%) were AIDS presenters. LP, AHD, and AIDS presenters were older and more frequently heterosexuals. Higher CD8+%, lower CD127+CD4+%, higher CD95+CD8+%, CD38+CD8+%, and CD45R0+CD38+CD8+% characterized LP/AHD/AIDS presentation. In multivariate analysis, older age, heterosexuality, higher CD8+%, and lower CD127+CD4+% were confirmed associated with LP/AHD. Lower CD4+ and higher CD38+CD8+% resulted independently associated with AIDS presentation. Conclusions. CD127 downregulation and immune activation characterize HIV+ patients presenting late and would be studied as additional markers of late presentation.