Cumulative insults to mitochondrial function may promote the emergence of 'syndrome X' and diabetes mellitus in HIV/HCV co-infected patients

The 'metabolic syndrome' or 'syndrome X' affects approximately a quarter of the general population of the United States. A significant number of patients, therefore, may have predisposing risk factors for developing 'syndrome X' and/or diabetes mellitus (DM) prior to HIV infection, hepatitis C (HCV) infection, and/or institution of highly active antiretroviral therapy (HAART). Metabolic perturbations identical to 'syndrome X' develop in many HIV-infected patients who are undergoing HAART. A series of cumulative and possibly synergistic insults to mitochondrial function which occur in HIV/HCV co-infected patients who are receiving HAART may promote the emergence of 'syndrome X' and DM. HIV-infected patients, especially those who are co-infected with HCV and who are undergoing HAART, may, therefore, be at increased risk of developing the cardiovascular complications that are associated with 'syndrome X' and DM.     

Nanomedicines in the treatment of patients with hepatitis C co-infected with HIV--focus on pegylated interferon-alpha

In immuno-competent individuals, the natural course of chronic hepatitis C virus (HCV) infection is highly variable and 5%-30% of patients develop cirrhosis over 20 years. Co-infection with HCV and human immunodeficiency virus (HIV) is an important prognostic factor and associated with more frequent and accelerated progression to cirrhosis. Until recently HIV/AIDS-related complications were life limiting in patients co-infected with HCV; the introduction of highly active antiretroviral treatment (HAART) and the better prognosis of HIV infection has made HCV-related complications an emerging health problem in HCV/HIV coinfected individuals. Treatment of chronic HCV infection has also evolved since the introduction of interferon-alpha. Recently, introduction of pegylated interferon-alpha (peginterferon-alpha) has resulted in an increase in sustained virus clearance rates of up to 80% in selected genotypes and patient populations. The safety and efficacy of modern anti HCV treatment regimens - based on peginterferon-alpha in combination with ribavirin - was evaluated in 4 controlled trials. Sustained clearance of hepatitis C virus can be achieved in up to 35% of patients with HIV/HCV co-infection, and novel HCV treatment regimens based on peginterferon-alpha have no negative effect on the control of HIV disease. In conclusion, if HIV infection is well controlled and CD4+ cell counts >100/mm3, treatment of chronic hepatitis C with peginterferon in combination with ribavirin is safe and should be given for 48 weeks regardless of the HCV genotype. Introduction of peginterferon-alpha has significantly improved adherence to treatment and treatment efficacy; in particular sustained virologic response in patients with HCV genotype 1 or 4 infection improved, but sustained viral clearance in only 7%-38% of patients infected with genotype I and 4 cannot be the final step in development of effective treatments in patients with HCV/HIV co-infection.     

Is Antiretroviral Therapy Causing Long-Term Liver Damage? A Comparative Analysis of HIV-Mono-Infected and HIV/Hepatitis C Co-Infected Cohorts

The effects of highly active antiretroviral therapy (HAART) on progression of hepatic fibrosis in HIV-hepatitis C virus (HCV) co-infection are not well understood. Deaths from liver diseases have risen in the post-HAART era, yet some cross-sectional studies have suggested that HAART use is associated with improved fibrosis rates. In a retrospective cohort of 533 HIV mono-infected and 127 HIV/HCV co-infected patients, followed between January 1991 and July 2005 at a university-based HIV clinic, we investigated the relationship between cumulative HAART exposure and hepatic fibrosis, as measured by the aspartate aminotransferase-to-platelet ratio index (APRI). We used a novel methodological approach to estimate the dose-response relationship of the effect of HAART exposure on APRI. HAART was associated with increasing APRI over time in HIV/HCV co-infected patients suggesting that they may be experiencing cumulative hepatotoxicity from antiretrovirals. The estimated median change (95% confidence interval) in APRI per one year of HAART intake was of −0.46% (−1.61% to 0.71%) in HIV mono-infected compared to 2.54% (−1.77% to 7.03%) in HIV/HCV co-infected patients. Similar results were found when the direct effect of HAART intake since the last visit was estimated on the change in APRI. HAART use associated is with increased APRI in patients with HIV/HCV co-infection. Therefore treatment for HCV infection may be required to slow the growing epidemic of end-stage liver disease in this population.     

Association between Use of HMG CoA Reductase Inhibitors and Mortality in HIV-Infected Patients

Introduction

HIV infection is a disease associated with chronic inflammation and immune activation. Antiretroviral therapy reduces inflammation, but not to levels in comparable HIV-negative individuals. The HMG-coenzyme A reductase inhibitors (statins) inhibit several pro-inflammatory processes and suppress immune activation, and are a logical therapy to assess for a possible salutary effect on HIV disease progression and outcomes.

Methods

Eligible patients were patients enrolled in the Johns Hopkins HIV Clinical Cohort who achieved virologic suppression within 180 days of starting a new highly active antiretroviral therapy (HAART) regimen after January 1, 1998. Assessment was continued until death in patients who maintained a virologic suppression, with right-censoring of their follow-up time if they had an HIV RNA > 500 copies/ml. Cox proportional hazards regression was used to assess statin use as a time-varying covariate, as well as other demographic and clinical factors.

Results

A total of 1538 HIV-infected patients fulfilled eligibility criteria, of whom 238 (15.5%) received a statin while taking HAART. There were 85 deaths (7 in statin users, 78 in non-users). By multivariate Cox regression, statin use was associated with a relative hazard of 0.33 (95% CI: 0.14, 0.76; P = 0.009) after adjusting for CD4, HIV-1 RNA, hemoglobin and cholesterol levels at the start of HAART, age, race, HIV risk group, prior use of ART, year of HAART start, NNRTI vs. PI-based ART, prior AIDS-defining illness, and viral hepatitis coinfection. Malignancy, non-AIDS-defining infection and liver failure were particularly prominent causes of death.

Discussion

Statin use was associated with significantly lower hazard of dying in these HIV-infected patients who were being effectively treated with HAART as determined by virologic suppression. Our results suggest the need for confirmation in other observational cohorts, and if confirmed, the need for a clinical trial of statin use in HIV infection.     

High prevalence of hypertension and placental insufficiency, but no in utero HIV transmission, among women on HAART with stillbirths in Botswana

Background

Increased stillbirth rates occur among HIV-infected women, but no studies have evaluated the pathological basis for this increase, or whether highly active antiretroviral therapy (HAART) influences the etiology of stillbirths. It is also unknown whether HIV infection of the fetus is associated with stillbirth.

Methods

HIV-infected women and a comparator group of HIV-uninfected women who delivered stillbirths were enrolled at the largest referral hospital in Botswana between January and November 2010. Obstetrical records, including antiretroviral use in pregnancy, were extracted at enrollment. Verbal autopsies; maternal HIV, CD4 and HIV RNA testing; stillbirth HIV PCR testing; and placental pathology (blinded to HIV and treatment status) were performed.

Results

Ninety-nine stillbirths were evaluated, including 62 from HIV-infected women (34% on HAART from conception, 8% on HAART started in pregnancy, 23% on zidovudine started in pregnancy, and 35% on no antiretrovirals) and 37 from a comparator group of HIV-uninfected women. Only 2 (3.7%) of 53 tested stillbirths from HIV-infected women were HIV PCR positive, and both were born to women not receiving HAART. Placental insufficiency associated with hypertension accounted for most stillbirths. Placental findings consistent with chronic hypertension were common among HIV-infected women who received HAART and among HIV-uninfected women (65% vs. 54%, p = 0.37), but less common among HIV-infected women not receiving HAART (28%, p = 0.003 vs. women on HAART).

Conclusions

In utero HIV infection was rarely associated with stillbirths, and did not occur among women receiving HAART. Hypertension and placental insufficiency were associated with most stillbirths in this tertiary care setting.     

Elite suppressors harbor low levels of integrated HIV DNA and high levels of 2-LTR circular HIV DNA compared to HIV+ patients on and off HAART

Elite suppressors (ES) are a rare population of HIV-infected individuals that are capable of naturally controlling the infection without the use of highly active anti-retroviral therapy (HAART). Patients on HAART often achieve viral control to similar (undetectable) levels. Accurate and sensitive methods to measure viral burden are needed to elucidate important differences between these two patient populations in order to better understand their mechanisms of control. Viral burden quantification in ES patients has been limited to measurements of total DNA in PBMC, and estimates of Infectious Units per Million cells (IUPM). There appears to be no significant difference in the level of total HIV DNA between cells from ES patients and patients on HAART. However, recovering infectious virus from ES patient samples is much more difficult, suggesting their reservoir size should be much smaller than that in patients on HAART. Here we find that there is a significant difference in the level of integrated HIV DNA in ES patients compared to patients on HAART, providing an explanation for the previous results. When comparing the level of total to integrated HIV DNA in these samples we find ES patients have large excesses of unintegrated HIV DNA. To determine the composition of unintegrated HIV DNA in these samples, we measured circular 2-LTR HIV DNA forms and found ES patients frequently have high levels of 2-LTR circles in PBMC. We further show that these high levels of 2-LTR circles are not the result of inefficient integration in ES cells, since HIV integrates with similar efficiency in ES and normal donor cells. Our findings suggest that measuring integration provides a better surrogate of viral burden than total HIV DNA in ES patients. Moreover, they add significantly to our understanding of the mechanisms that allow viral control and reservoir maintenance in this unique patient population.     

Accelerated Immunodeficiency by Anti-CCR5 Treatment in HIV Infection

In 50% of progressing HIV-1 patients, CXCR4-tropic (X4) virus emerges late in infection, often overtaking CCR5-tropic (R5) virus as the dominant viral strain. This “phenotypic switch” is strongly associated with rapidly declining CD4⁺ T cell counts and AIDS onset, yet its causes remain unknown. Here, we analyze a mathematical model for the mechanism of X4 emergence in late-stage HIV infection and use this analysis to evaluate the utility of a promising new class of antiretroviral drugs—CCR5 inhibitors—in dual R5, X4 infection. The model shows that the R5-to-X4 switch occurs as CD4⁺ T cell activation levels increase above a threshold and as CD4⁺ T cell counts decrease below a threshold during late-stage HIV infection. Importantly, the model also shows that highly active antiretroviral therapy (HAART) can inhibit X4 emergence but that monotherapy with CCR5 blockers can accelerate X4 onset and immunodeficiency if X4 infection of memory CD4⁺ T cells occurs at a high rate. Fortunately, when CXCR4 blockers or HAART are used in conjunction with CCR5 blockers, this risk of accelerated immunodeficiency is eliminated. The results suggest that CCR5 blockers will be more effective when used in combination with CXCR4 blockers and caution against CCR5 blockers in the absence of an effective HAART regimen or during HAART failure.     

Interactions between HIV infection and chronic obstructive pulmonary disease: Clinical and epidemiological aspects

Introduction

An association between HIV infection and chronic obstructive pulmonary disease (COPD) has been observed in several studies.

Objective and methods

we conducted a review of the literature linking HIV infection to COPD, focusing on clinical and epidemiological data published before and during widespread highly active antiretroviral therapy (HAART).

Results

Interactions between HIV infection and COPD appear to be influenced by multiple factors. In particular, the bronchopulmonary tract can be damaged by HIV infection, the immunodeficiency it induces, and the resulting increase in the risk of pulmonary infections. In addition, the prevalence of smoking and intravenous drug use is higher in HIV-infected populations, also increasing the risk of COPD. Before the advent of HAART, respiratory tract infections probably played a major role. Since the late 1990s and the widespread use of HAART, the frequency of opportunistic infections has fallen but new complications have emerged as life expectancy has increased.

Conclusion

given the high prevalence of smoking among HIV-infected patients, COPD may contribute significantly to morbidity and mortality in this setting.     

Replication-competent simian immunodeficiency virus (SIV) Gag escape mutations archived in latent reservoirs during antiretroviral treatment of SIV-infected macaques

In response to pressure exerted by major histocompatibility complex (MHC) class I-mediated CD8(+) T cell control, human immunodeficiency virus (HIV) escape mutations often arise in immunodominant epitopes recognized by MHC class I alleles. While the current standard of care for HIV-infected patients is treatment with highly active antiretroviral therapy (HAART), suppression of viral replication in these patients is not absolute and latently infected cells persist as lifelong reservoirs. To determine whether HIV escape from MHC class I-restricted CD8(+) T cell control develops during HAART treatment and then enters latent reservoirs in the periphery and central nervous system (CNS), with the potential to emerge as replication-competent virus, we tracked the longitudinal development of the simian immunodeficiency virus (SIV) Gag escape mutation K165R in HAART-treated SIV-infected pigtailed macaques. Key findings of these studies included: (i) SIV Gag K165R escape mutations emerged in both plasma and cerebrospinal fluid (CSF) during the decaying phase of viremia after HAART initiation before suppression of viral replication, (ii) SIV K165R Gag escape mutations were archived in latent proviral DNA reservoirs, including the brain in animals receiving HAART that suppressed viral replication, and (iii) replication-competent SIV Gag K165R escape mutations were present in the resting CD4(+) T cell reservoir in HAART-treated SIV-infected macaques. Despite early administration of aggressive antiretroviral treatment, HIV immune escape from CD8(+) T cell control can still develop during the decaying phases of viremia and then persist in latent reservoirs, including the brain, with the potential to emerge if HAART therapy is interrupted.     

Plasma cholesterol efflux capacity from human THP-1 macrophages is reduced in HIV-infected patients: impact of HAART

The capacity of HDL to remove cholesterol from macrophages is inversely associated with the severity of angiographic coronary artery disease. The effect of human immunodeficiency virus (HIV) infection or its treatment on the ability of HDL particles to stimulate cholesterol efflux from human macrophages has never been studied. We evaluated the capacity of whole plasma and isolated HDL particles from HIV-infected subjects (n = 231) and uninfected controls (n = 200), as well as in a subset of 41 HIV subjects receiving highly active antiretroviral therapy (HAART) to mediate cholesterol efflux from human macrophages. Plasma cholesterol efflux capacity was reduced (−12%; P = 0.001) in HIV patients as compared with controls. HIV infection reduced by 27% (P < 0.05) the capacity of HDL subfractions to promote cholesterol efflux from macrophages. We observed a reduced ABCA1-dependent efflux capacity of plasma (−27%; P < 0.0001) from HIV-infected subjects as a result of a reduction in the efflux capacity of HDL3 particles. HAART administration restored the capacity of plasma from HIV patients to stimulate cholesterol efflux from human macrophages (9.4%; P = 0.04). During HIV infection, the capacity of whole plasma to remove cholesterol from macrophages is reduced, thus potentially contributing to the increased coronary heart disease in the HIV population. HAART administration restored the removal of cholesterol from macrophages by increasing HDL functionality.     

Mechanisms of lipid elevations associated with the treatment of patients with HIV infection

OBJECTIVE: Dyslipidemia and other metabolic abnormalities, which are associated with the use of highly active antiretroviral therapy (HAART) for the treatment of HIV infection, are of concern to patients and healthcare providers. The objective of this review is to present the current understanding of the dyslipidemia associated with the protease inhibitor (PI)-component of HAART: its possible origin, potential consequences, and management techniques. DATA SOURCES, STUDY SELECTION: Peer-reviewed, published literature was identified via MEDLINE. Other sources included abstracts from recent HIV-related conferences that presented data pertinent to the topic. Studies were selected based on their impact on our understanding of HIV infection and its treatment. DATA EXTRACTION, SYNTHESIS: Relevant portions of the publications considered were compiled and conclusions were drawn based on the clinical experience of the author. CONCLUSION: Dyslipidemia associated with current PIs should be a serious consideration when initiating long-term treatment of HIV infection. Current management techniques that include lipid-lowering agents may be improved and streamlined by incorporating a lipid-friendly PI into HAART.     

Hypovitaminosis D and Bone Mineral Density in Human Immunodeficiency Virus-Infected Men from India,with or without Antiretroviral Therapy

ObjectiveTo study the vitamin D status and bone mineral density (BMD) in men infected with human immunodeficiency virus (HIV) in a tertiary care center from southern India.MethodsWe conducted a cross-sectional study of 35 HIV-infected men (between 20 and 50 years old) receiving highly active antiretroviral therapy (HAART) (group 1) in comparison with 35 ageand body mass index-matched HIV-positive antiretroviral therapy-naïve men (group 2) and 35 HIV-negative healthy control subjects (group 3).ResultsA significantly greater proportion (P = .002) of patients (74%) in the HAART group had vitamin D deficiency (< 20 ng/mL) in comparison with the other 2 groups (37% in each group). The mean intact parathyroid hormone level was higher (P < .001) and the mean duration of exposure to sunlight was lower (P = .001) in the HAART group than in the other 2 groups. By logistic regression analysis, HAART was found to be significantly associated with vitamin D deficiency. The BMD in the femoral neck was significantly lower in men with HIV infection who were receiving HAART in comparison with the other 2 groups (P = .006). On multivariate logistic regression, older age, low body mass index, and high parathyroid hormone levels emerged as factors significantly associated with decreased BMD at the femoral neck.ConclusionA significant proportion of patients receiving HAART had vitamin D deficiency. The secondary hyperparathyroidism probably due to vitamin D deficiency is an important contributing factor for the observed changes in BMD. Vitamin D deficiency noted in this group is probably multifactorial, and further research is needed to determine whether the effect of HAART on vitamin D metabolism is an additional causative factor and what benefit vitamin D supplementation might confer in these patients. (Endocr Pract. 2010;16:547-553)     

Association between Highly Active Antiretroviral Therapy and Type of Infectious Respiratory Disease and All-Cause In-Hospital Mortality in Patients with HIV/AIDS: A Case Series

Background

Respiratory manifestations of HIV disease differ globally due to differences in current availability of effective highly active antiretroviral therapy (HAART) programs and epidemiology of infectious diseases.

Objective

To describe the association between HAART and discharge diagnosis and all-cause in-hospital mortality among hospitalized patients with infectious respiratory disease and HIV/AIDS.

Material and Methods

We retrospectively reviewed the records of patients hospitalized at a specialty hospital for respiratory diseases in Mexico City between January 1st, 2010 and December 31st, 2011. We included patients whose discharge diagnosis included HIV or AIDS and at least one infectious respiratory diagnosis. The information source was the clinical chart. We analyzed the association between HAART for 180 days or more and type of respiratory disease using polytomous logistic regression and all-cause hospital mortality by multiple logistic regressions.

Results

We studied 308 patients, of whom 206 (66.9%) had been diagnosed with HIV infection before admission to the hospital. The CD4+ lymphocyte median count was 68 cells/mm³ [interquartile range (IQR): 30–150]. Seventy-five (24.4%) cases had received HAART for more than 180 days. Pneumocystis jirovecii pneumonia (PJP) (n = 142), tuberculosis (n = 63), and bacterial community-acquired pneumonia (n = 60) were the most frequent discharge diagnoses. Receiving HAART for more than 180 days was associated with a lower probability of PJP [Adjusted odd ratio (aOR): 0.245, 95% Confidence Interval (CI): 0.08–0.8, p = 0.02], adjusted for sociodemographic and clinical covariates. HAART was independently associated with reduced odds (aOR 0.214, 95% CI 0.06–0.75) of all-cause in-hospital mortality, adjusting for HIV diagnosis previous to hospitalization, age, access to social security, low socioeconomic level, CD4 cell count, viral load, and discharge diagnoses.

Conclusions

HAART for 180 days or more was associated with 79% decrease in all-cause in-hospital mortality and lower frequency of PJP as discharge diagnosis. The prevalence of poorly controlled HIV was high, regardless of whether HIV was diagnosed before or during admission. HIV diagnosis and treatment resources should be improved, and strengthening of HAART program needs to be promoted.     

Viral suppression and immune restoration in the gastrointestinal mucosa of human immunodeficiency virus type 1-infected patients initiating therapy during primary or chronic infection

Although the gut-associated lymphoid tissue (GALT) is an important early site for human immunodeficiency virus (HIV) replication and severe CD4+ T-cell depletion, our understanding is limited about the restoration of the gut mucosal immune system during highly active antiretroviral therapy (HAART). We evaluated the kinetics of viral suppression, CD4+ T-cell restoration, gene expression, and HIV-specific CD8+ T-cell responses in longitudinal gastrointestinal biopsy and peripheral blood samples from patients initiating HAART during primary HIV infection (PHI) or chronic HIV infection (CHI) using flow cytometry, real-time PCR, and DNA microarray analysis. Viral suppression was more effective in GALT of PHI patients than CHI patients during HAART. Mucosal CD4+ T-cell restoration was delayed compared to peripheral blood and independent of the time of HAART initiation. Immunophenotypic analysis showed that repopulating mucosal CD4+ T cells were predominantly of a memory phenotype and expressed CD11 alpha, alpha(E)beta 7, CCR5, and CXCR4. Incomplete suppression of viral replication in GALT during HAART correlated with increased HIV-specific CD8+ T-cell responses. DNA microarray analysis revealed that genes involved in inflammation and cell activation were up regulated in patients who did not replenish mucosal CD4+ T cells efficiently, while expression of genes involved in growth and repair was increased in patients with efficient mucosal CD4+ T-cell restoration. Our findings suggest that the discordance in CD4+ T-cell restoration between GALT and peripheral blood during therapy can be attributed to the incomplete viral suppression and increased immune activation and inflammation that may prevent restoration of CD4+ T cells and the gut microenvironment.     

Comparison of epigenetic profiles of human oral epithelial cells from HIV-positive (on HAART) and HIV-negative subjects

HIV-infected subjects on highly active antiretroviral therapy (HAART) are susceptible to comorbid microbial infections in the oral cavity. We observed that primary oral epithelial cells (POECs) isolated from HIV+ subjects on HAART grow more slowly and are less innate immune responsive to microbial challenge when compared with POECs from normal subjects. These aberrant cells also demonstrate epigenetic differences that include reduction in histone deacetylase 1 (HDAC-1) levels and reduced total DNA methyltransferase (DNMT) activity specific to enzymes DNMT1 and DNMT3A. The DNMT activity correlates well with global DNA methylation, indicating that aberrant DNMT activity in HIV+ (on HAART) POECs leads to an aberrantly methylated epithelial cell phenotype. Overall, our results lead us to hypothesize that, in patients with chronic HIV infection on HAART, epigenetic changes in key genes result in increased vulnerability to microbial infection in the oral cavity.     

Early production of HIV-1 neutralising antibodies in patients following highly active antiretroviral treatment (HAART) during primary HIV infection

We investigate the effects of highly active antiretroviral therapy (HAART) on humoral immune responses during a 24-month follow up of 15 HIV patients with acute primary HIV infection. The patients were divided into three groups on the basis of the therapeutic protocol they were following at the time of entry: a) five naive patients (untreated or treated with only ZDV or AZT); b) five patients following a triple combination of ZDV+ lamivudine (3TC)+ saquinovir (SQV); and c) five patients on a four-drug combination of ZDV+3TC+SQV+ ritonavir (RTV). The results show that the early introduction of HAART greatly reduces plasma viremia levels and restores the number of CD4 cells. A significant correlation was found between anti HIV neutralising activity and the four-drug, but not the three-drug combination. The reduction in infectivity was directed against viruses of different clades and associated with immunoglobulin fractions. Moreover, the neutralising antibodies in the HAART-treated patients appeared after two weeks of treatment and remained stable throughout the 24 months of follow up. The early appearance of neutralising antibodies represent an important component of immune responses during primary HIV infection, may contribute towards immune reconstitution in patients on HAART, and give further information that may be useful in developing new strategies designed to eradicate the disease.     

Interleukin-15 modulates interferon-gamma and beta-chemokine production in patients with HIV infection: implications for immune-based therapy

Interleukin (IL)-15 is a cytokine that has lymphocyte stimulatory activity similar to that of IL-2, and plays important immunoregulatory functions during HIV disease. To evaluate the role of IL-15 in HIV infection the following patients were studied: 18 antiretroviral-naive patients with advanced disease; 19 patients with continuous viral suppression and immunological response after 48-120 weeks of highly active antiretroviral therapy (HAART); and 12 patients with evidence of virological and immunological HAART treatment failure. Nineteen healthy blood donors were included as controls. The production of IL-15 by human peripheral blood monocytes stimulated with lipopolysaccharide and Mycobacterium avium complex, the priming effect of IL-15 on IFN-gamma production from purified CD4(+) and CD8(+) T cells, and the ability of IL-15 to stimulate the beta-chemokine release from purified CD4(+) and CD8(+) T cells were analyzed. In the present work IL-15 production by human peripheral blood monocytes was significantly increased in HIV-infected patients with long-term virological and immunological response to HAART. IL-15 enhanced the in vitro priming of CD4(+) and CD8(+) T cells for IFN-gamma production, also in patients receiving HAART. Finally, IL-15 had positive effects on RANTES, MIP-1alpha, and MIP-1beta release by CD4(+) and CD8(+) T cells. In conclusion IL-15 could affect the immune response of HIV-infected patients by augmenting and/or modulating IFN-gamma production and beta-chemokine release. These data about functional properties of IL-15 could provide new implications for immune-based therapies in HIV infection.     

Frequency of circulating regulatory T cells increases during chronic HIV infection and is largely controlled by highly active antiretroviral therapy

Regulatory T cells (Tregs) act by suppressing the activation and effector functions of innate and adaptive immune responses. HIV infection impacts Treg proportion and phenotype, although discrepant results have been reported depending on the patient population and the way Tregs were characterized. The effects of highly active antiretroviral therapy (HAART) on Treg frequency have not been thoroughly documented. We performed a detailed longitudinal analysis of Treg frequency and phenotype in 11 HIV-infected individuals enrolled in a single, prospective clinical trial, in which all patients underwent the same treatment protocol and were sampled at the same time points. Tregs were characterized for their expression of molecules associated with activation, cell cycle, apoptosis, or function, and compared to circulating Tregs from a group of age-matched healthy individuals.Our results revealed increased proportions, but reduced absolute numbers of circulating CD3(+)CD4(+)FOXP3(+) Tregs in chronically infected HIV-infected patients. Treg frequency was largely normalized by HAART. Importantly, we show that similar conclusions were drawn regardless of the combination of markers used to define Tregs. Our results also showed increased expression of cell cycle markers (Ki67 and cyclin B) in Tregs from untreated infected individuals, which were decreased by HAART. However, the Treg phenotype in untreated patients was not consistent with a higher level of generalized activation, as they expressed very low levels of CD69, slightly elevated levels of HLA-DR and similar levels of GARP compared to Tregs from uninfected donors. Moreover, none of these markers was significantly changed by HAART. Treg expression of CTLA-4 and cytotoxic molecules was identical between patients and controls. The most striking difference in terms of functional molecules was the high expression of CD39 by Tregs in untreated patients, which HAART only partially controlled.     

Opportunistic infection as a cause of transient viremia in chronically infected HIV patients under treatment with HAART

When highly active antiretroviral therapy is administered for long periods of time to HIV-1 infected patients, most patients achieve viral loads that are “undetectable” by standard assay (i.e., HIV-1 RNA < 50 copies/ml). Yet despite exhibiting sustained viral loads below the level of detection, a number of these patients experience unexplained episodes of transient viremia or viral “blips”. We propose here that transient activation of the immune system by opportunistic infection may explain these episodes of viremia. Indeed, immune activation by opportunistic infection may spur HIV replication, replenish viral reservoirs and contribute to accelerated disease progression. In order to investigate the effects of intercurrent infection on chronically infected HIV patients under treatment with highly active antiretroviral therapy (HAART), we extend a simple dynamic model of the effects of vaccination on HIV infection [Jones, L.E., Perelson, A.S., 2002. Modeling the effects of vaccination on chronically infected HIV-positive patients. JAIDS 31, 369–377] to include growing pathogens. We then propose a more realistic model for immune cell expansion in the presence of pathogen, and include this in a set of competing models that allow low baseline viral loads in the presence of drug treatment. Programmed expansion of immune cells upon exposure to antigen is a feature not previously included in HIV models, and one that is especially important to consider when simulating an immune response to opportunistic infection. Using these models we show that viral blips with realistic duration and amplitude can be generated by intercurrent infections in HAART treated patients.     

Genetic characterization of rebounding human immunodeficiency virus type 1 in plasma during multiple interruptions of highly active antiretroviral therapy

Various strategies of interrupting highly active antiretroviral therapy (HAART) are being investigated for the treatment of human immunodeficiency virus (HIV) infection. Interruptions of greater than 2 weeks frequently result in rebound of plasma HIV RNA. In order to discern changes in the viral population that might occur during cycles of treatment interruption, we evaluated the homology of HIV-1 envelope gene sequences over time in 12 patients who received four to seven cycles of 4 weeks off HAART followed by 8 weeks on HAART by using the heteroduplex tracking assay and novel statistical tools. HIV populations in 9 of 12 patients diverged from those found in the first cycle in at least one subsequent cycle. The substantial genetic changes noted in HIV env did not correlate with increased or decreased log changes in levels of plasma HIV RNA (P > 0.5). Thus, genetic changes in HIV env itself did not contribute in a systematic way to changes in levels of plasma viremia from cycle to cycle of treatment interruption. In addition, the data suggest that there may be multiple compartments contributing to the rebound of plasma viremia and to viral diversity from cycle to cycle of intermittent therapy.