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Immune activation associated with HIV-1 infection contributes to morbidity and mortality. We studied whether chloroquine, through Toll-like receptor (TLR) antagonist properties, could reduce immune activation thought to be driven by TLR ligands, such as gut-derived bacterial elements and HIV-1 RNAs. AIDS Clinical Trials Group A5258 was a randomized, double-blind, placebo-controlled study in 33 HIV-1-infected participants off antiretroviral therapy (ART) and 37 participants on ART. Study participants in each cohort were randomized 1:1 to receive chloroquine 250 mg orally for the first 12 weeks then cross over to placebo for 12 weeks or placebo first and then chloroquine. Combining the periods of chloroquine use in both arms of the on-ART cohort yielded a modest reduction in the proportions of CD8 T cells co-expressing CD38 and DR (median decrease = 3.0%, p = .003). The effect on immune activation in the off-ART cohort was likely confounded by increased plasma HIV-1 RNA during chloroquine administration (median 0.29 log10 increase, p

BACKGROUND: Herpes zoster (HZ) risk is increased in human immunodeficiency virus (HIV)–infected persons. Live attenuated zoster vaccine (ZV) reduces HZ incidence and severity in adults; safety and immunogenicity data in HIV-infected adults are limited. METHODS: We conducted a randomized, double-blind, placebo-controlled trial in HIV-infected adults virally suppressed on antiretroviral therapy (ART). Participants, stratified by CD4(+) count (200–349 or ≥350 cells/µL), were randomized 3:1 to receive ZV or placebo on day 0 and week 6. The primary endpoint was serious adverse event or grade 3/4 signs/symptoms within 6 weeks after each dose. Immunogenicity (varicella zoster virus [VZV]–specific glycoprotein enzyme-linked immunosorbent assay and interferon-γ enzyme-linked immunospot assay responses) was assessed at 6 and 12 weeks postvaccination. RESULTS: Of 395 participants (296 ZV vs 99 placebo), 84% were male, 47% white, 29% black, and 22% Hispanic; median age was 49 years. Safety endpoints occurred in 15 ZV and 2 placebo recipients (5.1% [95% confidence interval {CI}, 2.9%–8.2%] vs 2.1% [95% CI, .3%–7.3%]; P = .26). Injection site reactions occurred in 42% of ZV (95% CI, 36.3%–47.9%) vs 12.4% of placebo recipients (95% CI, 6.6%–20.6%) (P < .001). Week 12 median natural log VZV antibody titer was higher for ZV (6.30 [Q1, Q3, 5.64, 6.96]) vs placebo (5.48 [Q1, Q3, 4.63, 6.44]; P < .001) overall and in the high CD4(+) stratum (P = .003). VZV antibody titers were similar after 1 or 2 ZV doses. Polymerase chain reaction–confirmed HZ occurred in 2 participants (1 ZV; 1 placebo); none was vaccine strain related. CONCLUSIONS: Two doses of ZV in HIV-infected adults suppressed on ART with CD4(+) counts ≥200 cells/µL were safe and immunogenic. CLINICAL TRIALS REGISTRATION: NCT00851786.

Background HIV-1-infected individuals with plasma RNAMethods We evaluated factors associated with residual viraemia in patients on suppressive ART who underwent screening for a raltegravir intensification trial (ACTG A5244). The screened population was HIV-1-infected adults receiving ART for ≥12 months with pre-ART HIV-1 RNA>100,000 copies/ml and on-therapy RNA levels below detection limits of commercial assays for ≥6 months. Results Of 103 patients eligible for analysis, the median age was 46 years and the median duration of viral suppression was 4.8 years. 62% had detectable viraemia (>0.2 copies/ml) by SCA (median 0.2 copies/ml, IQR 2 years (median 2.3 versus 0.2 copies/ml; P=0.016). Conclusions Among HIV-1-infected patients with pre-ART HIV-1 RNA>100,000 copies/ml, residual viraemia was detectable in the majority (62%) despite many years of suppressive ART. Higher level viraemia was associated with older age and

IL-7 is essential for T-cell homeostasis. Elevated serum IL-7 levels in lymphopenic states, including HIV infection, are thought to be due to increased production by homeostatic feedback, decreased receptor-mediated clearance, or both. The goal of this study was to understand how immune reconstitution through antiretroviral therapy (ART) in HIV+ patients affects IL-7 serum levels, expression of the IL-7 receptor (CD127), and T-cell cycling. Immunophenotypic analysis of T cells from 29 HIV− controls and 43 untreated HIV+ patients (30 of whom were followed longitudinally for ≤ 24 months on ART) was performed. Restoration of both CD4+ and CD8+ T cells was driven by increases in CD127+ naive and central memory T cells. CD4+ T-cell subsets were not fully restored after 2 years of ART, whereas serum IL-7 levels normalized by 1 year of ART. Mathematical modeling indicated that changes in serum IL-7 levels could be accounted for by changes in the receptor concentration. These data suggest that T-cell restoration after ART in HIV infection is driven predominantly by CD127+ cells and that decreases of serum IL-7 can be largely explained by improved CD127-mediated clearance.

During acute human immunodeficiency virus (HIV) infection, there is a massive depletion of CD4 + T cells in the gut mucosa that can be reversed to various degrees with antiretroviral therapy. Th17 cells have been implicated in mucosal immunity to extracellular bacteria, and preservation of this subset may support gut mucosal immune recovery. However, this possibility has not yet been evaluated in HIV-1-infected long-term nonprogressors (LTNPs), who maintain high CD4 + T cell counts and suppress viral replication in the absence of antiretroviral therapy. In this study, we evaluated the immunophenotype and function of CD4 + T cells in peripheral blood and gut mucosa of HIV-uninfected controls, LTNPs, and HIV-1-infected individuals treated with prolonged antiretroviral therapy (ART) (VL [viral load]+ T cell populations, including Th17 and cycling subsets, in the gut mucosa and a preserved T cell population expressing gut homing molecules in the peripheral blood. In addition, we observed no evidence of higher monocyte activation in LTNPs than in HIV-infected (HIV − ) controls. These data suggest that, similar to nonpathogenic simian immunodeficiency virus (SIV) infection, LTNPs preserve the balance of CD4 + T cell populations in blood and gut mucosa, which may contribute to the lack of disease progression observed in these patients.

We sought to determine the effects of interleukin-2 administered in combination with antiretroviral therapy (ART) on CD4+ T cells in the gut. Lymphocytes from whole blood, colon, and terminal ileum of HIV-infected adults treated with interleukin-2 and ART or ART alone were examined. There were no differences between groups in the proportion of CD4+ T cells or in expression of CD25 or Ki67 by CD4+ T cells in the gut. Although IL-2 administration leads to expansion of peripheral blood CD4+ T cells, there is no alteration in the proportion or activation of CD4+ T cells in the gut mucosa.

Among the accomplishments having the greatest impact during the first decade of the AIDS epidemic was the rapid development of effective tools and strategies to diagnose, treat, and prevent opportunistic infections. Prior to 1981, clinicians had little experience with managing infections such as pneumocystis pneumonia, Toxoplasma cerebritis, cytomegalovirus (CMV) retinitis, disseminated Mycobacterium avium complex infection, and chronic diarrhea due to cryptosporidia or microsporidia. Highly effective drugs to treat CMV and M. avium complex infection had not been developed for clinical practice, and many physicians used intravenous pentamidine, a relatively toxic drug, to treat pneumocystis pneumonia. Aided by randomized prospective clinical trials and the development of national guidelines to rapidly disseminate new information [1], clinicians quickly learned how to recognize and treat these syndromes and diseases. In the eras when no antiretroviral therapy (ART) was available or when ART was limited to single or dual nucleoside agents, median survival times after the diagnosis of the first AIDS-associated opportunistic infection were very limited, ranging from 2 to 22 months, depending on the infection [2]. Human immunodeficiency virus (HIV) testing was not widely available, and most patients presented to healthcare providers with an opportunistic infection. Accordingly, most patients had profoundly depressed CD4 + T-cell counts at the time of presentation. There were limited programs to support retention in care for HIV-infected patients and no effective treatments for restoring immunologic function. In the late 1990s, with the development and availability of more-effective ART, immunity could be more effectively and durably restored, and health outcomes improved dramatically. To supplement the Ryan White Act of 1990 [3],more federal and local programs were developed to support retention in care. The management of opportunistic infections was improved by developing new molecular diagnostic tests, by developing new drugs, and by completing well-designed prospective studies. Medical support improved, especially in critical care departments where ventilator management, treatment for septic shock, and management of intracranial pressure, for in

AIDS-related complications and mortality have decreased dramatically in the combination antiretroviral therapy (cART) era, but the risk of cardiovascular disease and other morbidities linked to chronic immune dysfunction and inflammation remains high [1]. Increased CD8 T-cell activation and inflammatory markers are associated with impaired CD4 T-cell recovery and excess mortality in ART recipients [1, 2]. Systemic translocation of microbial products such as lipopolysaccharide (LPS) across a permeable gut mucosa may contribute to persistent inflammation [2]. Individuals with chronic human immunodeficiency virus (HIV) infection have increased circulating levels of LPS, LPS-binding protein (LBP), and soluble CD14 (sCD14), an LPS coreceptor [2]. ART decreases but does not normalize these levels [2]. Thus, an agent that decreases levels of LPS and its inflammatory consequences may improve clinical outcomes in HIV infection. Sevelamer carbonate, a phosphate-lowering drug, decreases circulating LPS levels in patients with renal insufficiency, possibly by binding chylomicron-LPS complexes and preventing their reabsorption; in this population, sevelamer also reduces levels of sCD14, interleukin 6 (IL-6), C-reactive protein (CRP), and total and low-density lipoprotein (LDL) cholesterol [3–6]. These effects may contribute to the decreased mortality risk observed in sevelamer-treated patients undergoing dialysis [7]. Given the possible role of microbial translocation in HIV-associated inflammation and the potential for its reversal by sevelamer, we performed a single-arm, open-label clinical trial (AIDS Clinical Trials Group [ACTG] A5296), to test the hypothesis that 8 weeks of sevelamer treatment would decrease plasma LPS and sCD14 levels. We studied its effects in subjects who were not receiving cART because (1) sevelamer-cART interactions are unknown, (2) sevelamer might exacerbate tenofovir's phosphate-lowering effect, and (3) microbial translocation is more consistently elevated in untreated disease, increasing the likelihood of seeing an effect.

Background. Intermittent interleukin (IL)-2 administration to human immunodeficiency virus (HIV)-infected patients leads to CD4 + T cell expansions. The factors potentially affecting these expansions were investigated in the present study. Methods. A matched (for baseline CD4 + T cell count) case-control study was designed. Nonresponders (NRs) were defined as patients with a ≤10% increase in CD4+ T cell count 2 months after the third IL-2 cycle (week 24), compared with that at baseline (week 0). Control subjects experienced a ≥50% increase in CD4 + T cell count at week 24. Immunophenotype, Ki67 and forkhead box protein P3 (FoxP3) expression, and T cell receptor excision circle (TREC) measurements in T cells were evaluated at weeks 0 and 24 in both groups. Results. Control subjects and NRs did not differ significantly at baseline in age, viral load, CD4+ T cell count, nadir CD4 + T cell count, or CD8 + T cell count. At week 0, NRs had lower TREC levels per 1 X 10 6 T cells and higher levels of T cell proliferation and activation than did control subjects. At week 24, both groups experienced decreases in T cell proliferation and increases in CD25 and FoxP3 expression on CD4 + T cells, with TREC levels per 1 X 10 6 CD4 + T cells decreasing significantly only in control subjects. Conclusions. Increased immune activation can adversely affect CD4+ T cell expansions after IL-2 administration. Despite the lack of expansion, other evidence of IL-2-induced biological activity was observed.

BACKGROUND The interleukin-7 (IL-7)/IL-7 receptor alpha (IL-7Ralpha) system is an important regulator of T-cell homeostasis. We evaluated the IL-7/IL-7Ralpha system in a large cohort of HIV-infected patients, including a subset treated with intermittent IL-2. METHODS IL-7 serum levels and CD127 (IL-7Ralpha) expression on T cells were evaluated in a cross-sectional study of 36 healthy volunteers, 151 HIV-infected patients, and 83 HIV-infected patients who had received IL-2 therapy. Multivariate regression models were used to determine predictors of CD127 expression. RESULTS HIV-infected patients had higher IL-7 levels compared with healthy volunteers (P = 0.022) and IL-2-treated patients (P = 0.012). CD127 expression was significantly lower on CD4 and CD8 T cells of HIV-infected patients compared with healthy volunteers (P = 0.008 and P < 0.001, respectively), and CD127 median fluorescence intensity was lowest on CD4 T cells in IL-2-treated patients (P < 0.001 compared with HIV-infected patients). The proportion of naive and effector memory/effector T cells were significant predictors of CD127 expression on T cells. IL-2 immunotherapy led to the expansion of a CD25/CD127-low subset of CD4 T cells. CONCLUSIONS CD127 expression on T cells remains low in HIV-infected patients despite antiretroviral therapy, reflecting persistent aberration in the subset composition of the T-cell pool.

Background The pathogenesis of immunodeficiency due to human immunodeficiency virus (HIV)-1 is incompletely understood, but immune activation is believed to play a central role. Immunomodulatory agents that decrease immune activation may be useful in the treatment of HIV-1 infection. Methodology A randomized, double blind, placebo-controlled pilot study of leflunomide for 28 days was performed in participants with HIV-1 infection who were not receiving antiretroviral therapy. Participants randomized to leflunomide were subsequently treated with cholestyramine until leflunomide levels were below detection limit. Findings Treatment with leflunomide was well tolerated with mostly low-grade adverse events. Leflunomide administration reduced cycling of CD4 T cells (by ex vivo bromodeoxyuridine uptake and Ki67 expression) and decreased expression of activation markers (HLA-DR/CD38 co-expression) on CD8 T cells in peripheral blood. In addition, decreased expression of HIV-1 co-receptors was observed in both CD4 and CD8 T cells in the leflunomide group. There were no significant changes in naïve and memory T cell subsets, apoptosis of T cells or markers of microbial translocation. Conclusions Leflunomide was effective in reducing immune activation in the setting of chronic HIV-1 infection suggesting that targeting immune activation with immunomodulatory agents may be a feasible strategy. Trial Registration ClinicalTrials.gov NCT00101374