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New tuberculosis vaccine candidates that are in the development pipeline need to be studied in people with HIV, who are at high risk of acquiring Mycobacterium tuberculosis infection and tuberculosis disease and tend to develop less robust vaccine-induced immune responses. To address the gaps in developing tuberculosis vaccines for people with HIV, a series of symposia was held that posed six framing questions to a panel of international experts: What is the use case or rationale for developing tuberculosis vaccines? What is the landscape of tuberculosis vaccines? Which vaccine candidates should be prioritised? What are the tuberculosis vaccine trial design considerations? What is the role of immunological correlates of protection? What are the gaps in preclinical models for studying tuberculosis vaccines? The international expert panel formulated consensus statements to each of the framing questions, with the intention of informing tuberculosis vaccine development and the prioritisation of clinical trials for inclusion of people with HIV.

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 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

With the advent of highly effective antiretroviral therapy (ART), infection with human immunodeficiency virus (HIV) has become a chronic disease rather than a death sentence. Nevertheless, effectively treated individuals have a higher than normal risk for developing noninfectious comorbidities, including cardiovascular and renal disease. Although traditional risk factors of aging as well as treatment toxicity contribute to this risk, many investigators consider chronic HIV-associated inflammation a significant factor in such end-organ disease. Despite effective viral suppression, chronic inflammation persists at levels higher than in uninfected people, yet the stimuli for the inflammation and the mechanism by which inflammation persists and promotes disease pathology remain incompletely understood. This critical gap in scientific understanding complicates and hampers effective decision making about appropriate medical intervention. To better understand the mechanism(s) of chronic immune activation in treated HIV disease, three questions need answers: (1) what is the cause of persistent immune activation during treated HIV infection, (2) what are the best surrogate markers of chronic immune activation in this setting, and (3) what therapeutic intervention(s) could prevent or reverse this process? The NIH sponsored and convened a meeting to discuss the state of knowledge concerning these questions and the best course for developing effective therapeutic strategies. This report summarizes the findings of that NIH meeting.

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.

Administration of interleukin (IL)-2 to human immunodeficiency virus (HIV)-infected patients leads to significant increases in CD4 T cell counts. We previously have shown that IL-2 induces increased proliferation and survival of CD4 T cells. Deuterium labeling studies were undertaken to study the relationship between IL-2-induced increases in the CD4 T cell count and the effects of IL-2 on cell proliferation and survival. A strong inverse correlation was noted between the rate of decay of the label in CD4 cells and increases in CD4 cell counts (R =or- 0.67; P

Combination antiretroviral therapy can suppress human immunodeficiency virus (HIV) infection but cannot completely eradicate the virus. A major obstacle in the quest for a cure is the difficulty in targeting and measuring latently infected cells. To date, a single person seems to have been cured of HIV. Hematopoietic stem cell transplantation (HSCT) preceded this cancer patient's long-term sustained HIV remission, but researchers have been unable to replicate this cure, and the mechanisms that led to HIV remission remain to be established. In February 2014, the National Institute of Allergy and Infectious Diseases sponsored a workshop that provided a venue for in-depth discussion of whether HSCT could be exploited to cure HIV in cancer patients requiring such procedures. Participants also discussed how HSCT might be applied to a broader community of HIV-infected persons in whom the risks of HSCT currently outweigh the likelihood and benefits of HIV cure.

Over the past decade, the gut-associated lymphocytes have been shown to play a critical role in the early pathogenesis of HIV infection. Because of constant exposure to foreign antigens, the gut contains an abundance of activated effector memory CD4+ T cells that express CCR5 and are highly susceptible to HIV infection [1]. Primary HIV infections and simian immunodeficiency virus (SIV) infections lead to rapid and profound depletion of these cells [2-4], which is more pronounced than the depletion in peripheral blood or other lymphoid tissue and persists throughout the course of untreated infection. The administration of antiretroviral therapy during chronic infection is highly effective in increasing the number of CD4+ T cells and decreasing the proportion of activated T cells in peripheral blood. However, significant delay in CD4+ T cell restoration maybe seen in the gut, particularly in the lamina propria [5] . Despite the slow or incomplete resolution of the profound abnormalities seen in the gut mucosa of HIV-infected patients, a clear connection to clinical outcome in

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