Véronique Avettand-Fenoel

Post-Treatment HIV-1 Controllers with a Long-Term Virological Remission after the Interruption of Early Initiated Antiretroviral Therapy ANRS VISCONTI Study

Combination antiretroviral therapy (cART) reduces HIV-associated morbidities and mortalities but cannot cure the infection. Given the difficulty of eradicating HIV-1, a functional cure for HIV-infected patients appears to be a more reachable short-term goal. We identified 14 HIV patients (post-treatment controllers [PTCs]) whose viremia remained controlled for several years after the interruption of prolonged cART initiated during the primary infection. Most PTCs lacked the protective HLA B alleles that are overrepresented in spontaneous HIV controllers (HICs); instead, they carried risk-associated HLA alleles that were largely absent among the HICs. Accordingly, the PTCs had poorer CD8+ T cell responses and more severe primary infections than the HICs did. Moreover, the incidence of viral control after the interruption of early antiretroviral therapy was higher among the PTCs than has been reported for spontaneous control. Off therapy, the PTCs were able to maintain and, in some cases, further reduce an extremely low viral reservoir. We found that long-lived HIV-infected CD4+ T cells contributed poorly to the total resting HIV reservoir in the PTCs because of a low rate of infection of naïve T cells and a skewed distribution of resting memory CD4+ T cell subsets. Our results show that early and prolonged cART may allow some individuals with a rather unfavorable background to achieve long-term infection control and may have important implications in the search for a functional HIV cure.

Enhanced T cell recovery in HIV-1–infected adults through IL-7 treatment

HIV infection results in CD4+ T cell deficiency, but efficient combination antiretroviral therapy (c-ART) restores T cells and decreases morbidity and mortality. However, immune restoration by c-ART remains variable, and prolonged T cell deficiency remains in a substantial proportion of patients. In a prospective open-label phase I/IIa trial, we evaluated the safety and efficacy of administration of the T cell regulator IL-7. The trial included 13 c-ART-treated HIV-infected patients whose CD4+ cell counts were between 100 and 400 cells/microl and plasma HIV RNA levels were less than 50 copies/ml. Patients received a total of 8 subcutaneous injections of 2 different doses of recombinant human IL-7 (rhIL-7; 3 or 10 microg/kg) 3 times per week over a 16-day period. rhIL-7 was well tolerated and induced a sustained increase of naive and central memory CD4+ and CD8+ T cells. In the highest dose group, 4 patients experienced transient increases in viral replication. However, functional assays showed that the expanded T cells responded to HIV antigen by producing IFN-gamma and/or IL-2. In conclusion, in lymphopenic HIV-infected patients, rhIL-7 therapy induced substantial functional and quantitative changes in T cells for 48 weeks. Therefore, patients may benefit from intermittent therapy with IL-7 in combination with c-ART.

Heterogeneity in HIV Suppression by CD8 T Cells from HIV Controllers: Association with Gag-Specific CD8 T Cell Responses

“HIV controllers” (HICs) are rare individuals in whom HIV-1 plasma viral load remains undetectable without antiretroviral treatment. This spontaneous viral control in HICs is usually associated to strong functional HIV-specific CD8+ T cell responses. Accordingly, we have recently shown that CD8+ T cells from HICs strongly suppress ex vivo HIV-1 infection of autologous CD4+ T cells, suggesting a crucial role of this response in vivo. Knowledge of the mechanisms underlying the CD8+ T cell antiviral activity might help to develop effective T cell-based vaccines. In the present work, we further characterized the HIV-suppressive capacity of CD8+ T cells in 19 HICs. CD8+ T cells from 14 of the 19 HICs showed strong HIV-suppressive capacity ex vivo. This capacity was stable over time and was partially effective even on other primate lentiviruses. HIV-suppressive capacity of CD8+ T cells correlated strongly with the frequency of HIV-specific CD8+ T cells, and in particular of Gag-specific CD8+ T cells. We also identified five HICs who had weak HIV-suppressive CD8+ T cell capacities and HIV-specific CD8+ T cell responses. Among these five HICs, at least three had highly in vitro replicative viruses, suggesting that the control of viremia in these patients is not due to replication-defective viruses. These results, on the one hand, suggest the importance of Gag responses in the antiviral potency of CD8+ T cells from HICs and, on the other hand, propose that other host mechanisms may contribute to restraining HIV infection in HICs.

Distinct Genetic Loci Control Plasma HIV-RNA and Cellular HIV-DNA Levels in HIV-1 Infection: The ANRS Genome Wide Association 01 Study

Previous studies of the HIV-1 disease have shown that HLA and Chemokine receptor genetic variants influence disease progression and early viral load. We performed a Genome Wide Association study in a cohort of 605 HIV-1-infected seroconverters for detection of novel genetic factors that influence plasma HIV-RNA and cellular HIV-DNA levels. Most of the SNPs strongly associated with HIV-RNA levels were localised in the 6p21 major histocompatibility complex (MHC) region and were in the vicinity of class I and III genes. Moreover, protective alleles for four disease-associated SNPs in the MHC locus (rs2395029, rs13199524, rs12198173 and rs3093662) were strikingly over-represented among forty-five Long Term HIV controllers. Furthermore, we show that the HIV-DNA levels (reflecting the HIV reservoir) are associated with the same four SNPs, but also with two additional SNPs on chromosome 17 (rs6503919; intergenic region flanked by the DDX40 and YPEL2 genes) and chromosome 8 (rs2575735; within the Syndecan 2 gene). Our data provide evidence that the MHC controls both HIV replication and HIV reservoir. They also indicate that two additional genomic loci may influence the HIV reservoir.

Long-term immunovirologic control following antiretroviral therapy interruption in patients treated at the time of primary HIV-1 infection.

Five out of 32 patients who received very early and prolonged antiretroviral therapy displayed an unusual, sustained immunovirological control after treatment discontinuation (mean duration: 77 months). These ‘post-treatment controllers’ did not have the genetic characteristics of spontaneous ‘elite’ controllers, although they shared very low and stable level of viral reservoir. Treatment may have dramatically decreased this reservoir and preserved potent HIV-specific immunologic responses, inducing a new balance between the virus and the hosts immune system in these patients.

Long-term antiretroviral therapy initiated during primary HIV-1 infection is key to achieving both low HIV reservoirs and normal T cell counts

OBJECTIVES To characterize viro-immunological outcomes following long-term combined antiretroviral therapy (cART) initiated during primary HIV infection (PHI) or chronic HIV infection (CHI) and to identify factors predictive of optimal viro-immunological responder (OVIR) status. METHODS This was a prospective, single-centre cohort study of HIV-1-infected patients on effective cART. Total cell-associated HIV DNA levels and T cell counts before and during treatment were used to identify factors predictive of OVIR status {i.e. low HIV DNA level [<2.3 log10 copies/10(6) peripheral blood mononuclear cells (PBMCs)], together with normalization of the absolute/relative CD4+ T cell counts and CD4+/CD8+ ratio}. RESULTS A total of 307 patients were enrolled, of whom 35 started cART during PHI (<4 months post-infection) and 272 during CHI. HIV DNA decay was modelled with a non-linear mixed-effects model that showed two phases of HIV DNA decay, both of which were significantly more pronounced in the PHI group. At the end of follow-up, after a median of 4 years of viral suppression (<50 copies/mL), HIV DNA levels were lower in the PHI group than in the CHI group (median = 2.15 versus 2.84 log10 copies/10(6) PBMCs; P< 0.0001). Immune reconstitution was more rapid and sustained in the PHI group (median = 883 versus 619 CD4+ cells/mm(3); 41% versus 31% CD4+; CD4+/CD8+ 1.31 versus 0.77; all P< 0.0001). Finally, OVIR status was obtained in 19/35 (54%) and 7/272 (3%) patients in the PHI and CHI groups (P< 0.0001), respectively. In a logistic regression analysis, cART initiation during PHI (OR = 16, 95% CI = 3.5-72.3) and HIV DNA level <3.3 log10 before treatment (OR = 4.8, 95% CI = 1.2-19.3) were independently predictive of OVIR status. CONCLUSIONS Initiating cART during PHI represents a major opportunity to reduce HIV reservoirs and achieve optimal immune reconstitution.

Impact of Norovirus/Sapovirus-Related Diarrhea in Renal Transplant Recipients Hospitalized for Diarrhea

Background. Diarrhea of unspecified cause frequently occurs after renal transplantation and is usually ascribed to mycophenolic acid toxicity. Norovirus (NoV) and sapovirus (SaV) have been sporadically reported to cause chronic diarrhea in immunocompromised patients. Methods. We undertook a retrospective study (2008–2009) to examine the clinical and epidemiologic significance of NoV and SaV infections in adult renal transplant recipients hospitalized for acute or chronic diarrhea. Results. Ninety-six renal transplant recipients were hospitalized for diarrhea at our institution during a 16-month period, 87 of whom were included in the study, including 46 patients with chronic diarrhea. Among 41 patients with unexplained diarrhea, 20 patients were screened for NoV/SaV, 16 of whom were positive. Fifteen of them (94%) had chronic diarrhea. When compared with bacterial and parasitic infections, NoV/SaV infections were associated with a greater weight loss at the time of admission, a 8.7-fold longer duration of symptoms and a more frequent need for mycophenolic acid dosage reduction. Eighty-one percent of patients hospitalized for NoV/SaV-associated diarrhea experienced acute renal failure. Five and one patients subsequently had biopsy-diagnosed active graft rejection and oxalate nephropathy, respectively. Ten of the 14 patients who underwent a longitudinal study of NoV/SaV stools clearance exhibited a prolonged viral shedding period with a median time of 289 days (107–581 days). Conclusions. Our study indicates that NoV/SaV infection causes posttransplant chronic diarrhea potentially complicated by severe kidney graft impairment.

Immune Responses Driven by Protective Human Leukocyte Antigen Alleles From Long-term Nonprogressors Are Associated With Low HIV Reservoir in Central Memory CD4 T Cells

BACKGROUND The stable immune control of human immunodeficiency virus (HIV) in long-term nonprogressors (LTNPs) with protective human leukocyte antigen (HLA) alleles raises the question of whether and how these alleles influence the immune distribution of the HIV reservoirs. METHODS Cell-associated HIV-DNA levels were quantified in blood sorted resting CD4 T-cell subsets from 8 LTNPs with and 10 without HLA-B*27 or HLA-B*57 alleles (HLA-B27/B57). RESULTS A remarkably lower infection level of central memory CD4 T cells (T(CM)) was an exclusive feature that distinguished the HLA-B27/B57 HIV reservoirs from the other ones. In LTNPs, T(CM) protection was correlated with preservation of T(CM) counts, which correlated positively with the magnitude of HIV Gag-specific CD8 T cells. In HLA-B27/B57 LTNPs, a lower activation level of their memory CD4 T cells was associated with lower amounts of cell HIV-DNA in each resting memory CD4 subset and were also associated with higher ratios of HIV Gag-specific CD8 T cells per infected resting CD4 T cell (effector/target [E/T]). As a result, HLA-B27/B57 E/T ratios were negatively correlated with the contribution of memory CD4 T-cell subsets to the total HIV reservoirs. CONCLUSIONS The potent antiviral immunity governed by the protective HLA-B27/B57 alleles, by limiting T(CM) infection and pool exhaustion, are associated with a reduced T(CM) contribution to the HIV reservoir.

Elite controllers as a model of functional cure.

Purpose of reviewThe limitations of life-long antiretroviral therapies for the HIV infection lead to a novel concept of a functional cure developing innovative therapeutic strategies to generate a long-term remission of HIV replication without treatment. This concept requires an understanding of the mechanisms by which HIV is controlled in conditions of undetectable virus replication, before developing ambitious therapies blocking durably viral replication – and ultimately eradicating HIV. Recent findingsRecent literature shows that the exceptional elite controller status is usually not driven by virus gross genetic defects, despite some virus attenuation resulting from immune selective pressure, but is frequently determined by hosts genetic factors permitting robust cell-mediated immunity to control the virus replication and reservoirs. Lack of immunity and immune deficiency can however limit this model in some cases and only a subgroup in whom both the virus and the immune deficiency are controlled, that is the elite long-term controllers, might represent the best current model for a functional cure. SummaryThis review examines whether the exceptional HIV-infected elite controllers, who spontaneously and durably maintain extremely low virus replication, might be considered as a model for a functional cure and whether the mechanisms identified in these exceptional individuals might serve to identify therapeutic or vaccine strategies.

Adipose Tissue Is a Neglected Viral Reservoir and an Inflammatory Site during Chronic HIV and SIV Infection

Two of the crucial aspects of human immunodeficiency virus (HIV) infection are (i) viral persistence in reservoirs (precluding viral eradication) and (ii) chronic inflammation (directly associated with all-cause morbidities in antiretroviral therapy (ART)-controlled HIV-infected patients). The objective of the present study was to assess the potential involvement of adipose tissue in these two aspects. Adipose tissue is composed of adipocytes and the stromal vascular fraction (SVF); the latter comprises immune cells such as CD4+ T cells and macrophages (both of which are important target cells for HIV). The inflammatory potential of adipose tissue has been extensively described in the context of obesity. During HIV infection, the inflammatory profile of adipose tissue has been revealed by the occurrence of lipodystrophies (primarily related to ART). Data on the impact of HIV on the SVF (especially in individuals not receiving ART) are scarce. We first analyzed the impact of simian immunodeficiency virus (SIV) infection on abdominal subcutaneous and visceral adipose tissues in SIVmac251 infected macaques and found that both adipocytes and adipose tissue immune cells were affected. The adipocyte density was elevated, and adipose tissue immune cells presented enhanced immune activation and/or inflammatory profiles. We detected cell-associated SIV DNA and RNA in the SVF and in sorted CD4+ T cells and macrophages from adipose tissue. We demonstrated that SVF cells (including CD4+ T cells) are infected in ART-controlled HIV-infected patients. Importantly, the production of HIV RNA was detected by in situ hybridization, and after the in vitro reactivation of sorted CD4+ T cells from adipose tissue. We thus identified adipose tissue as a crucial cofactor in both viral persistence and chronic immune activation/inflammation during HIV infection. These observations open up new therapeutic strategies for limiting the size of the viral reservoir and decreasing low-grade chronic inflammation via the modulation of adipose tissue-related pathways.