In-Depth Characterization of Full-Length Archived Viral Genomes after Nine Years of Posttreatment HIV Control.

In the search for control of human immunodeficiency virus type 1 (HIV-1) infection without antiretroviral therapy, posttreatment controllers (PTCs) are models of HIV remission. To better understand their mechanisms of control, we characterized the HIV blood reservoirs of 8 PTCs (median of 9.4 years after treatment interruption) in comparison with those of 13 natural HIV infection controllers (HICs) (median of 18 years of infection) and with those of individuals receiving efficient antiretroviral therapy initiated during either primary HIV infection (PHIs; n = 8) or chronic HIV infection (CHIs; n = 6). This characterization was performed with single-genome amplification and deep sequencing. The proviral diversity, which reflects the history of past viral replication, was lower in the PTCs, PHIs, and aviremic HICs than in the blipper HICs and CHIs. The proportions of intact and defective proviruses among the proviral pool in PTCs were not significantly different from those of other groups. When looking at the quantities of proviruses per million peripheral blood mononuclear cells (PBMCs), they had similar amounts of intact proviruses as other groups but smaller amounts of defective proviruses than CHIs, suggesting a role of these forms in HIV pathogenesis. Two HICs but none of the PTCs harbored only proviruses with deletion in nef; these attenuated strains could contribute to viral control in these participants. We show, for the first time, the presence of intact proviruses and low viral diversity in PTCs long after treatment interruption, as well as the absence of evolution of the proviral quasispecies in subsequent samples. This reflects low residual replication over time. Further data are necessary to confirm these results. IMPORTANCE Most people living with HIV need antiretroviral therapy to control their infection and experience viral relapse in case of treatment interruption, because of viral reservoir (proviruses) persistence. Knowing that proviruses are very diverse and most of them are defective in treated individuals, we aimed to characterize the HIV blood reservoirs of posttreatment controllers (PTCs), rare models of drug-free remission, in comparison with spontaneous controllers and treated individuals. At a median time of 9 years after treatment interruption, which is unprecedented in the literature, we showed that the proportions and quantities of intact proviruses were similar between PTCs and other individuals. Unlike 2/7 spontaneous controllers who harbored only nef-deleted proviruses, which are attenuated strains, which could contribute to their control, no such case was observed in PTCs. Furthermore, PTCs displayed low viral genetic diversity and no evolution of their reservoirs, indicating very low residual replication, despite the presence of intact proviruses.

Transient viral exposure drives functionally-coordinated humoral immune responses in HIV-1 post-treatment controllers.

HIV-1 post-treatment controllers are rare individuals controlling HIV-1 infection for years after antiretroviral therapy interruption. Identification of immune correlates of control in post-treatment controllers could aid in designing effective HIV-1 vaccine and remission strategies. Here, we perform comprehensive immunoprofiling of the humoral response to HIV-1 in long-term post-treatment controllers. Global multivariate analyses combining clinico-virological and humoral immune data reveal distinct profiles in post-treatment controllers experiencing transient viremic episodes off therapy compared to those stably aviremic. Virally-exposed post-treatment controllers display stronger HIV-1 humoral responses, and develop more frequently Env-specific memory B cells and cross-neutralizing antibodies. Both are linked to short viremic exposures, which are also accompanied by an increase in blood atypical memory B cells and activated subsets of circulating follicular helper T cells. Still, most humoral immune variables only correlate with Th2-like circulating follicular helper T cells. Thus, post-treatment controllers form a heterogeneous group with two distinct viral behaviours and associated immune signatures. Post-treatment controllers stably aviremic present "silent" humoral profiles, while those virally-exposed develop functionally robust HIV-specific B-cell and antibody responses, which may participate in controlling infection.

Influence of lifelong cumulative HIV viremia on long-term recovery of CD4+ cell count and CD4+/CD8+ ratio among patients on combination antiretroviral therapy.

OBJECTIVE: We explored the impact of lifelong cumulative HIV viremia on immunological recovery during antiretroviral therapy, according to the timing of treatment initiation. METHODS: We estimated lifelong cumulative HIV viremia in patients followed in the ANRS PRIMO cohort since primary infection, including 244 patients who started treatment during PHI and had at least one treatment interruption, and 218 patients who started treatment later but with no interruptions. The impact of cumulative viremia on current immunological status was analysed using linear and logistic regression models. RESULTS: At the last visit on treatment, median CD4 cell count was 645 cells/µl in the early/intermittent treatment group (median time from infection 9.5 years, 4.8 years of continuous treatment since last resumption), and 654 cells/µl in the deferred/continuous treatment group (median time from infection 6.1 years, 3.0 years of continuous treatment). Only 36.1 and 39.8% of patients achieved a CD4/CD8 ratio of more than 1, respectively. Current CD4 cell count was not associated with cumulative HIV viremia in either group. In contrast, patients with high cumulative HIV viremia (>66th percentile vs. <33rd percentile) were less likely to achieve a CD4/CD8 ratio of more than 1 (26.8 vs. 43.3%, P = 0.003), even after controlling for the baseline CD4/CD8 ratio, treatment duration, sex and age. Much higher CD4 cell count and CD4/CD8 ratio were reached in early/continuous treatment, that is low viremia exposure group. CONCLUSION: Our results underline the critical need in early-treated patients to maintain adherence, in order to limit cumulative HIV viremia and optimize immunological recovery, notably the CD4/CD8 ratio.