Viremic non-progressors (VNPs), a distinct group of HIV-1-infected individuals, exhibit no signs of disease progression and maintain persistently elevated CD4+ T cell counts for several years despite high viral replication. Comprehensive characterization of homeostatic cellular immune signatures in VNPs can provide unique insights into mechanisms responsible for coping with viral pathogenesis as well as identifying strategies for immune restoration under clinically relevant settings such as antiretroviral therapy (ART) failure. We report a novel homeostatic signature in VNPs, the preservation of the central memory CD4+ T cell (CD4+ T CM) compartment. In addition, CD4+ T CM preservation was supported by ongoing interleukin-7 (IL-7)-mediated thymic repopulation of naive CD4+ T cells leading to intact CD4+ T cell homeostasis in VNPs. Regulatory T cell (Treg) expansion was found to be a function of preserved CD4+ T cell count and CD4+ T cell activation independent of disease status. However, in light of continual depletion of CD4+ T cell count in progressors but not in VNPs, Tregs appear to be involved in lack of disease progression despite high viremia. In addition to these homeostatic mechanisms resisting CD4+ T cell depletion in VNPs, a relative diminution of terminally differentiated effector subset was observed exclusively in these individuals that might ameliorate consequences of high viral replication. VNPs also shared signatures of impaired CD8+ T cell cytotoxic function with progressors evidenced by increased exhaustion (PD-1 upregulation) and CD127 (IL-7Rα) downregulation contributing to persistent viremia. Thus, the homeostatic immune signatures reported in our study suggest a complex multifactorial mechanism accounting for non-progression in VNPs.

BackgroundHIV-2 infection is characterised by a longer asymptomatic phase and slower AIDS progression than HIV-1 infection. Identifying unique immune signatures associated with HIV-2 pathogenesis may thus provide therapeutically useful insight into the management of HIV infection. This study examined the dynamics of the CD4+T cell compartment, critical in disease progression, focussing on chronic HIV-2 and HIV-1 infected individuals at various stages of disease progression.MethodsA total of 111 participants including untreated and treated HIV infected individuals and seronegative individuals were enrolled in this study. The relative proportion of CD4+T cell subsets, expressing CD25 (IL-2Rα) and CD127 (IL-7R), in HIV infected individuals and seronegative controls were assessed by multiparametric flow cytometry. Additionally, levels of immune activation and cytotoxic T lymphocytes in both the CD4+T and CD8+T cell compartments was evaluated.ResultsBoth treated and untreated, HIV-1 and HIV-2 infected individuals showed apparent dysregulation in CD4+ T cell subset frequency that was associated with disease progression. Furthermore, longitudinal sampling from a group of HIV-1 infected individuals on virologically effective ART showed no significant change in dysregulated CD4+T cell subset frequency. For both ART naïve and receiving groups associations with disease progression were strongest and significant with CD4+ T cell subset frequency compared to per cell expression of IL-2Rα and IL-7Rα. In untreated HIV-2 infected individuals, T cell activation was lower compared to ART naïve HIV-1 infected individuals and higher than seronegative individuals. Also, the level of Granzyme-B expressing circulating T cells was higher in both ART-naïve HIV-1 and HIV-2 infected individuals compared to seronegative controls.ConclusionDysregulation of IL-2 and IL-7 homeostasis persists in CD4+T cell subsets irrespective of presence or absence of viremia or antiretroviral therapy in HIV infection. Furthermore, we report for the first time on levels of circulating Granzyme-B expressing CD4+T and CD8+T cells in chronic HIV-2 infection. Lower immune activation in these individuals indicates that persistent immune activation driven CD4+T cell depletion, as observed in untreated HIV-1 infected individuals, may not be as severe and provides evidence for a disparate pathogenesis mechanism. Our work also supports novel immunomodulatory therapeutic strategies for both HIV-1 and HIV-2 infection.Electronic supplementary materialThe online version of this article (10.1186/s12879-019-3743-7) contains supplementary material, which is available to authorized users.

Summary The role of suppressive anti‐retroviral therapy (ART) in eliciting restoration of dysregulated immune function remains unclear in HIV‐1 infection. Also, due to tailoring of therapeutic regimens towards HIV‐1, this possible impairment of therapy may be even more pronounced in HIV‐2 and dual (HIV‐D) infection. Thus, we evaluated the impact of ART on immune restoration by assessing T cell functions, including HIV specific responses in HIV‐1‐, HIV‐2‐ and HIV‐D‐infected individuals. Both ART‐treated and naive infected subjects showed persistently altered frequency of CD4+ T cell subsets [regulatory T cells (Treg), naive/central memory, effector memory], increased immune activation, cytoxicity and decreased frequency of natural killer T (NKT)‐ like cells and T helper type 17 (Th17)/Treg ratio with elevated microbial translocation. Further, HIV‐specific responses were dominated by gag‐specific CD4+ T cells in virologically suppressed HIV‐D individuals, suggesting retention of T cell memory for both viruses. Increased antigen‐specific responses, including dual‐functional interleukin (IL)‐2/interferon (IFN)‐γ CD4+ T cells, were detected in therapy receiving HIV‐2‐infected individuals indicative of a greater and more functionally diverse T cell memory repertoire. We delineated immune signatures specific to therapy‐naive single HIV infection, as well as a unique signature associated with HIV‐2 disease progression and immune restoration. Circulating Treg frequency, T cell activation and microbial translocation levels correlated with disease progression and immune restoration among all types of HIV infection. Also, memory responses negatively correlated, irrespective of type of infection, in ART receiving infected individuals, with CD4 rebound and decreased pan T cell activation. Our data highlight the need for adjunct immunomodulatory therapeutic strategies to achieve optimal immune restoration in HIV infection.