Th1/17 Polarization of CD4 T Cells Supports HIV-1 Persistence during Antiretroviral Therapy

Abstract

The ability to persist long term in latently infected CD4 T cells represents a characteristic feature of HIV-1 infection and the predominant barrier to efforts aiming at viral eradication and cure. Yet, increasing evidence suggests that only small subsets of CD4 T cells with specific developmental and maturational profiles are able to effectively support HIV-1 long-term persistence. Here, we analyzed how the functional polarization of CD4 T cells shapes and structures the reservoirs of HIV-1-infected cells. We found that CD4 T cells enriched for a Th1/17 polarization had elevated susceptibilities to HIV-1 infection in ex vivo assays, harbored high levels of HIV-1 DNA in persons treated with antiretroviral therapy, and made a disproportionately increased contribution to the viral reservoir relative to their contribution to the CD4 T memory cell pool. Moreover, HIV-1 DNA levels in Th1/17 cells remained stable over many years of antiretroviral therapy, resulting in a progressively increasing contribution of these cells to the viral reservoir, and phylogenetic studies suggested preferential long-term persistence of identical viral sequences during prolonged antiretroviral treatment in this cell compartment. Together, these data suggest that Th1/17 CD4 T cells represent a preferred site for HIV-1 DNA long-term persistence in patients receiving antiretroviral therapy. A lthough antiretroviral therapy (ART) is highly effective in suppressing HIV-1 replication and clinical HIV-1 disease manifestations, small reservoirs of HIV-1-infected cells persist despite treatment and can lead to rapid viral rebound once treatment is stopped (1, 2). Identifying the functional and phenotypic characteristics of cell subsets that harbor replication-competent virus during suppressive antiretroviral therapy is a critical step for developing interventional strategies to target residual viral reservoirs. Most available evidence supports the notion that latently infected CD4 T cells containing chromosomally integrated but transcriptionally silent HIV-1 DNA represent the most dominant cell population responsible for HIV persistence despite treatment (3-5). However, it is increasingly recognized that such cells represent a phenotypically diverse cell population that consists of a variety of different cell subsets with distinct developmental profiles and functional properties (6-10), divergent levels of permissiveness to HIV-1 infection and latency, and, most likely, different susceptibilities to clinical strategies or pharmaceutical agents aiming at reversing viral latency and inducing HIV-1 eradication.From a developmental perspective, memory CD4 T cell evolution can be described as a hierarchical process during which immature, long-lived cells undergo progressive commitment to more differentiated cell types (11). Recent data suggest that the initial, most immature population of memory CD4 T cells consists of a small number of extremely long-lasting cells that phenotypically express a mix of naive and memory cell markers and display ...

HIV persists in CCR6+CD4+ T cells from colon and blood during antiretroviral therapy

“…Our findings are consistent with those recently published by Lichterfeld's and Lewin's groups [64, 65] for peripheral blood CCR6 + T-cells. All these findings are in line with a model in which the CCR6-CCL20 axis plays a critical role HIV latency establishment in resting CD4 + T-cells [89] and support the need for early intervention to block HIV infection of CCR6 + T-cells.…”

“…We also demonstrated that blood CCR6 + T-cells with T CM and Th17 and/or Th1Th17 phenotypes were enriched in integrated HIV-DNA; and that HIV reactivation is induced more robustly in CCR6 + versus CCR6 − T M , T CM , and T EM , upon TCR triggering in the presence of ATRA. These findings are consistent with the concept that fractions of Th17 cells are long-lived [61, 62, 63 ] and support HIV reservoir persistence during ART [ 63 , 64, 65]. HIV uses the molecular machinery of the host cells for integration into specific sites [73].…”

“…However, such strategies cannot be applied at large scale. Our current findings, together with those published by other groups [64, 65], point to the potential beneficial effect of a temporary depletion of CD4 + CCR6 + T-cells, depletion that may result in a significant reduction of HIV reservoirs in ART-treated individuals. Although the antibody-mediated depletion of B cells is beneficial for autoimmunity [102], the success of CCR6 + CD4 + T-cell-depletion in HIV-infected individuals will require careful investigations in animal models and clinical trials.…”

“…The developmental plasticity [59, 60], combined with the long-lived properties of Th17 cells [61, 62], recently raised new questions relative to their potential contribution to HIV persistence during ART. Although the contribution of blood Th17 to HIV reservoir persistence during ART is supported by recent studies by our group [63] and others [64, 65], this aspect remains poorly investigated at mucosal sites. Further studies in this area are important to orient new cell-subset targeted eradication strategies.…”

HIV-1 selectively targets gut-homing CCR6+CD4+ T cells via mTOR-dependent mechanisms

“…The nonrestoration of GALT Th17 cells leads to significant damages of the intestinal barrier, thus allowing microbial translocation, a cause for chronic immune activation and occurrence of non-AIDS comorbidities during ART (3,6,33). Despite their dramatic depletion, long-lived Th17 cells contribute to HIV reservoir persistence during ART (34,35). Consistently, our group identified a subset of CCR6 + CCR4 -…”