Targeting Th17 cells in HIV-1 remission/cure interventions

Since the discovery of HIV-1, progress has been made in deciphering the viral replication cycle and mechanisms of host–pathogen interactions that has facilitated the implementation of effective antiretroviral therapies (ARTs). Major barriers to HIV-1 remission/cure include the persistence of viral reservoirs (VRs) in long-lived CD4+ T cells, residual viral transcription, and lack of mucosal immunity restoration during ART, which together fuel systemic inflammation. Recently, T helper (Th)17-polarized cells were identified as major contributors to the pool of transcriptionally/translationally competent VRs. In this review, we discuss the functional features of Th17 cells that were elucidated by fundamental immunology studies in the context of autoimmunity. We also highlight recent discoveries supporting the possibility of extrapolating this knowledge toward the identification of new putative Th17-targeted HIV-1 remission/cure strategies. The human T helper (Th)17 cell master regulator RORC2 promotes HIV-1 transcription and outgrowth.STAT3 and LCK were identified as sites of HIV-1 integration in T cell lymphomas of patients living with HIV-1 (PLWH). STAT3 and LCK are expressed at relatively high amounts in Th17 cells.The nuclear receptor AHR identifies nonpathogenic Th17 cells in humans, positively regulates HIV-1 transcription in CD4+ T cells, but negatively regulates HIV-1 replication in macrophages.Human mechanistic target of rapamycin (mTOR) is a key metabolic sensor that can be targeted by the type 1 diabetes mellitus drug metformin to interfere with viral reservoirs in CD4+ T cells of antiretroviral therapy-treated PLWH. The mTOR pathway is highly activated in Th17 cells.