Targeting Th17 cells in HIV-1 remission/cure interventions

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. 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. 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. metabolic pathway involving mTOR, allowing the synthesis of ATP by glucose oxidation. diversity of a given element (e.g., microbial species) within a specific community or area/ecosystem. a combination of antiretroviral drugs administered in PLWH to prevent the development of AIDS (a condition appearing when CD4+ T-cell counts decrease below 200 cells/mm3) and to maintain the viral load below 40–50 HIV-1 RNA copies/ml of plasma (limit of detection of commercial viral load quantification assays). diversity of a given element (e.g., microbial species) between distinct communities or areas/ecosystems. experimental therapeutic strategy aiming to induce deep latency of HIV-1 reservoirs preventing their reactivation even without ART. combination of chromatin immunoprecipitation with gene sequencing. This method analyzes the interaction between DNA and protein to identify genome-wide DNA binding sites of transcription factors. HIV-1-infected individuals without ART progressing to AIDS and with a viral load above 5000 HIV-1 RNA copies/ml of plasma. HIV-1-infected individuals who maintain a viral load below 50 HIV-RNA copies/ml of plasma without ART for at least a year. experimentally induced neuroimmune disorder that mimics major characteristics of multiple sclerosis, including inflammation patterns, demyelination, loss of axons, and gliosis animal model of human endogenous uveitis in which the disease is induced by immunization of the susceptible animal with retinal antigens, which elicits a T cell response against the neural retina. transfer of fecal microbiome from one individual to another. The procedure can be achieved by different routes, such as colonoscopy, capsules, nasogastric tube, or enema. FICZ is a high-affinity AhR ligand produced by photolysis of Trp exposed to visible light. Due to its rapid metabolic degradation, it induces only a brief expression of AhR-related genes. The processing of FICZ results in multiple metabolites. steroid hormone involved in the regulation of various physiological functions, from immune responses to reproductive activities; used as a therapeutic tool for its anti-inflammatory and immunosuppressive features. HIV-1 genome contains LTRs in 5′ and 3′. The 5′LTR is needed for HIV-1 gene expression, contains binding sites that interact with viral factors (Tat) and host cellular transcription factors. The 3’LTR terminates the transcription by adding the poly A tail. flow cytometry-based assay allowing the specific recognition of HIV-1-infected cells and, thus, the translationally competent VRs, by combining two different antibodies (anti-HIV-p24 antibodies) targeting two different antigens of the HIV-1 Gag protein. flow cytometry assay used to simultaneously detect transcriptional competent HIV-1 reservoir by in situ RNA hybridization and phenotype infected cells. intracellularly express the HIV-1 Gag protein. group of immune disorders characterized by an elevated quantity of IgE in the serum, skeletal abnormalities, frequent skin and lung bacterial infections, and rash/eczema. In most cases, it is due to mutations in STAT3 or an altered STAT3 signaling pathway. group of chronic inflammatory conditions in the gastrointestinal tract; includes Crohn’s disease and ulcerative colitis. ligand that reduces or inhibits the intrinsic activity of its receptor, but that shares the exact same receptor-binding sites as the activating ligand (agonist). HIV-1-infected individuals who maintain a CD4+ T cell count above 500 cells/mm3 without ART for at least 7 years after their infection without developing any HIV-1-related symptoms (ART-naïve >7 years, CD4+ T cell counts >500 cells/μl HIV-1-infected individuals). phenomenon by which commensal bacteria or their by-products migrate from the intestinal lumen into systemic circulation. isolated from peripheral blood monocytes (PBMCs) and cultured for 4–6 days with macrophage colony-stimulating factor (M-CSF) to induce cell differentiation into macrophages. metabolic pathway involving AMPK, allowing the synthesis of ATP by the electron transport chain at the mitochondrial membrane. ability of a host to accommodate the complete viral replication cycle leading to new infectious particles. in vitro latency model of Th17 cells. Primary CD4+ T cells of HIV-1-uninfected individuals are TCR stimulated and polarized with cytokines (i.e., IL-23 and TGF-β) to induce Th17 cell differentiation; these are HIV-1 infected in vitro and kept in culture to allow a quiescent state, leading to HIV-1 latency; cells are then restimulated to induce HIV-1 outgrowth. two-step experimental therapeutic strategy comprising HIV-1 reactivation from latency with a latency reversing agent (LRA) and boosting the immune system to target and kill HIV-1-infected cells; it aims to eradicate the whole HIV-1 reservoir. Tat (transactivator protein), a HIV-1 regulatory protein, induces transcription elongation by binding to the CDK9 protein of the cellular transcriptional elongation factor P-TEFb. dysfunction leading to poor effector functions frequently observed during chronic infection and cancer; characterized by the expression of exhaustion markers, such as PD-1 and CTLA-4. reprogramming of one cell type into another without passing through a pluripotent state. anatomical site or cell population harboring replication-competent HIV-1, allowing viral persistence despite adhesion to an optimal ART. individuals infected with HIV-1 who maintain a viral load between 50 and 5000 HIV-1 RNA copies/ml of plasma without ART for at least a year.