Antiretroviral therapy (ART) has improved the quality of life of HIV-infected subjects. However, the persistence of long-lasting viral reservoir poses a major obstacle for viral eradication. Early HIV infection is characterized by a cascade of inflammatory cytokines followed by a negative feedback loop of anti-inflammatory cytokines, such as IL10, in order to reestablish homeostasis. Interestingly, viruses have evolved mechanisms that exploit the immunoregulatory function of IL10 for immune evasion, suppression, and tolerance to promote their own survival. As a result, some viruses, as HIV, can persist for life in infected hosts. HIV persists in a small pool of long-lived latently infected quiescent CD4 T cells and molecular mechanisms that maintain the survival of productively infected cells is not completely understood.
In a cohort of ART-treated HIV aviremic subjects, IL10 was increased in blood and lymph nodes as compared to healthy controls. IL10 producing cells, including T cells, macrophages and B cells were in close proximity to cells with viral DNA in lymph nodes of infected subjects. Importantly IL10 triggered several cellular processes that promoted HIV persistence including the survival of infected cells, the upregulation of several co-inhibitory receptors (Co-IRs) which are involved in the establishment of HIV latency and immune dysfunction; confirming the ex vivo and in vitro gene signatures we also have shown that IL-10 is a potent regulator of TFH differentiation, a major HIV reservoir. Genetic manipulation i.e in vitro knockout of STAT3, the transcription factor downstream of IL10/IL10R engagement, or functional inactivation of this pathway through the use of a neutralizing antibody to IL10, led to decreased T cell survival, downmodulation of Co-IRs expression and decreased TFH frequencies, and consequently led to a significantly lower frequency of HIV infected cells in vitro. These data confirm the role of IL-10 as a trigger for HIV persistence.
In vivo blockade of the IL10 pathway in aviremic chronically infected Rhesus macaques, using an anti-IL10 antibody, led to reversion of all the pathways observed in humans as associated to HIV reservoir maintenance, and resulted in significant decrease on SIV provirus. The NHP pre-clinical data confirmed the safety of this intervention which could be targeted for HIV Cure in humans.