HIV-specific T cell responses reflect substantive in vivo interactions with antigen despite long-term therapy

Abstract

Antiretroviral therapies (ARTs) abrogate HIV replication; however, infection persists as long-lived reservoirs of infected cells with integrated proviruses, which reseed replication if ART is interrupted. A central tenet of our current understanding of this persistence is that infected cells are shielded from immune recognition and elimination through a lack of antigen expression from proviruses. Efforts to cure HIV infection have therefore focused on reactivating latent proviruses to enable immune-mediated clearance, but these have yet to succeed in reducing viral reservoirs. Here, we revisited the question of whether HIV reservoirs are predominately immunologically silent from a new angle: by querying the dynamics of HIV-specific T cell responses over long-term ART for evidence of ongoing recognition of HIV-infected cells. In longitudinal assessments, we show that the rates of change in persisting HIV Nef-specific responses, but not responses to other HIV gene products, were associated with residual frequencies of infected cells. These Nef-specific responses were highly stable over time and disproportionately exhibited a cytotoxic, effector functional profile, indicative of recent in vivo recognition of HIV antigens. These results indicate substantial visibility of the HIV-infected cells to T cells on stable ART, presenting both opportunities and challenges for the development of therapeutic approaches to curing infection.

HIV-1 Genomes Are Enriched in Memory CD4 + T-Cells with Short Half-Lives

“…In agreement with these findings, a recent study has revealed that HIV-1-specific T-cell response, and, more specifically, HIV-1 Nef-specific response continues during long-term ART. These HIV-1 Nef-specific responses were associated with the frequency of HIV-1-infected cells and indicate recent in vivo recognition of the HIV-1 Nef antigen during ART ( 51 ). Therefore, viral protein expression in more activated cells with a short half-life/rapid turnover rate could protect genetically-intact genomes, which retain the ability to express protective viral proteins.…”

Epigenetic Features of HIV-Induced T-Cell Exhaustion Persist Despite Early Antiretroviral Therapy

“…Following one year of ART, we found relative expansion of the T EMRA T cells which persisted even after three years of treatment, suggesting a permanent alteration in the T cell pool or low-level persistent antigenic stimulation driving the differentiation of these cells. Indeed, there is now evidence of ongoing T cell recognition of HIV antigens during suppressive ART (53), further supporting that this may be a driver of immune activation and inflated CD8 T cell numbers in many individuals on ART. In contrast, the initiation of early ART resulted in near-normalisation of ICRs on bulk memory T cells after one (in the case of PD-1 and TIGIT) and three years (Tim-3) of treatment.…”

Pre-cART Immune Parameters in People Living With HIV Might Help Predict CD8+ T-Cell Characteristics, Inflammation Levels, and Reservoir Composition After Effective cART

“…Recent advances indicate that viral proteins were found to be expressed from latently infected CD4 + T cells, even from those harboring defective HIV proviruses, and that these cells are subjected to immune surveillance [ 62 , 63 ]. Very recently, Stevenson et al [ 64 ] showed that long-term CD8 + T-cell responses during cART are maintained by viral protein-mediated cell triggering. This indicates that CD8+ T-cell response during cART contributes to the dynamics of reservoir maintenance, and warrants more research to understand the molecular biology of HIV persistence during cART and its interaction with the CD8 + T-cell response in order to expand cure and vaccine research.…”