PD1 and LAG3 drive HIV persistence by regulation of T-cell homeostasis through distinct mechanisms
Significance: Although modern antiretroviral drugs are able to suppress nearly all HIV replication, the virus persists indefinitely as stably integrated genomes within long-lived memory CD4+ T-cells. Understanding how memory cells are generated and identifying biomarkers of latently infected cells and the mechanisms that drive the establishment and persistence of HIV is of high importance to specifically target and eliminate the persistent reservoir.
Salient Findings: We show that LAG3+ CD4+ T-cells inhibit cell cycle entry and proliferation through the production of the anti-inflammatory cytokines TGF-beta and IL-10, leading to a state of memory cell quiescence. By contrast, PD1+ expression on CD4+ cells do increase, in response to homeostatic expansion of cells harboring the HIV reservoir. These results highlight the distinct homeostatic mechanisms involved in HIV persistence and suggest that therapeutic manipulation of either LAG3 or PD1 pathways could reduce the size of the reservoir through distinct mechanisms.
Impact: We predict that the emerging family of anti-LAG-3 antibodies will reverse the anti-inflammatory effects of LAG-3 positive cells, leading to reversal of quiescence (and latency) and perhaps a reduce survival of latently infected cells. We also predict that anti-PD-1 antibodies will reduce the reservoir size by reversing cell quiescence in cells enriched for HIV and by enhancing HIV-specific immunity.