bNAbs and Anti-PD-1 in HIV

Antiretroviral therapy (ART) has significantly extended the life expectancy of people living with HIV-1 (PLWH), but it does not cure the infection. Broadly neutralizing antibodies (bNAbs), such as 3BNC117 and 10-1074, not only neutralize circulating virus but also engage the immune system to enhance HIV-1-specific CD8+ T cell responses and stimulate autologous neutralizing antibody production. In some individuals who discontinue ART, bNAb treatment resulted in long-term post-treatment control. However, a major obstacle to immunotherapeutic strategies in PLWH is the immune dysfunction that persists despite long-term suppressive ART. One contributing factor is the immune checkpoint receptor programmed death-1 (PD-1), which is expressed on T cells and suppresses their function when engaged by its ligands. Blocking PD-1 with monoclonal antibodies (mAbs) can reverse T cell exhaustion, a strategy that has resulted in extraordinary increases in survival and cure in cancer treatment and in ex vivo and animal studies of HIV. These findings support the rationale for incorporating PD-1 inhibition in HIV cure strategies. Low-dose nivolumab, an anti-PD-1 mAb, has been shown to be safe in clinical trials. The hypothesis is that combining a single low-dose of nivolumab with long-acting bNAbs (3BNC117-LS and 10-1074-LS) during an analytical treatment interruption (ATI) will reduce T cell exhaustion and boost HIV-1-specific immune responses, as a novel strategy to induce sustained virological control without ART even after the bNAbs have been cleared from the body.