Correlates of HIV-1 control after combination immunotherapy

The identification of therapeutic strategies to induce sustained antiretroviral therapy (ART)-free control of HIV infection is a major priority¹. Combination immunotherapy including HIV vaccination, immune stimulation, latency reversal and passive transfer of broadly neutralizing antibodies (bNAbs) has shown promise in non-human primate models^2-6, but few studies have translated such approaches into people. Here we performed a single-arm, proof-of-concept study in ten people living with HIV on ART, combining the following three approaches: (1) therapeutic vaccination with an HIV Gag conserved element-targeted DNA + IL-12 prime/modified vaccinia Ankara (MVA) boost regimen followed by (2) administration of two bNAbs (10-1074, VRC07-523LS) and a toll-like receptor 9 agonist (lefitolimod) during ART suppression, followed by (3) repeat bNAb administration at the time of ART interruption (Clinicaltrials.gov: NCT04357821 ). Seven out of the ten participants exhibited post-intervention control after pausing ART, independent of residual bNAb plasma levels. Robust expansion of activated CD8⁺ T cells early in response to rebounding virus correlated with a lower median viral load after peak viraemia off ART. These data suggest that combination immunotherapy approaches might prove effective in inducing sustained control of HIV by slowing rebound and improving CD8⁺ T cell responses, and that these approaches should continue to be optimized.