Neutralization of the Latent HIV Reservoir in Perinatal Infection

Johns Hopkins University, Baltimore MD

Investigators

Abstract

? DESCRIPTION (provided by applicant): Combination antiretroviral therapy (cART) has produced large decreases in human immunodeficiency virus (HIV)-1 morbidity and mortality, and cases such as the Mississippi Child and the Berlin Patient provide hope for HIV-1 remission and cure. However, HIV-1 establishes a latent reservoir in long-lived cells such as resting memory CD4+ T cells that persists for a lifetime and produces rebound viremia in a majority of HIV-infected individuals within 2-3 weeks of stopping cART. Approaches to target the latent reservoir are needed to achieve cART-free remission where infected persons can go off cART for prolonged periods without experiencing prompt virologic rebound. In addition to early cART (initiated within 2-3 months of HIV-1 infection), passive administration of broadly neutralizing antibodies (bNAbs) may target residual HIV-1-expressing cells and reduce the size of the latent HIV-1 reservoir. In the case of the Mississippi Child, who experienced 27-months of HIV-1 remission likely caused by very early cART initiation at 31 hours of age, rebound viremia was clonal and consistent with re-establishment of viremia from an infected cell population bearing founder virus. Whether bNAbs would have prevented re-establishment of viremia in the Mississippi Child is unknown but an intriguing possibility. Additionally, we have recently identified replication-intact, non-induced proviral genomes (NIPG) that are undetectable by standard HIV- 1 co-culture techniques that may contribute to virologic rebound off cART to a larger extent than induced proviruses. Therefore, knowledge of the capacity for bNAbs to neutralize persistent latent reservoir isolates that establishes infection in perinatal transmissio is critical for informing the utility of bNAbs as immunotherapeutics for children, which is the focus of this proposal. We hypothesize that analyses of the neutralization of induced and non-induced replication- competent latent reservoir isolates in perinatal HIV-1 infection will provide important clues on the role of this immunotherapeutic approach towards HIV-1 remission and cure for this population.