Higher HIV-1 Env gp120-Specific Antibody-Dependent Cellular Cytotoxicity (ADCC) Activity Is Associated with Lower Levels of Defective HIV-1 Provirus

Abstract

During HIV-1 (HIV) infection, continued administration of antiretroviral therapy (ART) can decrease a person’s viral load to undetectable levels and allow for a near-normal lifespan, though ART is not a cure due to a reservoir of cells that harbor latent, integrated HIV provirus capable of host immune evasion and stochastic reactivation. While the vast majority of HIV proviruses are defective due to large internal deletions or hypermutations, a fraction of proviruses are intact and replication competent which contribute to the rebound of viremia that occurs upon cessation of ART, necessitating its life-long administration. The majority of archived proviral sequences that persist on ART are genetically similar to those of circulating viruses at the time of ART initiation which suggests that factors present at this time can impact HIV reservoir dynamics, and that additional influences at this critical time for reservoir establishment may also be identified. Host immune responses such as Antibody-Dependent Cellular Cytotoxicity (ADCC), which act to clear infected cells, have been suggested to have the potential to impact reservoir size and characteristics. Children living with HIV represent a significant fraction of people living with HIV, yet studies of the pediatric HIV reservoir, especially those focused on its establishment during chronic HIV infection, are relatively few compared to those in adults. The work detailed in this thesis tested the hypothesis that the ability of autologous plasma antibodies to mediate ADCC against HIV Env at the time of ART initiation inversely correlates with the size of the established HIV reservoir. This was done using samples from the Pediatric Adherence Diary study, the rapid and fluorometric ADCC (RFADCC) assay, and the Cross-Subtype Intact Proviral DNA assay (CS-IPDA). The results demonstrated a moderate, inverse correlation between HIV Env gp120-specific ADCC activity in plasma at the time of ART initiation and the level of defective (r = -0.285, p-value = 0.0214), but not intact (r = -0.0321, p-value = 0.800), HIV proviral copies that persist during ART. These findings suggest that host immune factors prior to ART initiation may impact the proviruses that persist during ART. Additionally, it adds to the mounting evidence that cells harboring defective HIV provirus may face different immune selection pressures than cells harboring intact provirus.