Rapid disease progression and viral reservoir formation in SIV-infected infant macaques

Despite significant reductions in mother-to-child HIV transmission (MTCT), HIV infection during breastfeeding still occurs at unacceptably high rates, contributing to 150,000 new infections annually. Children are more susceptible to AIDS-related illnesses than adults, with those under two years of age being more likely to succumb to rapid disease progression than any other age group. Rapid progression in infants is characterized by immune dysfunction that can include CD4 T cell depletion, B cell dysfunction and hypo-gammaglobulinemia (low plasma levels of IgM/IgG). To investigate different rates of disease progression in infants, SIV-infected (SIV+) infant rhesus macaques have proven to be a valuable model system, recapitulating several aspects of pediatric HIV infection. Using this model, the Sodora laboratory identified a rapid progressor (RP) phenotype encompassing high SIV plasma viremia and low or undetectable levels of SIV-specific antibodies. Additional analyses revealed that RP infant macaques exhibit elevated and sustained type-1 Interferon (IFN-1) levels following the acute stage of the infection, IFN-induced protein expression within B cell follicles (BCF), and that these changes were associated with germinal center dysfunction within lymphoid tissues. These differences raise important questions about the mechanism by which sustained IFN-1 signaling potentially contributes to rapid HIV/SIV disease progression, as well as the relationship between progression rate and response to combination antiretroviral therapy (cART), immune recovery following treatment, and establishment and maintenance of the latent viral reservoir. Previous studies from Dr. Chahroudi’s laboratory (proposal co-investigator) revealed differences in the latent SIV reservoir in infant compared to adult macaques, including a bias toward naïve CD4 T cells in harboring the majority of latently infected cells in infants. These findings lead to our central hypotheses: 1. Rapid progression in SIV+ infant macaques results from an elevated and prolonged type-1 IFN response that inhibits formation of effective germinal centers in lymph nodes as well as an insufficient anti-SIV humoral immune response. 2. Rapid progression in infants results in delayed immune recovery and a larger latent reservoir during administration of combination antiretroviral therapy. Aim 1 will assess the ability of transiently administered IFN- 1 receptor antagonist, during the post-acute infection period to influence disease progression and immune outcome in infant macaques. Aims 2 and 3 will evaluate the effectiveness of antiretroviral therapy on immune recovery and latent viral reservoirs in both the RP and typically progressing infant macaques. Over the last 20 years, the Sodora laboratory has investigated immune factors that modulate SIV oral transmission and disease progression in the rhesus macaque model, and the experiments outlined here expand upon these previous studies. Undertaking experiments outlined in this proposal has the potential to identify therapeutic targets for HIV+ infants with distinct disease trajectories and will provide insights into immune therapeutic approaches that to aid in immune recovery and reservoir reduction.