Pioneering Precision Medicine Approaches for Immune Control of Pediatric HIV-1 Infection

Project Summary/Abstract, Immune Control (Project 4) Finding a cure for HIV-1 infection is of particular importance for the growing number of HIV-1-infected infants, children and teenagers who will have to take lifelong antiretroviral therapy if curative treatment options will not be available. Recent advances suggest that achieving a functional cure of HIV-1 infection may not require complete elimination of all intact HIV-1 proviruses; instead, it may be sufficient to target intact proviruses integrated in permissive chromatin positions that support HIV-1 transcription and are more susceptible to viral reactivation signals. This model for a cure of HIV-1 infection seems to be exemplified by elite controllers, in whom we documented a highly distinct chromosomal integration site landscape characterized by location of intact proviruses in heterochromatin regions. Notably, such a "blocked and locked" pattern of proviral integration sites likely represents the consequence of cellular immune selection forces that have successfully eliminated proviruses in accessible chromatin locations, while proviruses in heterochromatin positions can persist long term. This concept raises the possibility that immune-mediated selection mechanisms can be intensified or accelerated through therapeutic vaccination, and may be preferentially inducible in HIV-1-infected infants starting ART at early stages of infection. Here, we propose to conduct a detailed analysis of viral reservoir dynamics in infants undergoing dolutegravir-containing antiretroviral therapy (ART), with the ultimate aim of informing future clinical trials designed to induce a "blocked and locked" viral reservoir structure through personalized therapeutic mRNA vaccines incorporating autologous proviral sequences. In specific aim 1, we will investigate viral sequences near birth and determine the frequency of intact proviruses in infants started on dolutegravir-containing ART, relative to existing corresponding data from infants undergoing lopinavir/ritonavir-containing ART; these studies will allow us to track the natural evolution of intact and defective proviruses, and generate an atlas of intact proviruses that can be considered for inclusion into personalized therapeutic mRNA vaccines to be tested in future proof-of-principle studies. In specific aim 2, we will longitudinally evaluate the chromosomal positioning of intact proviruses during continuous ART in these infants; we hypothesize that immune-mediated selection mechanisms can at least in some infants promote and facilitate a proviral integration site landscape that approximates the "blocked and locked" proviral architecture observed in elite controllers; such selection mechanisms may then be further intensified through planned personalized mRNA vaccination in future studies. In specific aim 3, we will conduct pioneering studies to characterize the quantity and functionality of cellular and humoral immune responses induced by the licensed SARS-CoV2 mRNA vaccine in HIV-1-infected pediatric patients from Botswana; such studies will be highly informative for all future HIV-1-specific therapeutic vaccination approaches on the mRNA platform.