Virologic Determinants of Very Early Antiretroviral Treatment Responses of Infants with in utero HIV-1

Johns Hopkins University, Baltimore MD

Investigators

Abstract

Project Summary/Abstract Initiation of very early antiretroviral therapy (ART) in neonates with in utero HIV-1 leads to the possibility of long-term ART-free control in a small subset of neonates. In the IMPAACT P1115 clinical trial, very early ART has led to four cases of long-term, ART- free control in children. In addition to this outcome, sex differences were observed with respect to plasma viral load, cell-associated HIV-1 DNA concentrations, and the ability to maintain sustained virologic suppression. These observations are consistent with previously published research in other cohorts that revealed sex differences in HIV-1 replication capacity and interferon resistance with respect to in utero HIV-1 transmission. To further interrogate the virologic determinants that lead to the formation of the viral reservoir, we propose to create infectious molecular clones from the gag-pro and env regions of the near full-length single genome sequences from the proviral HIV- 1 DNA of IMPAACT P1115 participants. These recombinant viruses will be assayed for replication capacity and interferon resistance, which will be examined against early life biomarkers of in utero HIV-1 transmission such as plasma viral load, HIV-1 DNA concentrations, and biological sex. In addition to employing the conventional TZM-bl and CEM-GXR-25 immortalized cell lines to determine viral infectivity and replication capacity, we propose to also compare HIV-1 interferon resistance in primary CD4+ cells isolated from adult males and females or cord blood cells to also investigate the role of target cell type on interferon resistance. Altogether, these studies will fill a critical gap in our understanding of retroviral infection in fetal cells and by biological sex and their implication for sustained virologic control in postnatal life.