Project Grant R21AI186807

CHARACTERIZATION OF A NEW CXCR4-SPECIFIC RESTRICTION FACTOR - ABSTRACT HIV STRAINS VARY CONSIDERABLY IN BOTH GENETIC AND PHENOTYPIC FEATURES, BUT ALL VARIANTS USE CD4 AS THE PRIMARY RECEPTOR AND CONSEQUENTIALLY CD4+ T CELLS ARE THE MAJOR TARGET FOR VIRAL INFECTION. HOWEVER, VARIANTS MAY USE TWO DISTINCT CO-RECEPTORS, CCR5 AND/OR CXCR4 TO FACILITATE STEPS IN THE ENTRY PROCESS SUBSEQUENT TO CD4 BINDING. BOTH CCR5-USING VIRUSES (R5 VIRUSES) AND CXCR4-USING VIRUSES (X4 VIRUSES) ARE OFTEN PRESENT DURING CHRONIC AND LATER STAGES OF HIV INFECTION, BUT NEW INFECTIONS ARE ALMOST ALWAYS SEEDED BY R5 VIRUSES. THE HOST FACTORS THAT CONTRIBUTE TO THIS TRANSMISSION BOTTLENECK MAY HOLD CLUES TO HOST BIOLOGICAL DETERMINANTS OF HIV RISK, BUT THESE FACTORS HAVE REMAINED ELUSIVE. WE HAVE IDENTIFIED A HOST GENE EXPRESSED IN CD4+ T CELLS THAT RESTRICTS X4 VIRUS REPLICATION AND ENHANCES R5 VIRUS REPLICATION. THUS, THIS GENE, SLC35A2, REGULATES HIV INFECTION IN A MANNER THAT MIRRORS WHAT IS OBSERVED DURING TRANSMISSION. THIS IS THE FIRST EXAMPLE OF A GENE THAT SPECIFICALLY RESTRICTS X4 VIRUS INFECTION. BECAUSE THIS GENE WAS ONLY RECENTLY DISCOVERED, ITS ROLE IN INFECTION IN MUCOSAL CD4+ T CELLS, WHICH ARE PARTICULARLY IMPORTANT IN SEXUAL HIV TRANSMISSION, HAS NOT BEEN DEFINED. WE PROPOSE HERE TO EXAMINE THE EFFECT OF SLC35A2 ON R5 VERSUS X4 VIRUS INFECTION IN PRIMARY MUCOSAL CD4+ T CELLS USING BOTH SINGLE VIRUS INFECTIONS AS WELL AS VIRUS COMPETITION EXPERIMENTS. OUR PROPOSED EXPERIMENTS WILL ALSO TEST THE HYPOTHESIS THAT SLC35A2, WHICH IS A TRANSPORTER OF UDP-GALACTOSE AND THUS PLAYS A ROLE IN GLYCOSYLATION, ACTS THROUGH THE CORECEPTOR EARLY IN THE VIRAL LIFECYCLE, DURING FUSION. THESE PROPOSED HIGH-RISK, HIGH-PAY OFF STUDIES HAVE THE POTENTIAL TO REVEAL A UNIQUE ROLE FOR SLC35A2 IN HIV TRANSMISSION BIOLOGY AND ADDRESS A LONG-STANDING PUZZLE IN THE FIELD - NAMELY WHY ARE R5 VIRUSES SELECTED FOR TRANSMISSION.