Project Grant R01AI179465

VIRAL AND HOST DETERMINANTS OF DONOR-SPECIFIC ANTI-HIV/SIV IMMUNITY MEDIATED BY APOBEC3-ENZYME - PROJECT SUMMARY HUMAN APOBEC3 ENZYMES, PARTICULARLY APOBEC3D, APOBEC3F, APOBEC3G, AND STABLE HAPLOTYPES OF APOBEC3H, CAN INDUCE G>A MUTATIONS IN THE HIV-1 GENOME. OFTEN, THESE MUTATIONS, PARTICULARLY THOSE INFLICTED BY APOBEC3G, WHICH IS A POTENT ANTI-HIV ENZYME, GENERATE STOP CODONS AND LEAD TO HIV-1 INACTIVATION. STUDIES HAVE SHOWN THAT APOBEC3 ENZYMES CAN ALSO INDUCE SUB-LETHAL LEVELS OF MUTATIONS THAT LEAD TO HIV-1 DIVERSIFICATION AND DRUG RESISTANCE. MUTATIONS INFLICTED BY DIFFERENT VARIANTS OF APOBEC3 ENZYMES VARY SUBSTANTIALLY IN TERMS OF BOTH THEIR EXTENT AND SEQUENCE CONTEXT. FOR EXAMPLE, APOBEC3H HAPLOTYPE II OFTEN INDUCES MANY G>A MUTATIONS. BY CONTRAST, APOBEC3H HAPLOTYPE I INDUCES LITTLE OR NO CHANGES IN THE HIV-1 GENOME. ANALYSIS OF ALL REPORTED HIV-1 SEQUENCES FROM ~37,000 PATIENTS SHOW THAT THE EXTENT AND PATTERN OF VIRAL MUTAGENESIS BY APOBEC3 ENZYMES ARE HIGHLY DONOR-SPECIFIC. IT IS HYPOTHESIZED THAT VARIATIONS IN BOTH APOBEC3 AND HIV-1 GENES ARE RESPONSIBLE FOR THE OBSERVED DIFFERENCES IN VIRAL MUTATION PROFILES. THE PRELIMINARY DATA SUGGEST THESE VARIATIONS CREATE A COMPLEX CASCADE OF PATIENT-SPECIFIC INTERACTIONS BETWEEN HIV- 1 AND APOBEC3 ENZYMES UNDERLYING HIV-1 HEALTH DISPARITIES INCLUDING RESPONSES TO ANTIRETROVIRAL TREATMENTS. THIS PROPOSAL AIMS TO INTEGRATE DIVERSE VIRAL AND HOST DATASETS AND USE A COMBINATION OF COMPUTATIONAL AND EXPERIMENTAL TECHNIQUES TO IDENTIFY THE MOLECULAR DETERMINATES OF DIFFERENTIAL VIRAL MUTAGENESIS, AND ELUCIDATE THEIR ROLES IN PATIENT-SPECIFIC RESPONSES TO ANTIRETROVIRAL THERAPIES.