This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Determine whether cellular immune responses influence HIV transmission among heterosexual Zambian couples, and control early infection, and whether TRIM5a polymorphisms influence infection in exposed individuals. HLA-liked Gag, nef, and pol polymorphisms have been identified in 350 chronically infected Zambian individuals. These have been used to study escape, reversion, and compensatory mutations in 144 acutely infected subjects followed longitudinally for two years after infection. Near-full-length clade A HIV sequences for two Rwanda transmission pairs with 1 year of follow-up have also revealed new information on immune-driven evolution. Microsoft Research collaborators are examining polymorphisms related to class I and class II HLA alleles and alleles for killer cell immunoglobin-like receptors (KIR). The KIR2DS4*001 allele was associated with higher viral loads in chronically infected partners and accelerated viral transmission (1). Unfavorable HLA alleles A*3601 and DRB*0102 were associated with higher viral loads in 563 seroprevalent but not in 221 seroconverter subjects, whereas favorable A*74, B*13, B*57 or Cw*18, and A*30+Cw*03 alleles were associated with reduced viral loads, but only in the seroconverter group (2). Collaborative studies with the Goulder lab in Oxford showed that significant variation in the gag capsid is primarily due to escape mutations produced by protective alleles HLA-B*57, -5801, and -8101 and covarying HLA-independent polymorphisms arising in conjunction with these escapes which may represent compensatory changes (3). Collaborations with the Goepfert Lab at UAB has shown cryptic epitopes induce immunogenic responses (4). These results may help in designing more effective vaccines.