We coinfected rhesus macaques with CXC chemokine receptor 4-and CC chemokine receptor 5-specific simian͞human immunodeficiency viruses (SHIVs) to elucidate the basis for the early dominance of R5-tropic strains seen in HIV-infected humans. We found no intrinsic barrier to the transmission and dissemination of highdose X4-SHIV in the dually infected macaques. In animals that maintained a viral set point, the R5 virus predominated. The time of appearance of R5 dominance coincided with the development of virus-specific immunity (3-6 weeks postinfection), suggestive of differential immune control of the two viruses. Indeed, after depletion of CD8 ؉ T cells in the coinfected animals, X4 virus emerged, supporting the concept that differential CD8 ؉ T cellmediated immune control of X4-and R5-SHIV replication is responsible for the selective outgrowth of R5 viruses. These findings provide critical insights into a key question related to HIV pathogenesis and have important implications for the development and testing of antiviral vaccines and therapeutics.

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