Background:  The underlying mechanism for R5 dominance and emergence of X4 variants late in infection remains undefined.  Pathogenic chimeric envelope SHIVs that transmit, replicate and induce disease with comparable efficiencies when inoculated singly into naïve rhesus macaques, but are specific for either the CCR5 (SHIV_SF162P3) or CXCR4 (SHIV_SF33A) co-receptor, provided the opportunity to address this issue in co-challenged macaques. Methods: Naïve rhesus macaques were inoculated either intravenously (IV) or intravaginally (IVAG) (seven macaques per group) with a mixture of SHIV_SF162P3 and SHIV_SF33A isolates.  Plasma viral loads and T cell-subsets were analyzed, and viral genotype determined by sequence analysis of the V3-V5 env region. To assess the role of CTL in determining R5 dominance, a subset of infected macaques was administered the anti-CD8 chimeric mouse-human antibody cM-T807 (kindly provided by Drs. H Reimann and Joern Schmitz).  Results:  Within the first weeks after viral inoculation, both CXCR4- and CCR5-specific viruses were readily amplified from the plasma of coinfected animals, with no obvious barrier to CXCR4 viral transmission or replication noted.  Within three to six weeks after inoculation, a time coincident with the onset of acquired anti-viral immunity, CCR5 viruses dominated in macaques with high viral set-points. Animals with low viral set-points did not consistently replicate either virus.  To investigate whether CTLs differentially control CXCR4 and CCR5 viral replication in dually-infected macaques, animals were experimentally depleted of CD8⁺ T cells at the time of R5 dominance. A dramatic change in the genotype of circulating virus was observed, such that in the absence of CD8⁺ T cells, a burst of CXCR4 virus replication was observed.  Conclusions: Coinfection of rhesus macaques with CXCR4- and CCR5-specific SHIVs recapitulates natural HIV-1 infection such that both viral phenotypes are transmitted, and CCR5 viruses dominate within weeks of viral infection.  Experimental depletion of CD8⁺ T cells suggest that CTL may play a role in the dominance of CCR5 viral replication observed in HIV infection.