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Evolution of a simian immunodeficiency virus pathogen. envelope gene from virion-associated RNA in plasma from infected animals by the heteroduplex mobility assay (HMA) and by DNA sequence analysis. We found that a more diverse population of SIV genetic variants was present in the earliest virus-positive plasma samples from all five IV SIVmac251-inoculated monkeys and from two of five IVAG SIVmac251-inoculated monkeys. In contrast, we found a relatively homogeneous population of SIV envelope variants in three of five monkeys inoculated IVAG with SIVmac251 stock and in two monkeys infected after IVAG inoculation with plasma from an SIV-infected animal. In some IVAG-inoculated animals, the transmitted SIV variant was the most common variant in the inoculum. However, a specific viral variant in the SIVmac251 stock was not consistently transmitted by IVAG inoculation. Thus, it is likely that host factors or stochastic processes determine the specific viral variants that infect an animal after IVAG SIV exposure. In addition, our results clearly demonstrate Brassinolide that the route of inoculation is associated with the extent and breadth of the genetic complexity of the viral variant population in the earliest stages of systemic infection. Human immunodeficiency virus EIF2B (HIV) transmission by sexual, intravenous (IV), and perinatal routes is often associated with the acquisition of a limited distribution of genetic variants (45, 48C50). In many instances, the proviral DNA sequence of the transmitted variant represents a minor variant in the donor’s virus population (45, 49, 50). Given the extent Brassinolide of genetic diversity between HIV isolates, these findings have been interpreted to suggest that HIV transmission may involve selective entry or selective amplification of specific viral variants (45, 48, 49). The inherent limitations of all studies using human samples include small sample sizes and uncertainty as to the genetic identity and the extent of genetic diversity of the virus population in the donor at the time of transmission. Thus, the mechanisms that underlie the sexual transmission of HIV variants are unclear, and they are difficult to assess because of the difficulties in establishing the precise time of infection and in obtaining samples before immune pressures affect viral variant populations (12). The simian immunodeficiency virus (SIV) macaque model for intravaginal (IVAG) HIV transmission (30, 31) is particularly valuable for evaluating the role of viral selection during sexual transmission. The model allows access to information that is usually unattainable in human studies, such as the genotypic and phenotypic properties of the infecting virus, knowledge of the exact time of virus exposure, and the characteristics of viral variants in the infected host immediately after transmission. Previous studies of SIV transmission using rhesus macaques inoculated by the IV and IVAG routes have shown that the genetic complexity of the SIV populations detected in peripheral blood is associated with the method of challenge; greater diversity accompanied IV inoculation of SIV (10, 11, 36, 42). Some have concluded that these results mean that selective SIV transmission occurs after IVAG inoculation (11, 36); however, a specific SIV variant has not been detected in multiple individual outbred macaques after IVAG inoculation with a genetically diverse virus stock. Here we extend previous investigations of SIV transmission in several ways. As in earlier SIV transmission studies, we IV- or IVAG-inoculated outbred rhesus macaques with the same genetically heterogeneous SIVmac virus stock and analyzed the extent of Brassinolide V1-V2 envelope diversity in plasma from each animal. In an effort to determine if a particular SIV variant or subset of variants would be consistently transmitted by serial mucosal passage, we also used virus in plasma from SIV-infected macaques to perform serial IV and IVAG inoculations. If viral variants Brassinolide possessing a unique ability to cross the vaginal mucosal surface and establish systemic infection exist in the SIV inoculum, then serial IVAG passage of plasma SIV variants should result in selection for a particular genetic variant(s). Further, it is likely that serial passage will select viral variants with.