Route of simian immunodeficiency virus inoculation determines the complexity but not the identity of viral variant populations that infect rhesus macaques

A better understanding of the host and viral factors associated with human immunodeficiency virus (HIV) transmission is essential to developing effect ive strategies to curb the global HIV epidemic. Here we used the rhesus mac aque-simian immunodeficiency virus (SIV) animal model of HIV infection to s tudy the range of viral genotypes that are transmitted by different routes of inoculation and by different types of viral inocula. Analysis of transmi tted variants was undertaken in outbred rhesus macaques inoculated intraven ously (IV) or intravaginally (IVAG) with a genetically heterogeneous SIVmac 251 stock derived from a well-characterized rhesus macaque viral isolate. I n addition, we performed serial IV and IVAG passage experiments using plasm a from SIV-infected macaques as the inoculum. We analyzed the V1-V2 region of the SIV envelope gene from virion-associated RNA in plasma from infected animals by the heteroduplex mobility assay (HMA) and by DNA sequence analy sis. We found that a more diverse population of SIV genetic variants was pr esent in the earliest virus-positive plasma samples from all five IV SIVmac 251-inoculated monkeys and from two of five IVAG SIVmac251-inoculated monke ys. In contrast, we found a relatively homogeneous population of SIV envelo pe variants in three of five monkeys inoculated IVAG with SIVmac251 stock a nd in two monkeys infected after NAG inoculation with plasma from an SIV-in fected animal. In some NAG-inoculated animals, the transmitted SN variant w as the most common variant in the inoculum. However, a specific viral varia nt in the SIVmac251 stock was not consistently transmitted by IVAG inoculat ion. 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 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.