Dissecting the steps in early Simian Immunodeficiency Virus dissemination following mucosal and intravenous infection of rhesus macaques

In cases of HIV transmission, the typical delay from exposure to detectable viremia is approximately one week. This delay from exposure to viremia suggests that during initial expansion of virus from a limited number of founder lineages, there exists a period of low infected cell population. It is during this period of low infected cell population that the virus may be more vulnerable to clearance via primed immune responses targeting infected cells (e.g., antibody-dependent cellular cytotoxicity (ADCC) or CD8+ T cell killing/suppression). Potential future prophylactic harnessing of these immune mechanisms for early virally infected cell clearance will rely on an understanding of the earliest stages of viral replication and dissemination. The factors that dictate the rate of early viral spread, termed the "dissemination bottleneck" could include target-cell-mediated effects, the anatomical microenvironment, or the organ of the first infected cells. In this study, we use the barcoded Simian Immunodeficiency Virus (SIV) infection model to assess the contribution of various anatomical and cellular mechanisms to the SIV dissemination bottleneck. Viral, cellular, and anatomically-mediated heterogeneity in viral replication each introduce a degree of variability into the early phases of viral spread, and when multiple founder lineages are present, this variability in early growth results in a large distribution in lineage sizes. Therefore, we use a comparison of viral lineage size variability across multiple experimental SIV infection models to examine the relative contribution to the overall dissemination bottleneck of viral-mediated stochasticity of cellular infection (e.g., integration site), infected cell phenotype (e.g., activation state), anatomical variability, and initial viral spread within the genital tract. We estimate that inherent heterogeneity in viral production by infected cells corresponds to 23 to 44% of the dissemination bottleneck, but the majority (56 to 77%) arises from anatomical heterogeneity (presumably heterogeneity in how conducive local microenvironments are to viral replication).