Abstract Studies have shown that there are distinct differences in clinical presentation and transmission rates between HIV-1 subtype A and C. These differences include an increased rate of disease progression for subtype C infections vs. subtype A, as well as increased transmission rates associated with subtype C vs. subtype A (2, 3). One key aspect of early HIV-1 infection that has been elucidated is the role of the transmitted-founder (TF) virus, which is the viral variant that establishes systemic HIV-1 infection. Early events in a new HIV-1 infection, influenced in particular by the replicative capacity (RC) of the TF virus, have been shown to have a profound effect on the trajectory of disease (4, 5). While characteristics of TFs compared to non-transmitted (NT) viral variants have been investigated, the role that the TF phenotype plays in HIV-1 subtype differences has not been investigated. The purpose of this proposed study is to determine the role that viral phenotypes and the impact of the host has on the clinical differences observed between subtype A and C HIV-1 infections. Our hypothesis is that the basis of observed differences in disease progression and transmission rate between HIV-1 subtype A and subtype C infections is due to different phenotypic properties in the subtype A TF virus and differing interactions of the TF with the innate immune system. We aim to investigate whether there are phenotypic differences between the TFs of different subtypes and how the TFs of different subtypes interact with dendritic cells (DCs) and the associated innate immune system to determine if these factors correlate with the differences observed between clinical presentation and transmission rates. In our first aim, we will investigate if viral phenotypes of subtype A and subtype C TFs are associated with the different rates of disease progression by measuring the replicative capacity (RC) of subtype C TFs vs. subtype A TFs. We will also investigate the ability of subtype C and subtype A TFs to mediate trans-infection, where DCs carry HIV-1 to CD4 T cells and then transfer the virus through an immune synapse to susceptible CD4 T cells. In the final part of aim 1, we will compare the level of pre-adaptation in subtype A TFV compared to subtype C TFV to see if subtype C is able to more efficiently evade the adaptive immune response of the host. Our second aim will examine whether the differences seen between subtypes can be attributed to different innate immune responses triggered by interaction of the TF virus with DCs. We will determine this by comparing RNA expression and secreted molecule profiles from DCs derived from the female reproductive tract (FRT DCs) after exposure to subtype A or subtype C TFs. Finally, we will examine how FRT DCs pulsed with subtype A or C TFs stimulate resting CD4 T cells by comparing RNA expression profiles of the CD4 T cells. The outcome of this research will be a better understanding of early interactions of the ...