Human and simian immunodeficiency virus (HIV and SIV) may co-opt antigen capture and presentation functions of antigen presenting cells (APCs) to facilitate infection of CD4+ T-cells. To address whether the replicative capacity of SIV in the host may be associated with the extent of viral replication in response to APC-T-cell interactions, we compared the replicative phenotypes of cloned early and late-stage SIVmne variants of known pathogenicity. Here, we show that the highly pathogenic late variant SIVmne027 replicates more efficiently in both macrophage- and dendritic cell (DC)-T-cell cocultures than the minimally pathogenic early virus SIVmneCl8. Contact between either macrophages or DC and T-cells increases replication of SIVmne027. Our analysis also demonstrates that mutations in pol and nef contribute to the greater replicative capacity of SIVmne027 in DC- or macrophage-T-cell cocultures. Together, these data suggest that variant viruses that evolve to replicate vigorously in response to APC-T-cell interactions may have increased replicative capacity in vivo.