A robust simian-human immunodeficiency virus (SHIV)-rhesus macaque (RM) model of HIV latency and cure is needed. Our group has generated >20 SHIVs encoding various HIV-1 Envs of interest, including transmitted/founder (TF) Envs. TF SHIVs encode a substitution at Env residue 375 that confers consistent early viral kinetics in RM, although longitudinal kinetics are more variable. Further, TF SHIVs have not been evaluated for their suitability for HIV latency and cure research. For my first aim, I evaluated two promising TF SHIVs, SHIV.191859 and SHIV.CH848, for their viral kinetics and persistence during suppressive combination antiretroviral therapy (cART). These SHIVs demonstrated consistent early viral kinetics, rapid viremic suppression following cART initiation, and viral rebound following treatment interruption, mirroring HIV infection. Reservoir analyses of both peripheral and lymphoid cells revealed systemic virus dissemination and establishment of viral reservoirs that persisted despite cART. The viral dynamics and reservoir biology of SHIV.191859, and to a lesser extent SHIV.CH848, suggest that these TF SHIVs are promising reagents for a SHIV model of HIV latency and cure. For my second aim, I endeavored to engineer an enhanced clone of SHIV.CH505, a TF SHIV that is of significant interest to the HIV field but replicates variably over time in RM. A common signature of mutations that arose in 10 SHIV.CH505-infected RM with high VLs was identified via single genome sequencing. To assess the contribution of signature mutations to viral fitness in vitro, a library of clones containing signature mutations alone or in combination was generated; these clones demonstrated modestly enhanced replication in isolation and significantly enhanced replication in combination compared to the parental (TF) virus. 8 combination clones that exhibited desirable characteristics in vitro were tested in vivo. A clone containing 5 mutations compared to the TF, 5MA, dramatically outcompeted all other viruses, including the TF, when tested in vivo in 7 RM. TZM-bl neutralization assays revealed that 5MA retained a native Env conformation. Further, 5MA demonstrated significantly enhanced entry into target cells compared to the TF. We have generated a minimally adapted SHIV.CH505 with enhanced replication that has broad applications for HIV research in RM.