Differential Outcomes Following Optimization of Simian-Human Immunodeficiency Viruses From Clades AE, B and C.

Simian-human immunodeficiency virus (SHIV) infection of rhesus monkeys is an important preclinical model for HIV-1 vaccines, therapeutics, and cure strategies. SHIVs have been optimized by incorporating HIV-1 Env residue 375 mutations that mimic the bulky or hydrophobic residues typically found in SIV Env to improve rhesus CD4 binding. We applied this strategy to three SHIV challenge stocks (SHIV-SF162p3, SHIV-AE16, SHIV-325c) and observed three distinct outcomes. We constructed six Env375 variants (M, H, W, Y, F, S) for each SHIV, and we performed a pool competition study in rhesus monkeys to define the optimal variant for each SHIV prior to generating large-scale challenge stocks. We identified SHIV-SF162p3S/wildtype, SHIV-AE16W, and SHIV-325cH as the optimal variants. SHIV-SF162p3S could not be improved as it already contained the optimal Env375 residue. SHIV-AE16W exhibited similar replicative capacity to the parental SHIV-AE16 stock. In contrast, SHIV-325cH demonstrated 2.6-log higher peak and 1.6-log higher setpoint viral loads compared with the parental SHIV-325c stock. These data demonstrate the diversity of potential outcomes following Env375 modification in SHIVs. Moreover, the clade C SHIV-325cH challenge stock may prove useful for evaluating prophylactic or therapeutic interventions against clade C HIV-1.ImportanceWe sought to enhance the infectivity of three SHIV stocks by optimization of a key residue in HIV-1 Env (Env375). We developed three new SHIV stocks: SHIV-SF162p3S/wildtype, SHIV-AE16W, and SHIV-325cH. SHIV-SF162p3S could not be optimized, SHIV-AE16W proved comparable to the parental virus, and SHIV-325cH demonstrated markedly enhanced replicative capacity compared to the parental virus.