Pegu, Amarendra, Lovelace, Sarah E., DeMouth, Megan E., Cully, Michelle D., Morris, Daniel J., Li, Yingying, Wang, Keyun, Schmidt, Stephen D., Choe, Misook, Liu, Cuiping, Chen, Xuejun, Viox, Elise, Rowshan, Ariana, Taft, Justin D., Zhang, Baoshan, Xu, Kai, Duan, Hongying, Ou, Li, Todd, John-Paul, and Kong, Rui
The fusion peptide (FP) on the HIV-1 envelope (Env) trimer can be targeted by broadly neutralizing antibodies (bNAbs). Here, we evaluated the ability of a human FP-directed bNAb, VRC34.01, along with two vaccine-elicited anti-FP rhesus macaque mAbs, DFPH-a.15 and DF1W-a.01, to protect against simian-HIV (SHIV)BG505 challenge. VRC34.01 neutralized SHIVBG505 with a 50% inhibitory concentration (IC50) of 0.58 μg/ml, whereas DF1W-a.01 and DFPH-a.15 were 4- or 30-fold less potent, respectively. VRC34.01 was infused into four rhesus macaques at a dose of 10 mg/kg and four rhesus macaques at a dose of 2.5 mg/kg. The animals were intrarectally challenged 5 days later with SHIVBG505. In comparison with all 12 control animals that became infected, all four animals infused with VRC34.01 (10 mg/kg) and three out of four animals infused with VRC34.01 (2.5 mg/kg) remained uninfected. Because of the lower potency of DF1W-a.01 and DFPH-a.15 against SHIVBG505, we infused both Abs at a higher dose of 100 mg/kg into four rhesus macaques each, followed by SHIVBG505 challenge 5 days later. Three of four animals that received DF1W-a.01 were protected against infection, whereas all animals that received DFPH-a.15 were protected. Overall, the protective serum neutralization titers observed in these animals were similar to what has been observed for other bNAbs in similar SHIV infection models and in human clinical trials. In conclusion, FP-directed mAbs can thus provide dose-dependent in vivo protection against mucosal SHIV challenges, supporting the development of prophylactic vaccines targeting the HIV-1 Env FP. Editor's summary: The fusion peptide (FP) on the HIV-1 envelope protein is a conserved site that can be targeted by neutralizing antibodies. However, the extent of protection conferred by FP-directed antibodies in the context of mucosal infection is unclear. Here, Pegu et al. tested three different anti-FP antibodies, including one human antibody and two rhesus macaque antibodies, for their ability to neutralize HIV-1 in vitro and confer protection against simian-HIV (SHIV) challenge of rhesus macaques in vivo. All three antibodies conferred protection against mucosal challenge with SHIV at clinically meaningful titers, supporting further development of both anti-FP antibody therapies and vaccines designed to elicit anti-FP humoral responses. —Courtney Malo [ABSTRACT FROM AUTHOR]