LAUSR

A combination of HIV-1–specific broadly neutralizing antibodies is necessary to protect rhesus monkeys against a mixed SHIV challenge. Swatting away a swarm Monoclonal antibodies are being tested as therapy for many infections, including HIV. However, increasing evidence suggests that therapy with a single agent may encourage resistant viral strains to emerge. Julg et al. tested how potent HIV neutralizing antibodies could combat challenge with a mix of SHIV strains in nonhuman primates. They found that monotherapy with anti-V3 PGT121 or anti-V2 PGDM1400 allowed for selection of resistant viruses and subsequent replication in the animals. Dual antibody administration conferred complete protection, confirming that combination therapy may be necessary for protective efficacy against HIV in people. HIV-1 sequence diversity presents a major challenge for the clinical development of broadly neutralizing antibodies (bNAbs) for both therapy and prevention. Sequence variation in critical bNAb epitopes has been observed in most HIV-1–infected individuals and can lead to viral escape after bNAb monotherapy in humans. We show that viral sequence diversity can limit both the therapeutic and prophylactic efficacy of bNAbs in rhesus monkeys. We first demonstrate that monotherapy with the V3 glycan-dependent antibody 10-1074, but not PGT121, results in rapid selection of preexisting viral variants containing N332/S334 escape mutations and loss of therapeutic efficacy in simian-HIV (SHIV)–SF162P3–infected rhesus monkeys. We then show that the V3 glycan-dependent antibody PGT121 alone and the V2 glycan-dependent antibody PGDM1400 alone both fail to protect against a mixed challenge with SHIV-SF162P3 and SHIV-325c. In contrast, the combination of both bNAbs provides 100% protection against this mixed SHIV challenge. These data reveal that single bNAbs efficiently select resistant viruses from a diverse challenge swarm to establish infection, demonstrating the importance of bNAb cocktails for HIV-1 prevention.