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.

HIV-1序列多样性为用于治疗和预防的广泛中和抗体（bNAb）的临床开发提出了重大挑战。在大多数感染HIV-1的个体中都观察到了关键bNAb表位的序列变异，并且在人类中bNAb单药治疗后可能导致病毒逃逸。我们显示病毒序列多样性可以限制恒河猴中bNAbs的治疗和预防功效。我们首先证明，使用V3聚糖依赖性抗体10-1074而不是PGT121单药治疗可快速选择包含N332 / S334逃逸突变的既存病毒变体，并在感染猿猴HIV（SHIV）-SF162P3的治疗中丧失疗效恒河猴。然后，我们表明，单独的V3聚糖依赖性抗体PGT121和单独的V2聚糖依赖性抗体PGDM1400都无法保护免受SHIV-SF162P3和SHIV-325c的混合攻击。相反，两种bNAb的组合可针对这种混合SHIV攻击提供100％的保护。这些数据表明，单个bNAb可以有效地从各种各样的挑战群中筛选出具有抗药性的病毒以建立感染，这证明了bNAb混合物对于预防HIV-1的重要性。