Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University, Cambridge, MA 02139, USA.
Sci Transl Med. 2017 Sep 20;9(408). doi: 10.1126/scitranslmed.aao4235.
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 序列多样性对广泛中和抗体（bnAbs）的临床开发提出了重大挑战，无论是用于治疗还是预防。在大多数感染 HIV-1 的个体中，都观察到关键 bnAb 表位的序列变异，并且在人类接受 bnAb 单药治疗后可能导致病毒逃逸。我们表明，病毒序列多样性可以限制 bnAbs 在恒河猴中的治疗和预防效果。我们首先证明，V3 糖基依赖性抗体 10-1074 的单药治疗，但不是 PGT121，会导致含有 N332/S334 逃逸突变的预先存在的病毒变体的快速选择，并导致感染 simian-HIV（SHIV）-SF162P3 的恒河猴丧失治疗效果。然后我们表明，V3 糖基依赖性抗体 PGT121 单独使用和 V2 糖基依赖性抗体 PGDM1400 单独使用都不能预防 SHIV-SF162P3 和 SHIV-325c 的混合挑战。相比之下，两种 bnAbs 的联合使用可以 100%预防这种混合 SHIV 挑战。这些数据表明，单一 bnAbs 可以从多样化的挑战群中有效地选择出耐药病毒以建立感染，这表明 bnAb 鸡尾酒在 HIV-1 预防中的重要性。
