Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305.
Sarafan ChEM-H, Stanford University, Stanford, CA 94305.
Proc Natl Acad Sci U S A. 2023 Feb 21;120(8):e2215792120. doi: 10.1073/pnas.2215792120. Epub 2023 Feb 16.
HIV-1 strains are categorized into one of three neutralization tiers based on the relative ease by which they are neutralized by plasma from HIV-1-infected donors not on antiretroviral therapy; tier-1 strains are particularly sensitive to neutralization while tier-2 and tier-3 strains are increasingly difficult to neutralize. Most broadly neutralizing antibodies (bnAbs) previously described target the native prefusion conformation of HIV-1 Envelope (Env), but the relevance of the tiered categories for inhibitors targeting another Env conformation, the prehairpin intermediate, is not well understood. Here, we show that two inhibitors targeting distinct highly conserved regions of the prehairpin intermediate have strikingly consistent neutralization potencies (within ~100-fold for a given inhibitor) against strains in all three neutralization tiers of HIV-1; in contrast, best-in-class bnAbs targeting diverse Env epitopes vary by more than 10,000-fold in potency against these strains. Our results indicate that antisera-based HIV-1 neutralization tiers are not relevant for inhibitors targeting the prehairpin intermediate and highlight the potential for therapies and vaccine efforts targeting this conformation.
HIV-1 毒株根据其在未接受抗逆转录病毒治疗的 HIV-1 感染者血浆中的相对易中和性，分为三个中和等级之一；1 级毒株特别容易被中和，而 2 级和 3 级毒株则越来越难以中和。以前描述的大多数广谱中和抗体（bnAbs）针对 HIV-1 包膜（Env）的天然前融合构象，但针对另一种 Env 构象——发夹前中间体的抑制剂的分层类别相关性尚不清楚。在这里，我们表明，两种针对发夹前中间体不同高度保守区域的抑制剂对 HIV-1 的所有三个中和等级的毒株具有惊人一致的中和效力（对于给定的抑制剂，在~100 倍以内）；相比之下，针对不同 Env 表位的最佳类别 bnAbs 对这些毒株的效力差异超过 10,000 倍。我们的结果表明，基于抗血清的 HIV-1 中和等级与针对发夹前中间体的抑制剂无关，并强调了针对这种构象的疗法和疫苗努力的潜力。
