Limited or no protection by weakly or nonneutralizing antibodies against vaginal SHIV challenge of macaques compared with a strongly neutralizing antibody
Limited or no protection by weakly or nonneutralizing antibodies against vaginal SHIV challenge of macaques compared with a strongly neutralizing antibody
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DOI：
10.1073/pnas.1103012108
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发表时间：
2011-07-05
影响因子：
11.1
通讯作者：
Moore, John P.
中科院分区：
文献类型：
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作者：
Burton, Dennis R.;Hessell, Ann J.;Moore, John P.
为了指导疫苗设计，我们评估了针对HIV-1 gp 120上的CD 4结合位点（CD 4 bs）的人单克隆抗体（MAbs）b12和b6以及针对gp 41上的免疫显性表位的F240是否可以预防猴HIV（SHIV）-162P4向猕猴的阴道传播。这两种抗gp 120单克隆抗体具有相似的单体gp 120结合特性，在体外测量，但b12是强中和和b6不是。F240是非中和的。以高剂量阴道施用，强中和单抗b12在7只动物中的7只中提供了灭菌免疫，b6在5只动物中的0只中提供了灭菌免疫，F240在5只动物中的2只中提供了灭菌免疫。与对照动物相比，b12的保护作用具有统计学意义，而F240的保护作用则无统计学意义。对于三只未受保护的F240处理的动物中的两只，存在降低病毒血症的趋势。F240的潜在保护作用可能与该抗体捕获感染性病毒粒子的能力相对较强有关。另外的被动转移实验也表明，所施用的抗gp 120单克隆抗体中和攻击病毒的能力对保护作用具有关键影响。此外，当合并所有实验的数据时，与其他未受保护的猕猴相比，接受MAb b6的动物中建立感染的创始病毒数量显著增加。因此，gp 120结合，弱中和的单克隆抗体的CD 4 bs，在最好的情况下，完全无效的保护。gp 41的非中和抗体可能具有有限的保护能力，但结果表明，HIV-1疫苗研究的中心重点应该是诱导有效的中和抗体。
To guide vaccine design, we assessed whether human monoclonal antibodies (MAbs) b12 and b6 against the CD4 binding site (CD4bs) on HIV-1 gp120 and F240 against an immundominant epitope on gp41 could prevent vaginal transmission of simian HIV (SHIV)-162P4 to macaques. The two anti-gp120 MAbs have similar monomeric gp120-binding properties, measured in vitro, but b12 is strongly neutralizing and b6 is not. F240 is nonneutralizing. Applied vaginally at a high dose, the strongly neutralizing MAb b12 provided sterilizing immunity in seven of seven animals, b6 in zero of five animals, and F240 in two of five animals. Compared with control animals, the protection by b12 achieved statistical significance, whereas that caused by F240 did not. For two of three unprotected F240-treated animals there was a trend toward lowered viremia. The potential protective effect of F240 may relate to the relatively strong ability of this antibody to capture infectious virions. Additional passive transfer experiments also indicated that the ability of the administered anti-gp120 MAbs to neutralize the challenge virus was a critical influence on protection. Furthermore, when data from all of the experiments were combined, there was a significant increase in the number of founder viruses establishing infection in animals receiving MAb b6, compared with other nonprotected macaques. Thus, a gp120-binding, weakly neutralizing MAb to the CD4bs was, at best, completely ineffective at protection. A nonneutralizing antibody to gp41 may have a limited capacity to protect, but the results suggest that the central focus of HIV-1 vaccine research should be on the induction of potently neutralizing antibodies.