Antibodies against the HIV-1 V1V2 loops were the only correlate of reduced infection risk in the RV144 vaccine trial, highlighting the V1V2 loops as promising targets for vaccine design. The V1V2 loops are structurally plastic, exhibiting either an α-helix-coil or β-strand conformation. V1V2-specific antibodies may thus recognize distinct conformations, and an antibody’s conformational specificity can be an important determinant of breadth and function. Restricting V1V2 conformational plasticity in an immunogen may thus provide control over the conformational specificity and quality of a vaccine-elicited antibody response.

Previously, we identified a V1V2 sequence variant (K155M) that results in enhanced recognition by cross-reactive antibodies recognizing the β-strand conformation. Here, we relate V1V2 antigenicity to immunogenicity by comparing the immunogenicity profiles of wildtype and K155M immunogens in two mouse models. In one model, immunization with gp70 V1V2 K155M but not wildtype elicited antibody responses that were cross-reactive to a panel of heterologous gp120 and gp140 antigens. In a second model, we compared the effect of K155M on immunogenicity in the context of gp70 V1V2, gD V1V2 and gp120, examining the effects of scaffold, epitope-focusing and immunization regimen. K155M variants, especially in the context of a gp120 immunogen, resulted in more robust, durable and cross-reactive antibody responses than wildtype immunogens. Restriction of the β-stranded V1V2 conformation in K155M immunogens may thus be associated with the induction of cross-reactive antibody responses thought to be required of a protective HIV-1 vaccine.

在 RV144 疫苗试验中，针对 HIV-1 V1V2 环的抗体是降低感染风险的唯一相关因素，这凸显了 V1V2 环作为疫苗设计的有希望的目标。V1V2 环在结构上是可塑的，呈现出 α 螺旋或 β 链构象。因此，V1V2 特异性抗体可以识别不同的构象，并且抗体的构象特异性可能是广度和功能的重要决定因素。因此，限制免疫原中的 V1V2 构象可塑性可以控制疫苗引发的抗体反应的构象特异性和质量。

此前，我们鉴定了 V1V2 序列变体 (K155M)，该变体可通过识别 β 链构象的交叉反应抗体增强识别能力。在这里，我们通过比较两种小鼠模型中野生型和 K155M 免疫原的免疫原性概况，将 V1V2 抗原性与免疫原性联系起来。在一个模型中，用gp70 V1V2 K155M而非野生型进行免疫引发了与一组异源gp120和gp140抗原发生交叉反应的抗体反应。在第二个模型中，我们比较了 K155M 在 gp70 V1V2、gD V1V2 和 gp120 背景下对免疫原性的影响，检查了支架、表位聚焦和免疫方案的影响。K155M 变体，特别是在 gp120 免疫原的情况下，比野生型免疫原产生更强大、持久和交叉反应的抗体反应。因此，K155M 免疫原中 β 链 V1V2 构象的限制可能与交叉反应性抗体反应的诱导有关，而交叉反应性抗体反应被认为是保护性 HIV-1 疫苗所必需的。