The high-affinity immunoglobulin receptor FcγRI potentiates HIV-1 neutralization via antibodies against the gp41 N-heptad repeat.
The high-affinity immunoglobulin receptor FcγRI potentiates HIV-1 neutralization via antibodies against the gp41 N-heptad repeat.
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DOI：
10.1073/pnas.2018027118
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发表时间：
2021-01-19
影响因子：
11.1
通讯作者：
Kim PS
中科院分区：
文献类型：
--
作者：
Montefiori DC;Filsinger Interrante MV;Bell BN;Rubio AA;Joyce JG;Shiver JW;LaBranche CC;Kim PS
尽管经过了几十年的研究，一种有效的HIV-1疫苗仍然遥不可及。一个潜在的疫苗靶点是gp41的n -七肽重复（NHR）区域，这是fda批准的药物enfuvirtide的靶点。然而，迄今为止，针对该区域的单克隆抗体和抗血清仅被适度中和。在这里，我们发现通过在细胞上表达FcγRI (CD64)，具有良好特征的抗nhr抗体D5的中和效力增加了5000倍。由于fc γ - ri在巨噬细胞和树突状细胞上表达，这与性传播后HIV-1感染的早期建立有关，因此这些结果可能对HIV-1疫苗的开发具有重要意义。HIV-1 gp41 n -七肽重复序列（NHR）区域在HIV-1病毒膜融合过程中短暂暴露，是一个经过验证的人类临床靶点，并被美国食品和药物管理局（FDA）批准的药物恩富维肽（enfuvirtide）抑制。然而，针对NHR的候选疫苗在动物中仅产生适度的中和活性；这种抑制在很大程度上仅限于1级病毒，它们对hiv -1感染者的血清中和最为敏感。在这里，我们发现，在表达FcγRI的TZM-bl细胞中，与不表达FcγRI的细胞相比，特征明确的nhr靶向抗体D5的中和活性增强了5000倍，导致许多2级病毒被中和（这些病毒不太容易被hiv -1感染个体的血清中和，是目前基于抗体的疫苗努力的目标）。此外，用基于nhr的候选疫苗（ccIZN36）3免疫的豚鼠的抗血清以依赖fc γ ri的方式中和来自多个分支的tier-2病毒。由于FcγRI在存在于粘膜表面的巨噬细胞和树突状细胞上表达，并与性传播后HIV-1感染的早期建立有关，因此这些结果可能对开发预防性HIV-1疫苗具有重要意义。
Despite decades of research, an effective HIV-1 vaccine remains elusive. One potential vaccine target is the N-heptad repeat (NHR) region of gp41, which is the target of the FDA-approved drug enfuvirtide. However, monoclonal antibodies and antisera targeting this region have only been modestly neutralizing to date. Here, we show that the neutralization potency of the well-characterized anti-NHR antibody D5 is increased >5,000-fold by expression of FcγRI (CD64) on cells. Since FcγRI is expressed on macrophages and dendritic cells, which are implicated in the early establishment of HIV-1 infection following sexual transmission, these results may be important to HIV-1 vaccine development. The HIV-1 gp41 N-heptad repeat (NHR) region of the prehairpin intermediate, which is transiently exposed during HIV-1 viral membrane fusion, is a validated clinical target in humans and is inhibited by the Food and Drug Administration (FDA)-approved drug enfuvirtide. However, vaccine candidates targeting the NHR have yielded only modest neutralization activities in animals; this inhibition has been largely restricted to tier-1 viruses, which are most sensitive to neutralization by sera from HIV-1–infected individuals. Here, we show that the neutralization activity of the well-characterized NHR-targeting antibody D5 is potentiated >5,000-fold in TZM-bl cells expressing FcγRI compared with those without, resulting in neutralization of many tier-2 viruses (which are less susceptible to neutralization by sera from HIV-1–infected individuals and are the target of current antibody-based vaccine efforts). Further, antisera from guinea pigs immunized with the NHR-based vaccine candidate (ccIZN36)3 neutralized tier-2 viruses from multiple clades in an FcγRI-dependent manner. As FcγRI is expressed on macrophages and dendritic cells, which are present at mucosal surfaces and are implicated in the early establishment of HIV-1 infection following sexual transmission, these results may be important in the development of a prophylactic HIV-1 vaccine.
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