Antibodies to CD4-induced sites in HIV gp120 correlate with the control of SHIV challenge in macaques vaccinated with subunit immunogens
Antibodies to CD4-induced sites in HIV gp120 correlate with the control of SHIV challenge in macaques vaccinated with subunit immunogens
复制标题
DOI：
10.1073/pnas.0707399104
复制
发表时间：
2007-10-30
影响因子：
11.1
通讯作者：
Pal, Ranajit
中科院分区：
文献类型：
--
作者：
DeVico, Anthony;Fouts, Timothy;Pal, Ranajit
位于HIV-1包膜糖蛋白（gp 120）的辅助受体结合位点内和周围的表位在附着于CD 4受体后表现出增强的暴露，并且包含病毒包膜上一些最保守和功能上最重要的残基。因此，对这些表位的抗体应答[称为CD 4诱导的（CD 4 i）]应该是高度交叉反应性的，并可能用于HIV疫苗的开发。为了解决这个问题，恒河猴接种亚单位免疫原，旨在提高体液免疫反应的CD 4 i表位和攻击直肠与SHIV（162 P3），它编码一个异源的包膜对免疫原。我们发现，与未接种疫苗的对照动物相比，用恒河猴全长单链（rhFLSC）复合物接种疫苗的动物表现出血浆病毒血症的清除显著加速，并且不存在长期组织病毒血症。与用gp 120、交联gp 120-CD 4复合物或单独的可溶性CD 4免疫的猕猴相比，这种感染控制与rhFLSC免疫的动物中对CD 4 i表位的更强应答相关。通过SHIV（162 P3）感染，这些应答在rhFLSC接种的动物中强烈增强。感染的控制与抗CD 4应答、总体抗gp 120结合滴度或常规测定中测量的中和活性无关。未接种过疫苗的动物在猴/人免疫缺陷病毒（SHIV）攻击后也产生了抗CD 4 i表位应答，其出现时间晚于总体抗gp 120应答，并与病毒血症下降至低设定点一致。总的来说，这些数据表明，CD 4 i表位抗体可能在控制SHIV感染中发挥作用，并为HIV疫苗开发提供见解。
Epitopes located in and around the coreceptor binding site of HIV-1 envelope glycoprotein (gp120) exhibit enhanced exposure after attachment to the CD4 receptor and comprise some of the most conserved and functionally important residues on the viral envelope. Therefore, antibody responses to these epitopes [designated as CD4-induced (CD4i)] should be highly cross-reactive and potentially useful for HIV vaccine development. To address this question, rhesus macaques were vaccinated with subunit immunogens designed to raise humoral responses against CD4i epitopes and challenged rectally with SHIV(162P3), which encodes a heterologous envelope versus the immunogen. We found that animals vaccinated with a rhesus full-length single-chain (rhFLSC) complex exhibited significantly accelerated clearance of plasma viremia and an absence of long-term tissue viremia compared with unvaccinated control animals. Such control of infection correlated with stronger responses to CD4i epitopes in the rhFLSC-vaccinated animals, compared with macaques immunized with gp120, crosslinked gp120-CD4 complexes, or soluble CD4 alone. These responses were strongly boosted in the rhFLSC-vaccinated animals by SHIV(162P3) infection. The control of infection was not associated with anti-CD4 responses, overall anti-gp120-binding titers, or neutralizing activity measured in conventional assays. Vaccine-naive animals also developed anti-CD4i epitope responses after simian/human immunodeficiency virus (SHIV) challenge, which appeared later than the overall anti-gp120 responses and in concert with the decline of viremia to a low set point. Collectively, these data suggest that antibodies to CD4i epitopes may play a role in controlling SHIV infection and provide insights for HIV vaccine development.