Contributions of anti-V2 antibodies in protection against HIV

免疫效应机制，赋予保护艾滋病毒的收购仍然知之甚少。来自初免/加强ALVAC+ gp 120蛋白疫苗的III期RV 144试验的最新数据表明，抗gp 120抗体应答具有潜在的保护作用，该试验使病毒获得总体减少31.2%。具体而言，在RV 144病例对照研究中评价的六个主要免疫学参数中，对HIV包膜gp 120的V2环的高IgG应答与保护免受HIV感染显著相关。然而，目前尚不清楚抗V2抗体是否具有阻断HIV感染的直接抗病毒功能。由于gp 120的V2和其他可变环的高度可变序列，它们被认为是HIV疫苗的不期望的靶标。虽然对V2序列的更仔细的研究已经证明了AA保守性的显著水平，包括保守的LDV/I基序，其参与了结合。4 B7整联蛋白，在用于粘膜传递的关键CD 4 T细胞靶标上表达的肠道归巢受体，抗-V2抗体对许多HIV-1具有很小或没有中和活性，1原代分离株，在常规测定条件下使用不表达<$4B7的靶细胞进行测定。我们在此提出利用非常规的体外和体内方法来研究抗V2抗体阻断HIV传播的能力。我们将首先通过改变孵育时间、温度、有或没有活性<$4B7的靶CD 4 T细胞、无细胞和细胞间传播来测量抗V2人单克隆抗体在体外阻断病毒感染的能力。其次，我们将在体内测试人抗V2单克隆抗体在人源化小鼠中的被动转移和病毒攻击中减少HIV获得的能力。最后，我们将评估通过疫苗接种产生的多克隆抗V2抗体在体外和体内介导病毒阻断的能力。我们的研究结果将确定抗V2抗体应答在预防HIV感染中的潜在贡献，为未来HIV疫苗的设计开辟新的途径。

Immune effector mechanisms that confer protection against HIV acquisition remains poorly understood. Recent data from the Phase III RV144 trial of the prime/boost ALVAC+gp120 protein vaccine, which delivered an overall 31.2% reduction in virus acquisition, suggest potential protective effects of anti-gp120 antibody responses. Specifically, of the six primary immunological parameters evaluated in the RV144 case-control study, high IgG responses to the V2 loop of HIV envelope gp120 significantly correlate with protection from HIV infection. However, it is unclear if anti-V2 antibodies have direct anti-viral functions for blocking HIV infection. V2 and other variable loops of gp120 are thought to be undesirable targets for HIV vaccines, due to their highly variable sequences. While a closer scrutiny of V2 sequences has demonstrated a significant level of AA conservation including a conserved LDV/I motif, which is involved in binding ¿4B7 integrin, the gut homing receptor expressed on key CD4 T cell targets for mucosal transmission, anti-V2 antibodies have little or no neutralizing activities against many HIV-1 primary isolates when measured under conventional assay conditions and with target cells expressing no ¿4B7. We propose herein to utilize non-conventional in vitro and in vivo approaches to investigate the capacity of anti-V2 antibodies to block HIV transmission. We will first measure the ability of anti-V2 human monoclonal antibodies to block virus infection in vitro by varying incubation time, temperature, target CD4 T cells with or without active ¿4B7, cell-free and cell-to-cell transmission. Secondly, we will test human anti-V2 monoclonal antibodies in vivo for the ability to reduce HIV acquisition in passive transfer and virus challenge in humanized mice. Finally, we will evaluate the ability of polyclonal anti-V2 antibodies raised by vaccination to mediate virus blocking in vitro and in vivo. Our results will define the potential contributions of anti-V2 antibody response in preventing HIV acquisition, opening a new venue for future design of HIV vaccines.