Contributions of anti-V2 antibodies in protection against HIV

描述（由申请人提供）：对预防艾滋病毒感染的免疫效应机制仍知之甚少。来自RV144 III期试验的最新数据显示，prime/boost ALVAC+gp120蛋白疫苗总体上降低了31.2%的病毒获得率，表明抗gp120抗体应答具有潜在的保护作用。具体来说，在RV144病例对照研究中评估的六个主要免疫学参数中，对HIV包膜gp120 V2环的高IgG应答与对HIV感染的保护显著相关。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。V2和gp120的其他可变环被认为是HIV疫苗不希望的靶标，因为它们的序列高度可变。虽然对V2序列的更仔细的检查已经证明了AA保护的显著水平，包括保守的LDV/I基序，它参与结合¿4¿7整合素，肠道归巢受体在关键的CD4 T细胞靶点上表达的粘膜传递，抗V2抗体对许多HIV-1初级分离株在常规检测条件下和靶细胞表达no¿4¿7时很少或没有中和活性。在此，我们建议利用非传统的体外和体内方法来研究抗v2抗体阻断HIV传播的能力。我们将首先测量抗v2人单克隆抗体在体外阻断病毒感染的能力，方法是改变孵育时间、温度、靶向CD4 T细胞是否具有活性、无细胞传播和细胞间传播。其次，我们将在体内测试人抗v2单克隆抗体在人源化小鼠的被动转移和病毒攻击中减少HIV获得的能力。最后，我们将评估的能力

DESCRIPTION (provided by applicant): 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 ¿4¿7 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 ¿4¿7. 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 ¿4¿7, 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. PUBLIC HEALTH RELEVANCE: A prophylactic vaccine is much needed for controlling the HIV/AIDS pandemic, but its development has faced tremendous challenges. The immune mechanisms needed to protect against this virus are not fully understood. This proposal aims to address how antibodies against the V2 loop of HIV envelope gp120 contribute to protection against HIV transmission.