Contributions of anti-V2 antibodies in protection against HIV

描述（由申请人提供）：对保护免受HIV感染的免疫效应机制仍知之甚少。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的显著水平的保守性，包括保守的LDV/I基序，其参与结合。7整联蛋白，在粘膜传递的关键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，当在常规测定条件下和用表达no <$4 <$7的靶细胞测量时，我们在此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。我们将首先通过改变孵育时间、温度、具有或不具有活性<$4 <$7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抗体介导体外和体内病毒阻断。 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。 公共卫生相关性：预防性疫苗对于控制艾滋病毒/艾滋病流行病是非常必要的，但其发展面临着巨大的挑战。保护免受这种病毒感染所需的免疫机制尚未完全了解。该提案旨在解决针对HIV包膜gp 120的V2环的抗体如何有助于防止HIV传播。

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.