Antibody-Based Enhancement of CMV Vaccine Vectors for HIV

项目摘要 超过3600万人感染了人类免疫缺陷病毒（艾滋病毒）， 人们每年。治疗和预防方面的一些进展有助于降低艾滋病毒发病率， 与艾滋病有关的死亡，但不足以阻止这一流行病的蔓延。需要有效的艾滋病毒疫苗 帮助减少新的艾滋病毒感染。正如RV 144泰国疫苗试验所证明的，一种成功的艾滋病毒疫苗 将需要诱导抗体以防止获得和细胞免疫应答以控制突破 病毒表达SIV抗原的恒河猴巨细胞病毒68-1株（RhCMV/SIV）能够严格控制 在50%接种疫苗的恒河猴中SIV复制。这种疫苗通过诱导效应子来保护动物 位于入口处的记忆T细胞。虽然免疫恒河猴的CD 8 + T细胞应答 是一个很好的特点和高度非传统的，它不直接与保护。相比之下， 已知RhCMV/SIV诱导的CD 4 + T细胞应答。因为恒河猴是远系繁殖的， 由于多种多样，它们的MHC II等位基因很复杂，阻碍了对CD 4 + T细胞反应的对照研究。与此相反的是， 中国猕猴具有有限的遗传多样性，我们可以识别MHC-II匹配的MCM。 因此，我们将用表达SHIV抗原的CyCMV接种MHC-II匹配的MCM，以研究CD 4 + T细胞的变化。 细胞反应。我们预测，SHIV特异性CD 4 + T细胞应答的频率和功能将与SHIV感染相关。 感染后的SHIV控制。此外，用于HIV的CMV疫苗载体不能防止感染， 不会引发中和抗体。因此，我们打算结合CyCMV诱导抗体， 通过将CyCMV与顺序的HIV-Env DNA/蛋白免疫组合进行疫苗接种。我们假设 CMV疫苗方案可以通过诱导HIV-Env特异性免疫应答来增强以防止获得。 抗体，并可以保护免受新的SHIV攻击病毒。最后，我们建议加强 本发明的目的在于提高对CMV疫苗载体的理解并增加该疫苗方案的保护效力。这些 这些发现将直接应用于即将进行的人体CMV疫苗载体HIV临床试验。

PROJECT SUMMARY Over 36 million people are living with human immunodeficiency virus (HIV) and it infects over 1 million new people every year. Several advancements in treatment and prevention have helped reduce HIV incidence and AIDS-related deaths, but are insufficient to stem the spread of the epidemic. An effective HIV vaccine is needed to help reduce new HIV infections. As demonstrated by the RV144 Thai Vaccine Trail, a successful HIV vaccine will need to induce both antibodies to prevent acquisition and a cellular immune response to control breakthrough virus. Rhesus cytomegalovirus, strain 68-1, expressing SIV antigens (RhCMV/SIV) enables stringent control of SIV replication in 50% of vaccinated rhesus macaques. This vaccine protects animals by inducing effector memory T cells that reside at the portals of entry. While the CD8+ T cell response in vaccinated rhesus macaques is well-characterized and highly unconventional, it does not directly correlate with protection. In contrast, little is known about the RhCMV/SIV-induced CD4+ T cell response. Because the rhesus macaque is outbred and diverse, their MHC II alleles are complex and prevent controlled studies of the CD4+ T cell response. In contrast, Mauritian cynomolgus macaques have limited genetic diversity and we can identify MHC-II-matched MCM. Therefore, we will vaccinate MHC-II-matched MCM with CyCMV expressing SHIV antigens to study the CD4+ T cell response. We predict that the frequency and function of the SHIV-specific CD4+ T cell response will correlate with post-infection SHIV control. In addition, CMV vaccine vectors for HIV do not protect against acquisition and do not elicit neutralizing antibodies. Therefore, we intend to induce antibodies in conjunction with CyCMV vaccination by combining CyCMV with sequential HIV-Env DNA/protein immunizations. We hypothesize that CMV vaccine regimens can be enhanced to protect against acquisition by the induction of HIV-Env specific antibodies and can protect against a novel SHIV challenge virus. In conclusion, we propose to enhance our understanding of CMV vaccine vectors and to increase the protective efficacy of this vaccine regimen. These findings will be directly applicable to impending clinical trials of CMV vaccine vectors in humans for HIV.