Antibody-Based Enhancement of CMV Vaccine Vectors for HIV

项目总结 超过3600万人携带人类免疫缺陷病毒(HIV)，它感染了100多万新的 每年都有人来。治疗和预防方面的几项进步有助于降低艾滋病毒发病率和 与艾滋病相关的死亡人数有所增加，但不足以遏制疫情的蔓延。需要一种有效的艾滋病毒疫苗 以帮助减少新的艾滋病毒感染。正如RV144泰国疫苗试验所证明的那样，一种成功的艾滋病毒疫苗 将需要诱导两种抗体来防止获得性抗体和细胞免疫反应以控制突破 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 SIV在50%接种疫苗的恒河猴中复制。这种疫苗通过诱导效应器来保护动物。 位于入口处的记忆T细胞。而恒河猴免疫后的CD8+T细胞反应 它具有很好的特点，而且非常非常规，它与保护没有直接关系。相比之下，几乎没有 已知RhCMV/SIV诱导的CD4+T细胞反应。因为恒河猴是远亲繁殖的， 多样性，他们的MHC II等位基因是复杂的，阻止了对CD4+T细胞反应的对照研究。相比之下， 毛里求斯食蟹猴的遗传多样性有限，我们可以鉴定出MHC-II匹配的MCM。 因此，我们将表达SHV抗原的CyCMV疫苗接种于MHC-II相合的MCM，以研究CD4+T细胞。 细胞反应。我们预测，SHIV特异性的CD4+T细胞反应的频率和功能将相关 感染后的SIV控制。此外，针对HIV的CMV疫苗载体不能防止获得和 不要引发中和抗体。因此，我们打算与CyCMV联合诱导抗体。 通过将CyCMV与HIV-Env DNA/蛋白质顺序免疫相结合进行疫苗接种。我们假设 CMV疫苗方案可以得到加强，以防止因诱导HIV-Env特异性感染而感染 抗体，并可以预防一种新的希沃克病毒挑战病毒。总之，我们建议加强我们的 了解巨细胞病毒疫苗载体，提高该疫苗方案的保护效力。这些 这些发现将直接适用于即将在人类身上进行的针对艾滋病毒的CMV疫苗载体的临床试验。

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.