Asmal Mohammed, Lane Sophie, Tian Meijuan, Nickel Gabrielle, Venner Colin, Dirk Brennan, Dikeakos Jimmy, Luedemann Corinne, Mach Linh, Balachandran Harikrishnan, Buzby Adam, Rao Srinivas, Letvin Norman, Gao Yong, Arts Eric J
Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Division of Infectious Diseases and HIV Medicine, Case Western Reserve University, Cleveland, OH 44106, USA; Department of Microbiology and Immunology, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, Canada.
Virology. 2016 Dec;499:298-312. doi: 10.1016/j.virol.2016.09.021. Epub 2016 Oct 7.
For studies on vaccines and therapies for HIV disease, SIV-HIV chimeric viruses harboring the HIV-1 env gene (SHIVenv) remain the best virus in non-human primate models. However, there are still very few SHIVenv viruses that can cause AIDS in non-CD8-depleted animals. In the present study, a recently created CCR5-using SHIVenv_B3 virus with env gene derived from acute/early HIV-1 infections (AHI) successfully established pathogenic infection in macaques. Through a series of investigations on the evolution, mutational profile, and phenotype of the virus and the resultant humoral immune response in infected rhesus macaques, we found that the E32K mutation in the Env C1 domain was associated with macaque pathogenesis, and that the electrostatic interactions in Env may favor E32K at the gp120 N terminus and "lock" the binding to heptad repeat 1 of gp41 in the trimer and produce a SHIVenv with increased fitness and pathogenesis during macaque infections.
对于艾滋病病毒疾病的疫苗和疗法研究，携带HIV-1 env基因的SIV-HIV嵌合病毒（SHIVenv）在非人灵长类动物模型中仍是最佳病毒。然而，能够在未进行CD8细胞耗竭的动物中引发艾滋病的SHIVenv病毒仍然非常少。在本研究中，一种最近构建的利用CCR5的SHIVenv_B3病毒，其env基因源自急性/早期HIV-1感染（AHI），成功在猕猴中建立了致病性感染。通过对该病毒在受感染恒河猴中的进化、突变谱、表型以及由此产生的体液免疫反应进行一系列研究，我们发现Env C1结构域中的E32K突变与猕猴发病机制相关，并且Env中的静电相互作用可能有利于gp120 N端的E32K，并“锁定”三聚体中与gp41七肽重复序列1的结合，从而在猕猴感染期间产生适应性和致病性增强的SHIVenv。
