Deciphering the impact of sex in early subtype C HIV infection and during HART

目前的估计表明，有1780万妇女感染了艾滋病毒-1，这是导致 育龄妇女死亡。然而，迄今为止，许多关于HIV-1传播和发病机制的研究 专注于单一性别，因此无法直接比较 男人和女人。这项资助中概述的初步实验利用了C型HIV-1亚型队列的样本 急性感染的赞比亚男人和女人，允许直接比较病毒，转录和 具有共同遗传背景的个体的性别间的免疫学特征。 矛盾的是，即使来自急性感染女性的CD4T细胞显著更高地激活 (CD38)女性的病毒载量始终低于男性，无论是在早期阶段还是在 感染的慢性期。另一方面，虽然女性表现出同样有效的病毒抑制水平 在抗逆转录病毒治疗(HART)方面，她们确实比男性承担了更大的非艾滋病共病负担。这些 观察结果可能是病毒、荷尔蒙和免疫之间的复杂相互作用的结果 因素，包括女性I型干扰素(干扰素)的产生增加，这可以同时 导致免疫激活以及限制病毒复制。为了更好地理解分子基础 这些基于性别的差异，我们提出了三个具体目标： 目的1：评估儿童CD4T细胞在免疫学和转录水平上的性别差异 早期感染。 目标2：在ART抑制的女性和男性中，定义免疫细胞激活的图景，自然 在性激素存在和不存在的情况下，潜伏的储存库以及它重新激活的可能性。 目的3：明确性激素调控病毒体外复制的机制和细胞来源。 拟议的实验将填补我们对潜在机制的理解的一个重大空白。 观察到男性和女性在HIV-1病程和共病方面的差异，一个重要的 在性别差异清楚地定义各种疾病的不同疾病结果的时候提出问题 设置。

Current estimates suggest that 17.8 million women are infected with HIV-1 and that it is the leading cause of death in women of reproductive age. However, many studies of HIV-1 transmission and pathogenesis to date have focused on a single sex and are thus unable to directly compare disease course and outcomes between men and women. The initial experiments outlined in this grant utilize samples from a cohort of subtype C HIV-1 acutely infected Zambian men and women that allow for direct comparison of viral, transcriptional and immunologic characteristics between the sexes in individuals with a common genetic background. Paradoxically, even though CD4+ T cells from acutely infected women are significantly more highly activated (CD38+) than in men, women have consistently lower viral load than men, both in the earliest stages and chronic phase of infection. On the other hand, while women exhibit similarly effective levels of viral suppression on antiretroviral treatment (HART), they do bear a greater burden of non-AIDS comorbidities than men. These observations likely result from a complex interaction between a number of viral, hormonal and immunological factors, including the increased production of type I interferons (IFN) in women which can simultaneously cause immune activation as well as restriction of viral replication. In order to understand the molecular basis of these sex-based differences, we propose three Specific Aims: Aim 1: Assess sex-specific differences in immunological and transcriptional profiles of CD4+ T cells in early infection. Aim 2: In ART-suppressed women and men, define the landscape of immune cell activation, the nature of the latent reservoir, and its potential for reactivation in the presence and absence of sex hormones. Aim 3: Define the mechanism and cell source of sex hormone modulation of viral replication in vitro. The proposed experiments will fill a significant gap in our understanding of the mechanisms underlying observed differences in HIV-1 disease course and comorbidities between men and women, an important question at a time when sex differences are clearly defining distinct disease outcomes in various disease settings.