Subtype Differences in HIV-1 Transmitted Founder Viruses

摘要 研究表明，在临床表现和传播率方面， HIV-1亚型A和C。这些差异包括C亚型的疾病进展率增加 感染与亚型A相比，以及与亚型C相比亚型A相关的传播率增加（2， 3）。已经阐明的早期HIV-1感染的一个关键方面是传播创始者（TF）的作用 病毒，这是病毒变异，建立系统性HIV-1感染。新的HIV-1感染的早期事件， 特别是受TF病毒的复制能力（RC）的影响，已被证明具有深刻的 对疾病轨迹的影响（4，5）。虽然与非传播性（NT）病毒相比，TF的特征 尽管已经研究了HIV-1的变异，但TF表型在HIV-1亚型差异中所起的作用还没有被证实。 被调查了这项研究的目的是确定病毒表型和细胞因子在病毒感染中的作用。 宿主对A亚型和C亚型HIV-1感染之间观察到的临床差异的影响。我们 这一假设的基础是观察到的疾病进展和传播率的差异， HIV-1A亚型和C亚型感染是由于A亚型TF病毒的不同表型特性所致 以及TF与先天免疫系统的不同相互作用。我们的目标是调查是否有 不同亚型的TF之间的表型差异以及不同亚型的TF如何相互作用 与树突状细胞（DC）和相关的先天免疫系统，以确定这些因素是否与 临床表现和传播率之间的差异。在我们的第一个目标中，我们将 研究A亚型和C亚型TF的病毒表型是否与不同的 通过测量亚型C TF与亚型A TF的复制能力（RC）来评估疾病进展。我们将 还研究了C亚型和A亚型TF介导转感染的能力，其中DC携带HIV-1 然后通过免疫突触将病毒转移到易感的CD 4 T细胞。在决赛中 作为目标1的一部分，我们将比较A亚型TFV与C亚型TFV的预适应水平， 如果亚型C能够更有效地逃避宿主的适应性免疫应答。我们的第二个目标是 检查亚型之间的差异是否可以归因于不同的先天免疫 TF病毒与DC相互作用引发的免疫应答。我们将通过比较RNA 来自女性生殖道来源的DC（FRT DC）的表达和分泌分子谱 在暴露于A亚型或C亚型TF之后。最后，我们将研究FRT DCs如何与A亚型或 通过比较CD 4 T细胞的RNA表达谱，C TF刺激静息的CD 4 T细胞。的结果 这项研究将更好地了解HIV-1转录因子与先天免疫的早期相互作用， 系统以及决定不同HIV-1的宿主病毒感染之间差异的病毒因子 亚型

Abstract Studies have shown that there are distinct differences in clinical presentation and transmission rates between HIV-1 subtype A and C. These differences include an increased rate of disease progression for subtype C infections vs. subtype A, as well as increased transmission rates associated with subtype C vs. subtype A (2, 3). One key aspect of early HIV-1 infection that has been elucidated is the role of the transmitted-founder (TF) virus, which is the viral variant that establishes systemic HIV-1 infection. Early events in a new HIV-1 infection, influenced in particular by the replicative capacity (RC) of the TF virus, have been shown to have a profound effect on the trajectory of disease (4, 5). While characteristics of TFs compared to non-transmitted (NT) viral variants have been investigated, the role that the TF phenotype plays in HIV-1 subtype differences has not been investigated. The purpose of this proposed study is to determine the role that viral phenotypes and the impact of the host has on the clinical differences observed between subtype A and C HIV-1 infections. Our hypothesis is that the basis of observed differences in disease progression and transmission rate between HIV-1 subtype A and subtype C infections is due to different phenotypic properties in the subtype A TF virus and differing interactions of the TF with the innate immune system. We aim to investigate whether there are phenotypic differences between the TFs of different subtypes and how the TFs of different subtypes interact with dendritic cells (DCs) and the associated innate immune system to determine if these factors correlate with the differences observed between clinical presentation and transmission rates. In our first aim, we will investigate if viral phenotypes of subtype A and subtype C TFs are associated with the different rates of disease progression by measuring the replicative capacity (RC) of subtype C TFs vs. subtype A TFs. We will also investigate the ability of subtype C and subtype A TFs to mediate trans-infection, where DCs carry HIV-1 to CD4 T cells and then transfer the virus through an immune synapse to susceptible CD4 T cells. In the final part of aim 1, we will compare the level of pre-adaptation in subtype A TFV compared to subtype C TFV to see if subtype C is able to more efficiently evade the adaptive immune response of the host. Our second aim will examine whether the differences seen between subtypes can be attributed to different innate immune responses triggered by interaction of the TF virus with DCs. We will determine this by comparing RNA expression and secreted molecule profiles from DCs derived from the female reproductive tract (FRT DCs) after exposure to subtype A or subtype C TFs. Finally, we will examine how FRT DCs pulsed with subtype A or C TFs stimulate resting CD4 T cells by comparing RNA expression profiles of the CD4 T cells. The outcome of this research will be a better understanding of early interactions of the HIV-1 TFs with the innate immune system as well as viral factors that determine differences between host-virus infections with different HIV-1 subtypes.