SIV antisense epitopes as novel markers of latency

 描述：HIV建立潜伏感染，阻碍完全治愈的努力。这种治愈的可能性取决于新的策略来识别，量化并最终消除潜伏感染的细胞。理想的方法是识别潜伏感染的细胞并消除它们，而不需要重新激活潜伏病毒。在这里，我们基于对HIV和SIV转录和翻译的新见解，证实了潜伏感染细胞的一种新标记物的存在。具体来说，我们假设潜伏感染与 病毒反义转录和翻译。已发表的关于HIV的数据和我们对SIV感染恒河猴的初步数据表明，当细胞活化程度较低时，受感染的CD 4 + T细胞中的反义转录更为突出，并且这些独特的转录物中有许多是聚腺苷酸化的，可以被翻译。此外，我们已经鉴定了在SIV和HIV感染期间发生的T细胞应答，其靶向源自反义转录物翻译的令人惊讶的保守肽。为了验证我们的假设，在目标1中，我们将使用SIV感染的恒河猴和HIV-1感染的人细胞比较潜伏感染的CD 4 T细胞与活化和感染的CD 4 T细胞之间的病毒转录（有义和反义）。为此，我们将使用一种新的链特异性深度测序方法。目标1的结果将使我们的努力集中在目标2上。在目标2中，我们将使用识别反义编码表位的T细胞，并测量它们杀死潜伏感染与活化和感染的CD 4 T细胞的能力。总之，这一提议有可能鉴定潜伏感染细胞的新标记物，并提出消除它们的方法。这些数据可能对开发治疗艾滋病毒的方法很重要。

 DESCRIPTION: HIV establishes latent infection, hampering efforts for a complete cure. The possibility of such a cure rests on new strategies to identify, quantify and ultimately eliminate latently infected cells. An ideal approach would be to identify latently infected cells and eliminae them without the need to reactivate the latent virus. Here, we posit the existence of a novel marker of latently infected cells, based on new insights into HIV and SIV transcription and translation. Specifically, we hypothesize that latent infection is associated with increased levels of viral antisense transcription and translation. Published data on HIV and our preliminary data with SIV infection of rhesus macaques indicate that antisense transcription in infected CD4+ T cells is more prominent when the cells are less activated, and that many of these unique transcripts are polyadenylated and could be translated. Further, we have identified T cell responses mounted during SIV and HIV infection that target surprisingly conserved peptides derived from translation of antisense transcripts. To test our hypothesis, in Aim 1, we will compare viral transcription (sense and antisense) between latently infected CD4 T cells and activated and infected CD4 T cells using both SIV-infected rhesus macaque and HIV-1 infected human cells. To do this, we will use a novel strand-specific deep sequencing approach. Results from Aim 1 will focus our efforts in Aim 2. In Aim 2, we will use T cells that recognize antisense-encoded epitopes and measure their ability to kill latently infected vs. activated and infected CD4 T cells. In sum, this proposal has the potential to identify a novel marker of latently infecte cells and suggest a means by which to eliminate them. These data could prove important to efforts to develop a cure for HIV.