THE ROLE OF CTL ESCAPE MUTATIONS IN ATTENUATING HIV-1 SUBTYPE C INFECTION

描述（由申请人提供）：I类人类白细胞抗原（HLA）位点决定了细胞毒性t淋巴细胞（ctl）靶向的HIV肽，是影响HIV-1感染者疾病进展速度的重要遗传因素（4;5）。HIV-1持续多样化的一个主要因素是持续逃避抗HIV宿主CTL反应（21;22）。CTL逃逸与病毒载量增加和疾病更快进展有关（11-14;29）。然而，CTL逃逸变异也可能比野生型具有更低的复制适应度，并与较慢的疾病进展相关（16;17;41;48）。此外，携带CTL逃逸突变的病毒在传播给hla不匹配的个体后会还原为野生型，这进一步证明CTL逃逸对病毒适应性有影响（6;7;9;10）。急性HIV感染与粘膜免疫系统的大量破坏有关（1;2），急性感染中较高的病毒载量与设定点较高的病毒载量有关(3)。因此，影响急性感染严重程度的因素可能对随后的疾病进展产生长期影响。从病毒学的角度来看，这两个因素包括：(a)病毒的固有特性，包括感染含有减毒CTL突变的病毒，这是病毒在以前的宿主中适应的结果；(b)感染后出现新的CTL逃逸突变。这两种进化途径的平衡可能对控制急性感染中的病毒复制有影响。我们假设一个相互作用的减毒突变网络可能是在一些人身上观察到的较低病毒载量的原因。通过对HIV-1亚型C感染的未用药个体产生的病毒序列的详细研究，我们的目标是：首先，确定在HIV-1亚型C感染后的前6个月内出现的与CTL逃逸相关的突变；第二，量化传播病毒中CTL逃逸突变的频率，以及它们在传播到HLA不匹配的宿主后两年内逆转的时间；第三，确定急性感染期间在个体病毒中检测到的CTL逃逸突变对疾病进展的影响。该项目的总体目标是通过CD+4 t细胞计数和病毒载量来确定影响临床疾病进展的衰减突变。目前的观点是，第一代基于CTL的疫苗可能只是部分有效。我们建议这类疫苗应包含逃避与病毒适应性成本相关的抗原表位，因为这可能会驱动尽管接种疫苗但仍被感染的个体的病毒衰减。公共卫生相关性：据估计，有500多万南非人感染了艾滋病毒，约占总人口的12%。疫苗开发是这个国家研究的一个主要焦点。本项目旨在鉴定HIV中的减毒CTL突变。第一代基于CTL的疫苗可能只是部分有效。我们建议这类疫苗应包含逃避与病毒适应性成本相关的抗原表位，因为这可能会驱动尽管接种疫苗但仍被感染的个体的病毒衰减。本项目先前通过CIPRA （U19 A151794-01）获得资助。

DESCRIPTION (provided by applicant): The Class I Human Leukocyte Antigen (HLA) locus determines the HIV peptides targeted by cytotoxic T-lymphocytes (CTLs) and is an important genetic factor that affects the rate of disease progression in HIV-1 infected individuals (4;5). A major contributor to ongoing HIV-1 diversification is continual escape from anti- HIV host CTL responses (21;22). CTL escape has been associated with increased viral loads and more rapid disease progression (11-14;29). However CTL escape variants may also have lower replicative fitness than the wild-type and are associated with slower disease progression (16;17;41;48). In addition, viruses harbouring CTL escape mutations undergo reversion to wild-type following transmission to HLA-mismatched individuals providing further evidence that CTL escape has an impact of viral fitness (6;7;9;10) . Acute HIV infection is associated with massive destruction of the mucosal immune system (1;2) and higher viral loads in acute infection have been associated with a higher viral load at set-point (3). Factors that influence the severity of acute infection may therefore have long term impact on subsequent disease progression. From a virological perspective, two such factors include (a) inherent properties of the virus including infection with viruses containing attenuating CTL mutations which are a consequence of viral adaptation in a previous host and (b) the emergence of new CTL escape mutations following infection. The counterbalance of these two evolutionary pathways may have implications in control of viral replication in acute infection. We hypothesize that an interacting network of attenuating mutations may be responsible for lower viral loads observed in some people. Through a detailed investigation of viral sequences generated from HIV-1 subtype C infected, drug naive individuals we aim to: first, identify mutations associated with CTL escape that emerge during the first 6 months following HIV-1 subtype C infection; second, to quantify the frequency of CTL escape mutations in transmitted viruses and the timing of their reversion over two years following their transmission to HLA mismatched hosts; and third, to determine the impact on disease progression of CTL escape mutations detected in viruses from individuals during acute infection. The overall objective of this project is to identify attenuating mutations that impact of clinical disease progression as measured by CD+4 T-cell count and viral loads. Current opinion is that first generation CTL based vaccines are likely to be only partially effective. We propose that such vaccines should contain epitopes where escape is associated with a fitness cost to the virus as this might drive the attenuation of viruses in individuals who become infected despite vaccination. PUBLIC HEALTH RELEVANCE: It is estimated that there are over 5 million South Africans infected with the HIV virus, representing roughly 12% of the population. Vaccine development is a major focus of research in this country. This project aims to identify attenuating CTL mutation in HIV. First generation CTL based vaccines are likely to be only partially effective. We propose that such vaccines should contain epitopes where escape is associated with a fitness cost to the virus as this might drive the attenuation of viruses in individuals who become infected despite vaccination. This project was previously funded through CIPRA (U19 A151794-01). .