"Viral and latent HIV reservoir characteristics in HIV patients with persistent low-level viremia

项目摘要 抗逆转录病毒疗法的成功与否通常以艾滋病毒感染者的比例来衡量 然而，用于确定病毒抑制的标准 在发达国家和发展中国家之间存在差异。发达国家将病毒抑制定义为 病毒载量（VL）低于50拷贝每毫升，而非洲大部分地区，接受世界卫生组织（WHO） 在资源有限的情况下，规定低于1000拷贝/ml作为病毒抑制（RLS）。这造成 一类RLS患者，持续低水平病毒血症（pLLV）为50-999拷贝/ml， 以及真正的病毒学抑制，因此没有得到太多的关注。由于病毒复制 在低水平病毒血症期间继续，这可能会助长耐药突变的扩散，扩大病毒的多样性， 病毒株，并增加病毒库的大小在那些与pLLV。然而，这一群体是否有更多的 不同的病毒株，具有更大的储库大小或作为目前耐药性上升的来源， 非洲没有被研究过。 这就造成了一个关键的知识差距，如果不加以填补，可能会使ART的成功脱轨，并成为一个瓶颈 在非洲的艾滋病治疗工作。 我们的工作假设是，ART治疗的PLWH与持续低水平的病毒血症有更大的病毒多样性， 更大的储库尺寸和耐药突变的选择。我们打算用两个假设来研究这个假设。 具体目标： 目的1：确定pLLV患者中的病毒多样性和耐药突变。我们假设 ART治疗期间低水平病毒血症的持续病毒复制扩大了病毒株的多样性， 出现耐药突变。首先，我们将进行横断面评估，以确定 pLLV患者中临床相关耐药突变的频率。第二，我们将跟踪患者 用pLLV治疗18个月，以确定耐药性的演变和那些突破耐药性的比例。 VL>1000。第三，我们将确定pLLV患者中HIV的患者间和患者内遗传多样性。 目的2：确定携带pLLV的HIV患者中HIV储库的特征。我们假设 持续的低病毒血症使pLLV患者的潜在病毒库更大，更多样化， 真正被压制的人。这里的问题是pLLV是否扩大了水库的大小， 克隆扩展如果是这样的话，将病毒带到这些无法检测到的地方将变得更加紧迫。 患者 所获得的知识将对我们的艾滋病毒控制计划有用;可能需要改变治疗指南 在加纳和非洲，并促使更广泛的研究与持续低病毒血症的人在资源- 有限的设置。

PROJECT SUMMARY The success of antiretroviral therapy (ART) is usually measured by the proportion of persons living with HIV (PLWH) who are virologically suppressed on ART. However, the standards used to determine viral suppression differ between the developed and the developing world. The developed countries define viral suppression as viral load (VL) less than 50 copies per ml, while most of Africa, accepts the World Health Organization (WHO) prescribed less than 1000 copies per ml as viral suppression in resource-limited settings (RLS). This has created a category of persons in RLS with persistently low-level viremia (pLLV) of 50-999 copies/ml who are lumped together with the truly virologically suppressed, and thus not given much attention. Since viral replication continues during low-level viremia, this may fuel the proliferation of resistance mutations, expand the diversity of viral strains and increase the viral reservoir size in those with pLLV. However, whether this population has more diverse viral strains, has a larger reservoir size or serve as a source of the current rise in drug resistance in Africa has not been studied. This creates a critical knowledge gap which if not filled could derail the success of ART and serve as a bottleneck in HIV cure efforts in Africa. Our working hypothesis is that ART-treated PLWH with persistent low-level viremia have greater virus diversity, larger reservoir size and select for drug resistance mutations. We intend to investigate this hypothesis with two specific aims: Aim 1: Determine viral diversity and drug resistance mutations among patients with pLLV. We hypothesize that continuous viral replication during low-level viremia on ART expands the diversity of viral strains and fuel the emergence of drug resistance mutations. First, we will perform a cross-sectional evaluation to determine the frequency of clinically-relevant drug resistance mutations in those with pLLV. Second, we will follow the patients with pLLV for 18 months to determine resistance evolution and the proportion of those who break through to VL>1000. Third, we will determine inter- and intra-patient genetic diversity of HIV in those with pLLV. Aim 2: Determine the characteristics of the HIV reservoir in HIV patients with pLLV. We hypothesize that persistent low viremia feeds the latent reservoir making it larger and more diverse in those with pLLV compared to the truly suppressed persons. The question here is whether pLLV enlarge the size of the reservoir and increase clonal expansion. If that were the case, it would become more urgent to bring the virus to undetectable in these patients. The knowledge gained will be useful for our HIV control programs; may call for changes in treatment guidelines in Ghana and Africa and prompt more extensive studies among persons with persistent low viremia in resource- limited settings.