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

“持续低水平病毒血症的 HIV 患者的病毒和潜伏 HIV 储存库特征

• 批准号: 10761824
• 负责人: EVELYN YAYRA BONNEY
• 金额: $ 14.79万
• 依托单位: NOGUCHI MEMORIAL INSTITUTE / MEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10761824
• 关键词: Africa; Attention; Biological Assay; Breeding; CD4 Positive T Lymphocytes; Categories; Cells; Characteristics; Clonal Expansion; Clonality; Code; Computer software; DNA; Developed Countries; Drug resistance; Evaluation; Evolution; Feeds; Frequencies; Genetic; Genetic Variation; Genotype; Ghana; HIV; HIV Genome; HIV-1; Individual; Infrastructure; Integrase; Knowledge; Length; Libraries; Life; Measures; Methods; Monitor; Participant; Patients; Peptide Hydrolases; Persons; Phylogenetic Analysis; Plasma; Population; Proliferating; Proviruses; RNA; RNA-Directed DNA Polymerase; Recombinants; Resistance; Resource-limited setting; Rest; Sampling; Source; Technology; Ultracentrifugation; Viral; Viral Load result; Viral reservoir; Viremia; Virion; Virus; Virus Latency; Virus Replication; World Health Organization; antiretroviral therapy; clinically relevant; cohort; deep sequencing; genome sequencing; integration site; latent HIV reservoir; nanopore; programs; resistance mutation; success; transcriptome sequencing; treatment guidelines; viral rebound

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.

项目摘要 抗逆转录病毒疗法（ART）的成功通常是通过艾滋病毒患者的比例来衡量的 （PLWH）在病毒学上受到艺术的抑制。但是，用于确定病毒抑制的标准 发达国家和发展中国家之间的不同。发达国家将病毒抑制定义为 病毒载荷（VL）每毫升少于50份，而大多数非洲则接受世界卫生组织（WHO） 在资源有限的设置（RLS）中，每毫升的规定少于1000份作为病毒抑制。这创建了 RLS中的一类人，持续的低级病毒血症（PLLV）为50-999副本/毫升 加上真正的病毒学抑制，因此没有给予太多关注。由于病毒复制 在低水平的病毒血症期间继续进行，这可能会促进阻力突变的扩散，扩大 病毒株并增加了PLLV患者的病毒储层大小。但是，这个人口是否有更多 各种病毒株，具有较大的储层大小或作为当前耐药性升高的来源 非洲尚未被研究。 这会产生一个关键的知识差距 在非洲的艾滋病毒治愈努力中。 我们的工作假设是，经过持续的低级病毒血症的艺术处理的PLWH具有更大的病毒多样性， 较大的储层尺寸，并选择耐药性突变。我们打算用两个 具体目的： AIM 1：确定PLLV患者的病毒多样性和耐药性突变。我们假设这一点 低水平病毒血症在ART上的连续病毒复制扩展了病毒株的多样性，并为 耐药性突变的出现。首先，我们将执行横截面评估以确定 PLLV患者中临床上耐药性突变的频率。其次，我们将跟随患者 使用PLLV持续18个月，以确定抵抗的演变以及那些破裂的人的比例 VL> 1000。第三，我们将确定PLLV患者中艾滋病毒的患者间遗传多样性。 AIM 2：确定HIV PLLV患者中HIV储量的特征。我们假设这一点 持续的低病毒血症喂养潜在储层，使其在PLLV的患者中更大，更多样化 真正被压抑的人。这里的问题是PLLV是否会扩大储层的大小并增加 克隆扩张。如果是这样，将病毒引起无法检测到的情况将变得更加迫切 患者。 获得的知识将对我们的艾滋病毒控制计划有用；可以要求改变治疗指南 在加纳和非洲，在资源中持续持续的低病毒血症患者促进了更广泛的研究 - 有限的设置。