Characterization of the HIV-1 Latent Reservoir in CCR5-Delta 32 Heterozygotes

CCR5-Delta 32 杂合子中 HIV-1 潜伏库的表征

• 批准号: 8603539
• 负责人: Satish Kumar Pillai
• 金额: $ 22.24万
• 依托单位: VITALANT
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8603539
• 关键词: Affect; Allogeneic Bone Marrow Transplantation; Antibodies; Base Pairing; Berlin; Blood; Bone Marrow Transplantation; Boston; CCR5 gene; CD4 Positive T Lymphocytes; CXCR4 gene; Cardiovascular Diseases; Cell surface; Cells; Data; Disease; Drug or chemical Tissue Distribution; Exhibits; Gene Mutation; Genetic; Genetic Materials; Genetic Variation; Gut associated lymphoid tissue; HIV; HIV Seropositivity; HIV-1; Half-Life; Heterozygote; Highly Active Antiretroviral Therapy; Human Genetics; Immune; Individual; Infection; Investigation; Kidney Diseases; Liver diseases; Lung diseases; Lymphoid Tissue; Molecular; Morbidity - disease rate; Mutation; Patients; Phenotype; Population; Reporting; Sorting - Cell Movement; Systems Biology; T-Lymphocyte Subsets; Techniques; Variant; Viral; Viral Genome; Virus; Virus Diseases; chemokine receptor; deep sequencing; design; insight; interest; longitudinal design; mortality; premature; public health relevance; senescence; translational approach; virus genetics

DESCRIPTION (provided by applicant): Although the advent of highly active antiretroviral therapy (HAART) has dramatically reduced the morbidity and mortality associated with HIV-1 infection, viral eradication is not achievable due to the persistence of latently- infected cells during treatment. Accumulating data suggest that "non-AIDS" cardiovascular, pulmonary, renal and hepatic diseases are amplified by HIV-1 infection, and even patients with viral suppression develop premature immune senescence. These realities have created a pronounced interest in developing strategies to eradicate HIV-1 in infected individuals. Recently, three cases have been reported that suggest a cure for HIV-1 may in fact be achievable. The "Berlin Patient" and two individuals from Boston, all of whom were HIV-positive and underwent allogeneic bone marrow transplantation, appear to be completely devoid of HIV-1 genetic material and exhibit waning anti-HIV-1 antibody levels. All three individuals share a common feature; they are heterozygous for the CCR5-delta 32 mutation (CCR5-?32). This 32 base pair deletion in the CCR5 gene affects the expression and stability of the CCR5 chemokine receptor which is utilized as an entry coreceptor by most HIV-1 strains. The three putative cases of HIV-1 eradication in CCR5-??32 heterozygotes warrant investigation into this mutation within the context of the HIV-1 reservoir and curative strategies. CCR5-??32 heterozygotes express significantly less CCR5 at the cell surface, impeding the entry of CCR5- tropic (R5) HIV-1. We hypothesize that CCR5-??32 heterozygotes harbor a smaller and less stable reservoir due to this deficit. Firstly, initial colonization of the HIV-1 reservoir is likely impeded in CCR5-??32 heterozygotes due to restriction of viral entry, resulting in a smaller reservoir before ART initiation. Secondly, the decay of the reservoir during ART may be accelerated in CCR5-??32 heterozygotes due to skewed cellular and tissue distribution of HIV-1, modulating the turnover rate, half-life and proliferative capacity of latently infected cells. This skewed distribution maybe driven in part by selection for alternative HIV-1 coreceptor usage in CCR5-??32 heterozygotes, including enrichment of CXCR4-using (X4) viruses which preferentially infect CXCR4-expressing cells such as naive CD4+ T cells. In this proposal, we will use a systems biology, translational approach to examine the size, cellular distribution, and viral genetic composition of the HIV-1 reservoir in the blood and lymphoid tissues of HIV-1-infected CCR5-??32 heterozygotes and case-matched CCR5 wildtype individuals. This study should yield valuable insights into the cellular and molecular determinants of HIV-1 persistence and eradication.

描述（由申请人提供）：尽管高效抗逆转录病毒疗法（HAART）的出现显著降低了与HIV-1感染相关的发病率和死亡率，但由于治疗期间潜伏感染细胞的持续存在，无法实现病毒根除。越来越多的数据表明，“非艾滋病”的心血管、肺、肾和肝疾病会因HIV-1感染而扩大，甚至病毒受到抑制的患者也会出现过早的免疫衰老。这些现实使人们对制定根除感染者体内HIV-1的战略产生了明显的兴趣。最近，有三个病例报告表明，治愈HIV-1实际上是可以实现的。这名“柏林患者”和两名来自波士顿的人都是艾滋病毒阳性，并接受了异基因骨髓移植，他们似乎完全缺乏HIV-1遗传物质，并且抗HIV-1抗体水平正在下降。这三个人有一个共同的特点，他们是杂合子的CCR 5-δ 32突变（CCR 5-？32）。CCR 5基因中的这32个碱基对缺失影响CCR 5趋化因子受体的表达和稳定性，CCR 5趋化因子受体被大多数HIV-1毒株用作进入辅助受体。CCR 5-？？中三个假定的HIV-1根除病例32个杂合子保证在HIV-1储库和治疗策略的背景下调查这种突变。CCR 5-？？32个杂合子在细胞表面表达显著较少的CCR 5，阻碍了嗜CCR 5（R5）HIV-1的进入。我们假设CCR 5-？？32个杂合子由于这种缺陷而具有较小且较不稳定的储库。首先，HIV-1储库的初始定殖可能在CCR 5-？？32个杂合子，由于病毒进入的限制，导致ART开始前的储库较小。第二，在ART过程中水库的衰减可能会加速在CCR 5-？？由于HIV-1的细胞和组织分布偏斜，调节潜伏感染细胞的周转率、半衰期和增殖能力，导致32个杂合子。这种偏态分布可能部分是由选择替代HIV-1辅助受体在CCR 5-？？32杂合子，包括富集CXCR 4-使用（X4）病毒，其优先感染CXCR 4-表达细胞，如初始CD 4 + T细胞。在这个建议中，我们将使用系统生物学，翻译的方法来检查的大小，细胞分布，和病毒的遗传组成， HIV-1感染者的血液和淋巴组织中的HIV-1储存库CCR 5-？？32例杂合子和病例匹配的CCR 5野生型个体。这项研究应该产生有价值的见解的细胞和分子的决定因素的HIV-1的持久性和根除。