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(申请人提供)：尽管高效抗逆转录病毒疗法(HAART)的出现极大地降低了与艾滋病毒-1感染相关的发病率和死亡率，但由于治疗期间潜伏感染的细胞持续存在，因此无法根除病毒。越来越多的数据表明，HIV-1感染会放大“非艾滋病”的心血管、肺脏、肾脏和肝脏疾病，甚至病毒抑制的患者也会出现过早的免疫衰老。这些现实引起了人们对制定在感染者中根除艾滋病毒-1的战略的明显兴趣。最近，有三个病例被报道，这表明治愈HIV-1实际上可能是可以实现的。这名“柏林患者”和两名来自波士顿的患者都是HIV阳性，并接受了异基因骨髓移植，似乎完全没有HIV-1遗传物质，抗HIV-1抗体水平正在下降。这三个个体都有一个共同的特征：他们都是CCR5-Delta 32突变(CCR5-？32)的杂合子。CCR5基因中32个碱基对的缺失影响了CCR5趋化因子受体的表达和稳定性，大多数HIV-1毒株利用CCR5受体作为进入辅助受体。在CCR5-？？32杂合子中，三个假定的HIV-1根除病例值得在HIV-1储存库和治疗策略的背景下对这种突变进行调查。CCR5-？？32个杂合子在细胞表面表达的CCR5显著减少，阻碍了CCR5嗜性(R5)HIV-1的进入。我们假设CCR5-？？32杂合子由于这一缺陷而拥有一个更小和更不稳定的储存库。首先，由于病毒进入的限制，在CCR5-？32杂合子中，HIV-1储存库的初始定植可能受到阻碍，导致在ART启动之前储存库较小。其次，在CCR5-？32杂合子中，由于HIV-1在细胞和组织中分布的倾斜，调节了潜伏感染细胞的周转率、半衰期和增殖能力，从而加速了抗逆转录病毒治疗期间储存库的衰退。这种不对称的分布可能部分是由于在CCR5-？32杂合子中选择了HIV-1辅助受体的替代用途，包括使用CXCR4的(X4)病毒的浓缩，这些病毒优先感染表达CXCR4的细胞，如幼稚的CD4+T细胞。在这项提案中，我们将使用系统生物学、翻译方法来检查病毒的大小、细胞分布和病毒基因组成。 32例杂合子和病例匹配的CCR5野生型个体的血液和淋巴组织中的HIV-1储存库。这项研究应该对HIV-1持续和根除的细胞和分子决定因素产生有价值的见解。