Characterization of the HIV-1 Latent Reservoir in CCR5-Delta 32 Heterozygotes
Characterization of the HIV-1 Latent Reservoir in CCR5-Delta 32 Heterozygotes
批准号:
8603539
负责人:
Satish Kumar Pillai
金额:
$22.24万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2013
资助国家:
美国
项目状态:
已结题
起止时间:
2013-08-15 至 2015-07-31
关键词:
AffectAllogeneic Bone Marrow TransplantationAntibodiesBase PairingBerlinBloodBone Marrow TransplantationBostonCCR5 geneCD4 Positive T LymphocytesCXCR4 geneCardiovascular DiseasesCell surfaceCellsDataDiseaseDrug or chemical Tissue DistributionExhibitsGene MutationGeneticGenetic MaterialsGenetic VariationGut associated lymphoid tissueHIVHIV SeropositivityHIV-1Half-LifeHeterozygoteHighly Active Antiretroviral TherapyHuman GeneticsImmuneIndividualInfectionInvestigationKidney DiseasesLiver diseasesLung diseasesLymphoid TissueMolecularMorbidity - disease rateMutationPatientsPhenotypePopulationReportingSorting - Cell MovementSystems BiologyT-Lymphocyte SubsetsTechniquesVariantViralViral GenomeVirusVirus Diseaseschemokine receptordeep sequencingdesigninsightinterestlongitudinal designmortalityprematurepublic health relevancesenescencetranslational approachvirus genetics
中文摘要
描述(由申请人提供):尽管高效抗逆转录病毒疗法(HAART)的出现显着降低了与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,病毒根除是无法实现的。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。“柏林患者”和来自波士顿的两名患者均为HIV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,并显示抗HIV-1抗体水平下降。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。
英文摘要
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.
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海外基金