The contribution of Tcell tolerance to latent HIV infection

T细胞耐受性对HIV潜伏感染的贡献

• 批准号: 8265553
• 负责人: Joseph K Wong
• 金额: --
• 依托单位: VETERANS AFFAIRS MED CTR SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-10-01 至 2014-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8265553
• 关键词: Address; Aftercare; Antiviral Agents; Attenuated; Biological Assay; Blood; Blood Circulation; CD4 Positive T Lymphocytes; Cardiovascular system; Cell Count; Cell model; Cells; Cessation of life; Characteristics; Chronic; Clinical; Coculture Techniques; Complex; CpG Islands; Cytotoxic T-Lymphocyte-Associated Protein 4; DNA; DNA Markers; Data; Development; Disease; Drug usage; Environment; Epigenetic Process; Evolution; Exhibits; Failure; Foundations; Frequencies; Funding; Future; Gene Expression; Genes; Gut associated lymphoid tissue; HIV; HIV Infections; HIV therapy; HIV-1; Health; Hepatic; Highly Active Antiretroviral Therapy; IL2 gene; Immune response; In Vitro; Individual; Institution; Intervention; Kidney; Kidney Diseases; Knowledge; Lead; Life; Light; Link; Liver diseases; Location; Malignant Neoplasms; Measures; Methylation; Modeling; Modification; Molecular; Molecular Target; Molecular Weight; Myocardial Infarction; Nature; Pathologic; Patients; Pattern; Peripheral; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phenotype; Ploidies; RNA; RNA Splicing; Recurrent disease; Relative (related person); Reporting; Repression; Research; Residual state; Rest; Shelter facility; Signal Transduction; Sorting - Cell Movement; Stimulus; Stroke; T cell anergy; T memory cell; T-Cell Activation; T-Lymphocyte; Testing; Time; Veterans; Viral; Viral Genes; Viral Load result; Viremia; Virus; Virus Latency; Work; anergy; antiretroviral therapy; attenuation; base; design; exhaust; exhaustion; immune activation; in vivo; latent infection; memory CD4 T lymphocyte; novel; peripheral blood; population based; programs; promoter; purge; receptor; research study; restoration; viral DNA

DESCRIPTION (provided by applicant): HIV-1 persists in patients despite years of suppressive treatment with antiretroviral therapy (ART) and results in disease relapse when treatment is interrupted. One major barrier to treatment eradication is a reservoir of latently infected CD4+ T-cells. Whether these latently infected cells give rise to low-level ongoing replication or episodically activate and produce virus is controversial but this viral persistence likely contributes to ongoing immuno-pathologic effects that include incomplete T-cell restoration and the global immune activation that are implicated in HIV associated cardiovascular, renal and hepatic disease even among those on highly active antiretroviral therapy (HAART). It has also been recently recognized that despite expressing some markers of T-cell activation, T-cells from HIV infected patients also exhibit markers of T-cell exhaustion or tolerance that may underlie the insufficiency of the immune response against HIV-1. Our work from the previous funding cycle suggests that the latent viral reservoir may be heterogeneous in composition in vivo and the molecular mechanisms underlying viral latency are likely complex. We find that both T-cells in the gut and those in the blood exhibit very low HIV expression levels despite high levels of T-cell activation. One unifying mechanism for the attenuated expression of HIV could be the T-cell exhaustion that appears to accompany HIV infection. Our preliminary data suggest that, paradoxically, after successful viral suppression on ART, the proportion of cells expressing CTLA-4, a marker of T-cell anergy, increases. In the current proposal we will investigate evolution of the cellular reservoir of virus from patients initiating therapy during chronic HIV infection by examining individual CD4 populations based on presence or absence of markers of activation and anergy. We will test the novel hypothesis that tolerance acquired as a byproduct of chronic HIV infection, attenuates viral expression and gives rise to the paradoxical retention of large numbers of cells with latent HIV infection during suppressive therapy. We will determine whether epigenetic modification of the HIV LTR coincides with epigenetic modification of promoters of genes associated with T-cell activation. Finally, we will examine the effects of agents designed to reactivate HIV from latency or that reverse T-cell anergy on virus expression from T-cells obtained from patients on suppressive therapy in order to form the foundation for future interventions to purge the latent reservoir.

描述（由申请人提供）：