Susceptibility of antigen-specific CD4 T cells to HIV: implications for HIV vacci

抗原特异性 CD4 T 细胞对 HIV 的敏感性：对 HIV 疫苗的影响

• 批准号: 8732199
• 负责人: Haitao Hu
• 金额: $ 21.73万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-05 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8732199
• 关键词: ALVAC; Acquired Immunodeficiency Syndrome; Address; Affect; Antigens; Antiviral Agents; Area; Biological Assay; CD4 Positive T Lymphocytes; Candida; Candida albicans; Cell Line; Cells; Chronic; Clinical; Clinical Research; Cytomegalovirus; Data; Development; Differentiation Antigens; Exposure to; Figs - dietary; Gene Expression; Genes; HIV; HIV Infections; HIV vaccine; HIV-1; HIV/SIV vaccine; Homing; Human; Immunity; Immunization; In Vitro; Infection; Interleukin-17; Intervention; Knowledge; Label; Lead; Measures; Memory; Microarray Analysis; Molecular; Opportunistic Infections; Outcome; Pathogenesis; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Phenotype; Population; Predisposition; Principal Investigator; Proliferating; Proteins; Public Health; Recombinants; Relative (related person); Reporting; Resistance; Risk; Role; Sampling; Small Interfering RNA; Sorting - Cell Movement; Specificity; Surrogate Markers; System; T cell response; T-Lymphocyte; Testing; Tetanus Toxoid; Time; Vaccine Design; Vaccines; Viral; base; cytokine; genome-wide; in vitro Assay; insight; interest; memory CD4 T lymphocyte; novel; pandemic disease; pathogen; permissiveness; pre-clinical; programs; public health relevance; research study; sensor; vaccine efficacy; vector; vector vaccine; vector-induced; viral RNA

DESCRIPTION: A central question to better understanding the pathogenesis of HIV infection is how memory CD4 T cells are infected and progressively depleted by HIV. Little is currently known about the impact of HIV infection on CD4 T cells of different pathogen or antigen specificities. Exploring this area is important for better understanding of the timing of different opportunistic infections in AIDS patients. In addition, identification of a functional population o vaccine-specific CD4 T cells that is "resistant" to HIV is critical for HIV vaccine design. We have established a novel system for studying the susceptibility of antigen-specific CD4 T cells to HIV, and have found that different antigen-specific CD4 T cells manifest marked differences in susceptibility to HIV infection. Our preliminary data show that compared to CD4 T cells specific to tetanus toxoid (TT) and Candida albicans (Candida), which are permissive to HIV, cytomegalovirus (CMV)-specific CD4 T cells are highly resistant to both R5 and X4 HIV with post-entry HIV restriction. Our microarray analysis identified a novel viral RNA sensor, IFIT1 that is highly upregulated in CMV-specific CD4 T cells. Of importance, in our ongoing experiments, we show that over-expression of IFIT1 inhibits HIV infection in A3R5 CD4 T cell line. Based on data already generated, we hypothesize that IFIT1 can inhibit HIV infection in human primary CD4 T cells and differential expression of IFIT1 regulates the permissiveness of antigen-specific CD4 T cells to HIV. We further propose to extend the novel system and observations to clinical HIV vaccine studies. Preferential infection of vaccine-induced CD4 T cells by HIV reduces the efficiency of vaccine-generated immunity. Our hypothesis is that a protective HIV vaccine should induce a type of vaccine-specific CD4 T cells that are "not readily susceptible" to HIV, and that different candidate HIV vaccines (e.g. different vectors) induce distinct phenotypes of vaccine- and/or vector-specific CD4 T cells that may impact their sensitivities to HIV. We will test peripheral blood mononuclear cell samples from three completed HIV vaccine trials: RV144 (ALVAC), RV158 (MVA) and IPCAVD 001(Ad26). Our hypotheses will be addressed in 2 Specific Aims: 1) To determine the role of IFIT1 in regulating the susceptibility of antigen-specific CD4 T cells to HIV and to further explore the mechanisms for inhibition of HIV by IFIT1; 2) To investigate the susceptibilities of different HIV vaccine-induced, antigen-specific CD4 T cells to HIV infection and the associated phenotypes in HIV vaccine trials. The proposed studies are exploratory, but expected to provide new insights to: 1) understand the mechanisms for the persistence of CMV-specific T cell immunity in AIDS patients; 2) identify a novel anti-HIV molecule with previously unidentified inhibitory mechanisms that could possibly lead to development of novel interventional strategies; 3) more thoroughly understand the quality of vaccine-generated CD4 T cell immunity and to provide proof of concept knowledge as to whether and how to induce functional, "HIV-resistant" CD4 T cells by an efficacious HIV vaccine.

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