IMPACT OF TUBERCULOSIS ON THE HIV RESERVOIR

结核病对艾滋病病毒库的影响

• 批准号: 10483895
• 负责人: George Kyei
• 金额: $ 14.52万
• 依托单位: UNIVERSITY OF GHANA MEDICAL CENTRE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-22 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10483895
• 关键词: Affect; African; Agonist; Antigens; Attention; Biological; Biological Assay; Blood; Bromodomain; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Clinical; Clonal Expansion; Coculture Techniques; Color; Country; DNA; Disease remission; Drug resistance; Ensure; Flow Cytometry; Future; GTP-Binding Protein alpha Subunits, Gs; Ghana; HIV; HIV-1; HIV/TB; HLA-DR Antigens; Histone Deacetylase Inhibitor; IL2RA gene; Immune response; Immunologics; Interferon Type II; Interferon-alpha; Interleukin-1 beta; Interleukin-10; Interleukin-17; Interleukin-2; Interleukin-6; Investigation; Knowledge; Life Expectancy; Light; Measures; Methods; Modeling; Mycobacterium tuberculosis antigens; Patients; Peptides; Pharmaceutical Preparations; Production; Protein Kinase C; Proviruses; Quantitative Reverse Transcriptase PCR; Radiology Specialty; Research; Response Latencies; Rest; Shock; T cell response; T-Lymphocyte; TNF gene; Testing; Tuberculosis; Viral; Viral Load result; Viral reservoir; Virus; antiretroviral therapy; biomarker panel; chimeric antigen receptor; co-infection; cohort; cost; cytokine; exhaustion; inhibitor; interleukin-22; latent HIV reservoir; neutralizing antibody; programmed cell death protein 1; programs; reactivation from latency; receptor vaccine; recruit; response; side effect; therapeutic vaccine; viral RNA

PROJECT SUMMARY Even though antiretroviral therapy (ART) can suppress HIV and increase life expectancy, it does not provide cure. Patients must commit to daily medications and deal with side effects, unsustainable costs and drug resistance. The main obstacle to an HIV cure is persistent provirus in the resting CD4+ T cell reservoir which produce virus under the right stimulation conditions. The most popular approaches for HIV cure or remission such as the shock and kill approach, broadly neutralizing antibodies, chimeric antigen receptors and therapeutic vaccines will all require some form of reactivation of the latent provirus. However, tuberculosis, an important factor that could affect the viral reservoir and its response to latency reversing agents (LRAs) has not received much attention in the context of HIV cure research. Over a third of HIV patients are infected with TB. Tuberculosis, including latent TB infection (LTBI), produces antigens that stimulate T cells, which could result in proliferation and alter the response of the reservoir to LRAs. Persistent stimulation could also result in T cell exhaustion. We are working with the hypothesis that TB antigens in the blood of co-infected patients stimulate T cells to increase the size of the reservoir and alter the responses of CD8+ and CD8+ T cells. We will investigate this hypothesis with the following specific aims: Aim 1: Identify differences in T cell responses between HIV and HIV/LTB patients. We hypothesize that in co- infected patients, CD4+ T cells will have decreased responses to LRA and CD8+ T cells will have reduced killing ability upon stimulation. First, we will compare the baseline activation status of resting T cells from virologically suppressed patients (VL <50 copies per ml) with HIV or HIV/LTBI. Second, we will stimulate the CD4+ and CD8+ T cells in each group for the production of relevant cytokines and the expression of the activation and exhaustion markers. Third, we will isolate resting T cells from patients and stimulate them with different LRAs. Fourth, we will determine the capacity of CD8+ T cells from co-infected patients to kill reactivated CD4+ T cells expressing HIV-1 antigens. Aim 2: Determine the size of the HIV reservoir in HIV only and HIV/LTB co-infected patients. We hypothesize that co-infected patients will have a larger reservoir size due to persistent stimulation that results in further CD4+ T cell seeding or clonal expansion. We will recruit 75 HIV only patients and 75 HIV-TB patients from our cohort with a viral load of <50 copies per ml for more than 2 years. We will isolate resting T cells to measure the size of the reservoir using the IPDA assay which measures only intact proviruses with potential to produce virus. This project will provide critically missing knowledge and understanding of how T cells in patient co-infected with TB respond to latency reversing agents, and give an indication on the size of the HIV reservoir in these patient. Information gained will be crucial in planning HIV cure studies in co-infected patients.

项目总结