CD8+ T cell mediated inhibition of HIV-1 replication in Elite Suppressors

CD8 T 细胞介导的精英抑制子中 HIV-1 复制的抑制

• 批准号: 8879353
• 负责人: JOEL N BLANKSON
• 金额: $ 40.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-30 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8879353
• 关键词: Accounting; Acquired Immunodeficiency Syndrome; Alleles; Autologous; Biological Assay; CD4 Lymphocyte Count; CD4 Positive T Lymphocytes; CD8B1 gene; Cell physiology; Cells; Cellular Immunity; Chronic; Collaborations; Defective Viruses; Development; Drops; Escape Mutant; Frequencies; HIV; HIV Antigens; HIV-1; HLA-B Antigens; Health; Highly Active Antiretroviral Therapy; Humoral Immunities; Immune response; Immune system; Immunologics; Immunotherapeutic agent; Individual; Infection; Integration Host Factors; Laboratories; Lead; Macaca mulatta; Mediating; Memory; Modeling; Patients; Peptides; Persons; Physiological; Play; Progressive Disease; Proviruses; Regimen; Relative (related person); Reporting; Resistance; Rest; Role; Shock; T cell response; T-Lymphocyte; Testing; Therapeutic; Time; Vaccines; Viral; Viral Load result; Viremia; Virus; Work; antiretroviral therapy; base; cohort; cytokine; design; gag Gene Products; improved; in vivo; killings; macrophage; novel; perforin; reactivation from latency; response; therapeutic vaccine; vaccine development

DESCRIPTION (provided by applicant): Elite suppressors are HIV-1 infected patients who maintain viral loads of <50 copies/ml without antiretroviral therapy. We have recently shown for the first time that replication competent virus can be isolated from some of these individuals suggesting that immunologic control of replication competent HIV-1 is possible. The mechanism of control has yet to be defined in these patients, but we have shown that superior humoral immunity is not the cause of control in many ES and neither is an intrinsic resistance to HIV-1 infection. We have shown that provirus from these patients also do not have higher levels of APOBEC 3G/F mediated hypemutation. Taken together it appears that superior HIV-specific cellular immunity plays a key role in the control of viremia in elite suppressors. While the mechanism of CD8+ T cell mediated control is unkown, it has been shown that elite suppressors and patients with progressive disease have similar frequencies of HIV-specific CTL. However, it has recently been shown that unstimulated CD8+ T cells from elite suppressors, but not patients with progressive disease, are able to control the replication of a laboratory strain of HIV-1 in autologous CD4+ T cells. This is a physiological model since the CD8+ T cells are not activated prior to being used in the assay and the CD4+ T cells process and present HIV antigens (as opposed to peptides being added to the cells in culture). The objective of this proposal is to determine the mechanisms by which this CD8+ T cell mediated control of this replication competent virus is achieved. We plan to determine whether CD8+ T cells are capable of controlling HIV replication in macrophages and whether they can kill these target cells when they are productively infected. We also plan to determine whether CD4+ T cells are capable of suppressing viral replication in macrophages and CD4+ T cells by direct killing activity or by cytokine secretion. Finally we will determine whether effector CD4+ and CD8+ T cells are capable of killing latently infected CD4+ T cells This work will be important for the development of vaccines that can be used to improve the HIV specific immune responses in HIV-1 infected individuals. This may allow some patients to control the virus without antiretroviral therapy for prolonged periods of time. This will also have major implications for strategies for HIV-1 eradication since clearance of latently infected cells is facilitated by effecor T cell responses.

描述（由申请人提供）：精英抑制者是HIV-1感染者，在未接受抗逆转录病毒治疗的情况下，病毒载量维持在<50拷贝/ml。我们最近首次表明，复制能力的病毒可以从这些人中的一些分离，这表明复制能力的HIV-1的免疫控制是可能的。这些患者的控制机制尚未确定，但我们已经表明，上级体液免疫不是许多ES控制的原因，也不是对HIV-1感染的内在抵抗力。我们已经表明，这些患者的前病毒也没有更高水平的APOBEC 3G/F介导的高突变。综上所述，似乎上级HIV特异性细胞免疫在精英抑制者的病毒血症控制中起关键作用。虽然CD 8 + T细胞介导的控制机制尚不清楚，但已显示精英抑制者和进行性疾病患者具有相似的HIV特异性CTL频率。然而，最近的研究表明，来自精英抑制者的未受刺激的CD 8 + T细胞，而不是患有进展性疾病的患者，能够控制HIV-1的实验室菌株在自体CD 4 + T细胞中的复制。这是一种生理模型，因为CD 8 + T细胞在用于测定之前未被活化，并且CD 4 + T细胞加工并呈递HIV抗原（与向培养物中的细胞中添加肽相反）。本提案的目的是确定这种CD 8 + T细胞介导的这种复制型病毒的控制实现的机制。我们计划确定CD 8 + T细胞是否能够控制巨噬细胞中的HIV复制，以及它们是否能够在有效感染时杀死这些靶细胞。我们还计划确定CD 4 + T细胞是否能够通过直接杀伤活性或细胞因子分泌抑制巨噬细胞和CD 4 + T细胞中的病毒复制。最后，我们将确定效应CD 4+和CD 8 + T细胞是否能够杀死潜伏感染的CD 4 + T细胞。 开发可用于改善HIV-1感染个体的HIV特异性免疫应答的疫苗。这可能使一些患者在没有抗逆转录病毒治疗的情况下长时间控制病毒。这也将对HIV-1根除策略产生重大影响，因为有效T细胞应答促进了潜伏感染细胞的清除。

项目成果

Characterization of Elite Suppressors Cell-Associated HIV-1 mRNA at Baseline and with T Cell Activation .

基线和 T 细胞激活中精英抑制因子细胞相关 HIV-1 mRNA 的表征â©â©。

• 发表时间: 2017
• 期刊: The Yale journal of biology and medicine
• 作者: Pohlmyer,ChristopherW;Bullen,CKorin;Martin,AlyssaR;Laird,GregoryM;Chioma,StanleyU;Walker-Sperling,VictoriaEK;Blankson,JoelN
• 通讯作者: Blankson,JoelN

Factors Associated With the Control of Viral Replication and Virologic Breakthrough in a Recently Infected HIV-1 Controller.

• DOI: 10.1016/j.ebiom.2017.01.034
• 发表时间: 2017-02
• 期刊: EBioMedicine
• 影响因子: 11.1
• 作者: Walker-Sperling VE;Pohlmeyer CW;Veenhuis RT;May M;Luna KA;Kirkpatrick AR;Laeyendecker O;Cox AL;Carrington M;Bailey JR;Arduino RC;Blankson JN
• 通讯作者: Blankson JN