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: 8212175
• 负责人: JOEL N BLANKSON
• 金额: $ 32.15万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-15 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8212175
• 关键词: Acquired Immunodeficiency Syndrome; Alleles; Antigen-Presenting Cells; Autologous; Biological Assay; Bypass; CD4 Lymphocyte Count; CD4 Positive T Lymphocytes; CD8B1 gene; Cell physiology; Cells; Cellular Immunity; Consensus; Defective Viruses; Detection; Development; Disease; Down-Regulation; Drops; Flow Cytometry; Frequencies; Gagging; Grant; HIV; HIV Antigens; HIV-1; HLA-B Antigens; Health; Histocompatibility Antigens Class I; Humoral Immunities; Immune response; Immune system; Immunologics; Individual; Infection; Integration Host Factors; Kinetics; Laboratories; MHC Class I Genes; Mediating; Memory; Mitogens; Modeling; Mutation; Natural Killer Cells; Patients; Peptides; Physiological; Plasma; Play; Predisposition; Progressive Disease; Proliferating; Proteins; Proviruses; Reporting; Resistance; Role; Specificity; T cell response; T-Lymphocyte; Testing; Time; Vaccines; Viral; Viral Load result; Viremia; Virus; Work; antigen processing; antiretroviral therapy; cytokine; cytotoxic; design; fitness; improved; in vivo; killings; novel strategies; recombinant virus; 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 hypermutation. 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 unknown, 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 identify the major subset of CD8+ T cells involved in this control. We will also distinguish between cytotoxic killing of target cells and non-cytotoxic mediated suppression of viral replication. We will define the kinetics of the CD8+ T cell mediated control and determine whether Nef mediated down regulation of MHC class I proteins is a mechanism used by the virus to evade this control of viral replication. 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. PUBLIC HEALTH RELEVANCE: Most patients infected with HIV-1 will develop a drop in their CD4 counts and frank AIDS as the virus replicates and destroys the immune system. A unique group of untreated HIV-1-infected patients, termed Elite Suppressors (ES) are able to completely control the virus and do not develop AIDS (1-3). This project plans to determine how CD8+ T cells from ES control the virus; the results may be applicable to the development of an effective HIV-1 vaccine.

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介导的超突变。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。我们计划确定参与该对照的CD 8 + T细胞的主要亚群。我们还将区分靶细胞的细胞毒性杀伤和非细胞毒性介导的病毒复制抑制。我们将定义CD 8 + T细胞介导的控制动力学，并确定Nef介导的MHC I类蛋白下调是否是病毒逃避病毒复制控制的机制。这项工作对于开发可用于改善HIV-1感染者的HIV特异性免疫应答的疫苗将是重要的。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。公共卫生关系：大多数感染HIV-1的患者在病毒复制和破坏免疫系统时，CD 4计数会下降，并出现明显的艾滋病。一组独特的未经治疗的HIV-1感染患者，称为精英抑制者（ES），能够完全控制病毒，不会发展为AIDS（1-3）。该项目计划确定来自ES的CD 8 + T细胞如何控制病毒;结果可能适用于开发有效的HIV-1疫苗。

项目成果

Evolution of the HIV-1 nef gene in HLA-B*57 positive elite suppressors.

HLA-B*57 阳性精英抑制基因中 HIV-1 nef 基因的进化。

• DOI: 10.1186/1742-4690-7-94
• 发表时间: 2010
• 期刊: Retrovirology
• 影响因子: 3.3
• 作者: Salgado,Maria;Brennan,TimothyP;O'Connell,KarenA;Bailey,JustinR;Ray,StuartC;Siliciano,RobertF;Blankson,JoelN
• 通讯作者: Blankson,JoelN

Circulating monocytes are not a major reservoir of HIV-1 in elite suppressors.

循环单核细胞并不是精英抑制因子中 HIV-1 的主要储存库。

• DOI: 10.1128/jvi.05409-11
• 发表时间: 2011
• 期刊: Journal of virology
• 影响因子: 5.4
• 作者: Spivak,AdamM;Salgado,Maria;Rabi,SAlireza;O'Connell,KarenA;Blankson,JoelN
• 通讯作者: Blankson,JoelN

Host factors dictate control of viral replication in two HIV-1 controller/chronic progressor transmission pairs.

• DOI: 10.1038/ncomms1697
• 发表时间: 2012-03-06
• 期刊: Nature communications
• 影响因子: 16.6

HIV type 1-mediated downregulation of HLA-B*57/B*5801 proteins on elite suppressor CD4+ T cells.

HIV 1 型介导的精英抑制 CD4 T 细胞上 HLA-B*57/B*5801 蛋白的下调。

• DOI: 10.1089/aid.2010.0144
• 发表时间: 2011
• 期刊: AIDS research and human retroviruses
• 影响因子: 1.5
• 作者: Sampah,MaameEfuaS;Ceccato,ChristinaM;Blankson,JoelN
• 通讯作者: Blankson,JoelN

Unstimulated primary CD4+ T cells from HIV-1-positive elite suppressors are fully susceptible to HIV-1 entry and productive infection.

来自 HIV-1 阳性精英抑制因子的未刺激的初级 CD4 T 细胞完全容易受到 HIV-1 的进入和生产性感染。

• DOI: 10.1128/jvi.01721-10
• 发表时间: 2011
• 期刊: Journal of virology
• 影响因子: 5.4
• 作者: Rabi,SAlireza;O'Connell,KarenA;Nikolaeva,Daria;Bailey,JustinR;Jilek,BenjaminL;Shen,Lin;Page,KathleenR;Siliciano,RobertF;Blankson,JoelN
• 通讯作者: Blankson,JoelN