HIV-Specific Granzyme B-Secreting but Not Gamma Interferon-Secreting T Cells Are Associated with Reduced Viral Reservoirs in Early HIV Infection
HIV-Specific Granzyme B-Secreting but Not Gamma Interferon-Secreting T Cells Are Associated with Reduced Viral Reservoirs in Early HIV Infection
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HIV 特异性颗粒酶 B 分泌而非γ干扰素分泌 T 细胞与早期 HIV 感染中病毒库减少相关
DOI：
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发表时间：
2017
影响因子：
5.4
通讯作者：
Mario A. Ostrowski
中科院分区：
文献类型：
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作者：
F. Yue;J. Cohen;M. Ho;A. Rahman;Jun Liu;S. Mujib;A. Saiyed;Sabrina Hundal;Alexandra Khozin;P. Bonner;Daheng Liu;E. Benko;C. Kovacs;Mario A. Ostrowski;Mario A. Ostrowski
摘要人类免疫缺陷病毒1型(HIV-1)感染治愈的一个主要障碍是尽管进行了联合抗逆转录病毒治疗(CART)，但仍建立了病毒库。目前尚不清楚HIV特异性细胞毒性T淋巴细胞(CTL)在HIV感染早期如何影响储存库的大小。28例早期HIV感染者接受CART治疗，随访48周。在基线和CART 48周后，通过细胞相关的前病毒DNA和病毒生长培养来测量外周CD4+T细胞中的HIV储存库。在基线时，对跨越艾滋病毒蛋白质组的多肽进行颗粒酶B和干扰素-γ的酶联免疫吸附斑点(ELISpot)分析。所有受试者在基线时都有可检测到的艾滋病毒特异性颗粒酶B和干扰素-γ反应。颗粒酶B应答的数量和特异性与干扰素-γ应答无关。颗粒酶B以TAT/REV为主，干扰素-γ以GAG为主。在基线和48周时，HIV特异性颗粒酶B T细胞应答与HIV前病毒载量呈负相关，在基线时与具有复制能力的病毒感染单位(IUPM)的CD4+T细胞呈负相关，但在48周时不显著。TAT/Rev-、Env-、Gag-和Vif特异的颗粒酶B反应与储层控制最密切相关。在基线或48周时，艾滋病毒特异性干扰素-γ应答与宿主大小没有相关性。颗粒酶B应答主要由CD8+T细胞贡献。因此，我们的发现表明，在感染早期诱导针对TAT、REV、ENV、GAG和VIF的有效的颗粒酶B产生的CTL可能能够防止建立大型病毒库，从而有助于减少HIV负担。重要性人类免疫缺陷病毒1型(HIV-1)感染治愈的一个主要障碍是建立病毒库，必须大幅减少或彻底根除病毒库才能治愈。仅靠联合抗逆转录病毒疗法(CART)无法清除这个病毒库。已有研究表明，CD8+细胞毒性T淋巴细胞(CTL)通过减少血浆病毒血症在控制早期HIV感染中起重要作用。然而，目前尚不清楚这些HIV特异性CTL是否会影响早期HIV感染的病毒库的建立。我们发现，针对HIV TAT/REV、ENV、GAG和VIF的HIV特异性颗粒酶B反应，而不是干扰素-γ反应，与基线和CART 48周时病毒储备量的减少有关。这些发现阐明了效应器CTL反应的性质，这种反应可能会限制储存库的大小，并对治疗研究和HIV疫苗产生影响。
ABSTRACT A major barrier to a human immunodeficiency virus type 1 (HIV-1) infection cure is the establishment of a viral reservoir in spite of combined antiretroviral therapy (cART). It is unclear how HIV-specific cytotoxic T lymphocytes (CTLs) influence the size of the reservoir in early HIV infection. Twenty-eight subjects with early HIV infection were recruited to receive cART and followed for 48 weeks. HIV reservoirs in peripheral CD4+ T cells measured by cell-associated proviral DNA and viral outgrowth cultures were determined at baseline and after 48 weeks of cART. At baseline, granzyme B and gamma interferon (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) assays were performed with peptides spanning the HIV proteome. All subjects had detectable HIV-specific granzyme B and IFN-γ responses at baseline. The quantity and specificity of granzyme B responses did not correlate with IFN-γ responses. For granzyme B, Tat/Rev was the most dominant whereas for IFN-γ, Gag predominated. HIV-specific granzyme B T cell responses negatively correlated with HIV proviral loads at baseline and at 48 weeks and with replication-competent viral infectious units per million (IUPM) CD4+ T cells at baseline but not significantly at 48 weeks. Tat/Rev-, Env-, Gag-, and Vif-specific granzyme B responses correlated most strongly with reservoir control. There was no correlation of HIV-specific IFN-γ responses with reservoir size at baseline or at 48 weeks. The majority of granzyme B responses were contributed by CD8+ T cells. Thus, our findings suggest that the induction of potent granzyme B-producing CTLs to Tat, Rev, Env, Gag, and Vif during early infection may be able to prevent the establishment of a large viral reservoir, thereby facilitating a reduced HIV burden. IMPORTANCE A major barrier to the cure of human immunodeficiency virus type 1 (HIV-1) infection is the establishment of a viral reservoir that must be significantly reduced or eradicated entirely to enable a cure. Combined antiretroviral therapy (cART) alone is unable to clear this viral reservoir. It has been shown that CD8+ cytotoxic T lymphocytes (CTLs) are important in controlling early HIV infection by reducing plasma viremia. However, it is not known if these HIV-specific CTLs influence the establishment of the viral reservoir in early HIV infection. We show that HIV-specific granzyme B responses targeting HIV Tat/Rev, Env, Gag, and Vif, but not IFN-γ responses, are associated with reduced virus reservoirs at baseline and at 48 weeks of cART. These findings shed light on the nature of the effector CTL response that might limit reservoir size with implications for cure research and HIV vaccines.
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DOI：
10.1073/pnas.95.15.8869
发表时间：
1998-07-21
影响因子：
11.1
作者：
Chun, TW;Engel, D;Fauci, AS
通讯作者：
Fauci, AS
影响因子：
6.4
作者：
Strain, MC;Little, SJ;Wong, JK
通讯作者：
Wong, JK
影响因子：
15.9
作者：
Bruner, Katherine M.;Hosmane, Nina N.;Siliciano, Robert F.
通讯作者：
Siliciano, Robert F.
DOI：
10.1073/pnas.96.26.15109
发表时间：
1999-12-21
影响因子：
11.1
作者：
Davey, RT;Bhat, N;Lane, HC
通讯作者：
Lane, HC