來(lái)自來(lái)自麻省普科醫(yī)院理根研究所和哈佛大學(xué)的研究人員組成的一個(gè)研究小組報(bào)告發(fā)現(xiàn)一類HIV特異性CD4T細(xì)胞可在HIV感染初期直接殺傷HIV感染細(xì)胞,，CD4T細(xì)胞過(guò)去被認(rèn)為主要是對(duì)其他免疫細(xì)胞起控制和支持作用,。這一研究發(fā)現(xiàn)將推動(dòng)幫助科學(xué)家們深入了解HIV的感染進(jìn)程,。研究論文發(fā)表在2月29日的《科學(xué)—轉(zhuǎn)化醫(yī)學(xué)》（Science Translational Medicine）雜志上。
文章的作者,、麻省普科醫(yī)院理根研究所成員,、哈佛大學(xué)醫(yī)學(xué)院醫(yī)學(xué)系助理教授Hendrik Streeck博士說(shuō)“我們發(fā)現(xiàn)在那些HIV急性感染后不久即能控制病毒復(fù)制的患者體內(nèi)生成了一類能夠殺傷HIV感染細(xì)胞的CD4T細(xì)胞。這些細(xì)胞似乎出現(xiàn)在HIV感染的極早期,，我們相信它們可能拉動(dòng)了疾病發(fā)展的序幕,。”
CD4T細(xì)胞的主要功能是輔助免疫系統(tǒng)中的其他細(xì)胞類型；過(guò)去的研究發(fā)現(xiàn)在HIV感染后會(huì)導(dǎo)致CD4T細(xì)胞大量死亡,，隨后機(jī)體免疫應(yīng)答出現(xiàn)全面崩潰,，表明了CD4T細(xì)胞的重要性。
Streeck說(shuō)：“每種成功獲得批準(zhǔn)的HIV疫苗都能在一定程度上誘導(dǎo)CD4T細(xì)胞應(yīng)答,。從大量其他病毒感染中我們知道當(dāng)存在強(qiáng)有力的CD4T細(xì)胞應(yīng)答時(shí),，免疫系統(tǒng)就能很好地控制感染。”因此,，盡管HIV特異性CD4細(xì)胞并非當(dāng)前疫苗研究的主要焦點(diǎn),，這些細(xì)胞仍可能在控制HIV感染中發(fā)揮重要作用,。
為了了解CD4T細(xì)胞應(yīng)答是否在HIV感染早期發(fā)揮了重要作用，理根研究所人員招募了由11位志愿者組成的一個(gè)研究對(duì)象小組,。這些志愿者都處于HIV感染的最早期,，此時(shí)HIV病毒的水平非常的高。在為期一年的研究過(guò)程中,，Streeck等基于志愿者體內(nèi)的HIV水平將他們分成了兩組：其中一組可持續(xù)將HIV維持在低水平,，而另一組則明顯喪失了對(duì)HIV復(fù)制的免疫控制。針對(duì)這一整年采集樣品的回顧分析結(jié)果表明兩組志愿者的CD4T細(xì)胞應(yīng)答存在驚人的差異,。無(wú)法控制HIV復(fù)制的志愿者的HIV特異性CD4應(yīng)答快速下降并維持在低水平,，而能夠有效控制病毒的志愿者相同的應(yīng)答卻顯著增高，表明HIV特異性CD4細(xì)胞在病毒控制中發(fā)揮了重要作用,。
實(shí)驗(yàn)發(fā)現(xiàn)HIV特異性CD4T細(xì)胞應(yīng)答顯示了細(xì)胞殺傷活性,，甚至有可能破壞了HIV感染的巨噬細(xì)胞。此外,，研究人員還發(fā)現(xiàn)借助一種特異性的細(xì)胞死亡蛋白granzymeA可將HIV特異性CD4細(xì)胞與那些缺乏病毒水平控制能力的細(xì)胞區(qū)分開(kāi)來(lái),。
為了驗(yàn)證上述研究發(fā)現(xiàn)，科研人員進(jìn)一步對(duì)更大群的HIV感染者進(jìn)行了檢測(cè),。發(fā)現(xiàn)在感染后不久,，HIV特異性CD4T細(xì)胞免疫應(yīng)答中g(shù)ranzymeA水平越高，患者病情發(fā)展則越慢,，且不需要接受抗逆轉(zhuǎn)錄病毒治療,。Streeck解釋說(shuō)：“這兩組之間關(guān)鍵的基礎(chǔ)差異與HIV特異性CD4T細(xì)胞應(yīng)答的特性有關(guān)。那些能夠?qū)⒉《揪S持在低點(diǎn)的個(gè)體,，早期的CD4應(yīng)答受到granzymeA表達(dá)的支配，基于此可以高度預(yù)測(cè)疾病的進(jìn)展速度,。”
Streeck指出特異性CD4T細(xì)胞活性與病毒水平抑制程度相關(guān),，表明利用疫苗來(lái)誘導(dǎo)這樣的應(yīng)答將對(duì)患者有益。此外,，granzymeA表達(dá)與更有效的HIV特異性CD4細(xì)胞應(yīng)答有關(guān)表明檢測(cè)該蛋白的水平將可以預(yù)測(cè)感染最初期的疾病后果,，這是用當(dāng)前的技術(shù)無(wú)法實(shí)現(xiàn)的。研究人員表示他們將更深入地開(kāi)展研究來(lái)揭示CD4細(xì)胞應(yīng)答的細(xì)胞殺傷性機(jī)制以及granzymeA功能和疾病預(yù)測(cè)應(yīng)用,。（生物谷 bioon.com）
doi:10.1126/scitranslmed.3003165
PMC:
PMID:
HIV-Specific Cytolytic CD4 T Cell Responses During Acute HIV Infection Predict Disease Outcome
Damien Z. Soghoian, Heiko Jessen, Michael Flanders, Kailan Sierra-Davidson, Sam Cutler, Thomas Pertel, Srinika Ranasinghe, Madelene Lindqvist, Isaiah Davis, Kimberly Lane, Jenna Rychert, Eric S. Rosenberg, Alicja Piechocka-Trocha1, Abraham L. Brass1, Jason M. Brenchley, Bruce D. Walker1, and Hendrik Streeck1
Early immunological events during acute HIV infection are thought to fundamentally influence long-term disease outcome. Whereas the contribution of HIV-specific CD8 T cell responses to early viral control is well established, the role of HIV-specific CD4 T cell responses in the control of viral replication after acute infection is unknown. A growing body of evidence suggests that CD4 T cells—besides their helper function—have the capacity to directly recognize and kill virally infected cells. In a longitudinal study of a cohort of individuals acutely infected with HIV, we observed that subjects able to spontaneously control HIV replication in the absence of antiretroviral therapy showed a significant expansion of HIV-specific CD4 T cell responses—but not CD8 T cell responses—compared to subjects who progressed to a high viral set point (P = 0.038). Markedly, this expansion occurred before differences in viral load or CD4 T cell count and was characterized by robust cytolytic activity and expression of a distinct profile of perforin and granzymes at the earliest time point. Kaplan-Meier analysis revealed that the emergence of granzyme A+ HIV-specific CD4 T cell responses at baseline was highly predictive of slower disease progression and clinical outcome (average days to CD4 T cell count <350/μl was 575 versus 306, P = 0.001). These data demonstrate that HIV-specific CD4 T cell responses can be used during the earliest phase of HIV infection as an immunological predictor of subsequent viral set point and disease outcome. Moreover, these data suggest that expansion of granzyme A+ HIV-specific cytolytic CD4 T cell responses early during acute HIV infection contributes substantially to the control of viral replication.
