本文選題：人類(lèi)免疫缺陷病毒-1 + 艾滋病��； 參考：《第四軍醫(yī)大學(xué)》2007年碩士論文

【摘要】： 獲得性免疫缺陷綜合征(AIDS)已經(jīng)奪取了近四千萬(wàn)人的生命并嚴(yán)重威脅著人類(lèi)健康。高效抗逆轉(zhuǎn)錄病毒療法雖然在抑制HIV-1復(fù)制、免疫重建、降低AIDS相關(guān)疾病的發(fā)病率及延長(zhǎng)HIV感染后發(fā)病時(shí)間上有良好的效果。然而由于這些抗病毒藥物價(jià)格昂貴、毒副作用大、HIV-1耐藥株的產(chǎn)生以及患者依從性不好影響了抗病毒治療的療效。因此安全有效的疫苗來(lái)控制HIV-1的流行和傳播將成為人類(lèi)戰(zhàn)勝HIV的重要武器。 特異性的細(xì)胞毒性T細(xì)胞(CTL)應(yīng)答在控制HIV-1和SIV復(fù)制中發(fā)揮重要作用。誘導(dǎo)機(jī)體產(chǎn)生針對(duì)HIV-1強(qiáng)烈的CTL應(yīng)答成為目前HIV-1疫苗研制的熱點(diǎn)。Nef蛋白是HIV感染早期表達(dá)的蛋白質(zhì)之一,同時(shí)也是HIV-1感染后CTL最早識(shí)別并產(chǎn)生應(yīng)答的靶蛋白。現(xiàn)已證實(shí)其能夠通過(guò)激活CD4淋巴細(xì)胞,提高病毒顆粒的感染性,增加CD4分子和MHC分子的內(nèi)吞,以及防止受感染細(xì)胞凋亡等多種途徑對(duì)HIV的復(fù)制起到重要的促進(jìn)作用。Vpu通過(guò)影響新合成CD4分子向細(xì)胞膜轉(zhuǎn)運(yùn)和增加CD4分子從細(xì)胞膜向細(xì)胞內(nèi)內(nèi)吞來(lái)下調(diào)細(xì)胞表面的CD4。Vpr蛋白通過(guò)促進(jìn)整合前復(fù)合物(PIC)從胞漿到胞核的轉(zhuǎn)運(yùn)對(duì)病毒感染靜止期的細(xì)胞起到了重要作用。Vpr還可以使宿主細(xì)胞的細(xì)胞周期在G2/M期滯留,結(jié)果容易引起的細(xì)胞凋亡,甚至引起分裂細(xì)胞凋亡。Vif可以通過(guò)抑制抗病毒因子APOBEC3G的活性,增強(qiáng)病毒的感染性。Vif也可以使細(xì)胞周期滯留在G2/M期。 本研究選取61例HIV-1感染者/AIDS患者和10例HIV抗體陰性的健康對(duì)照者作為研究對(duì)象。進(jìn)行CD4細(xì)胞計(jì)數(shù)、病毒載量檢測(cè)并收集一般的臨床資料。應(yīng)用覆蓋HIV-1B、C亞型附屬蛋白(Nef、Vpu、Vpr和Vif)的142個(gè)肽段作為抗原,刺激來(lái)自研究對(duì)象的CTL產(chǎn)生γ-干擾素,采用酶聯(lián)免疫斑點(diǎn)吸附試驗(yàn)(ELISpot)檢測(cè),來(lái)定量測(cè)定HIV-1附屬蛋白特異性CD8+T細(xì)胞應(yīng)答,對(duì)中國(guó)人群HIV-1附屬蛋白特異性CD8+T細(xì)胞應(yīng)答反應(yīng)進(jìn)行了較全面的研究。 本研究發(fā)現(xiàn)無(wú)論對(duì)HIV-1B亞型還是HIV-1C亞型附屬蛋白都能產(chǎn)生特異性CTL應(yīng)答,特別是Nef區(qū)蛋白的反應(yīng)頻率和累積應(yīng)答強(qiáng)度都較高(P0.001),B、C亞型間的應(yīng)答頻率和累積應(yīng)答強(qiáng)度都無(wú)顯著差別(P0.05),其免疫優(yōu)勢(shì)區(qū)也大致相同,并篩選出了附屬蛋白區(qū)的免疫優(yōu)勢(shì)區(qū)。附屬蛋白特異性的累積CTL應(yīng)答強(qiáng)度將近達(dá)到總應(yīng)答的21%。這些結(jié)果表明盡管HIV-1附屬蛋白的序列較短,但它們?cè)谡T導(dǎo)特異性的CTL應(yīng)答中發(fā)揮了重要作用。 總之,本課題初步研究了HIV-1附屬蛋白特異性的CTL應(yīng)答特征,評(píng)價(jià)了HIV-1附屬蛋白特異性的CTL應(yīng)答在HIV-1激發(fā)的CTL應(yīng)答中的地位,確定了HIV-1附屬蛋白區(qū)內(nèi)CD8+T細(xì)胞應(yīng)答的優(yōu)勢(shì)區(qū)域。為進(jìn)一步篩選CTL表位和制備安全、有效的HIV-1疫苗奠定了基礎(chǔ)。
[Abstract]:High effective antiretroviral therapy has a good effect on inhibiting HIV-1 replication, immune reconstruction, reducing the incidence of AIDS related diseases and prolonging the onset time of HIV infection. However, because of the high cost of these antiviral drugs, the production of HIV-1 resistant strains and the poor compliance of patients have affected the efficacy of antiviral therapy. Therefore, a safe and effective vaccine to control the prevalence and spread of HIV-1 will become an important weapon for human to defeat HIV. Specific cytotoxic T lymphocyte (CTL) responses play an important role in controlling HIV-1 and SIV replication. Inducing a strong CTL response to HIV-1 has become a hot spot in the development of HIV-1 vaccine. Nef protein is one of the proteins expressed in the early stage of HIV infection, and it is also the first target protein to recognize and produce the response of CTL after HIV-1 infection. It has been proved that it can increase the infectivity of virus particles and endocytosis of CD4 molecules and MHC molecules by activating CD4 lymphocytes. Vpu plays an important role in promoting the replication of HIV by affecting the transport of newly synthesized CD4 molecules to the cell membrane and increasing the CD4 molecule from cell membrane to endocytosis to down-regulate the cell surface. VPR protein plays an important role in the cytosolic transport from cytoplasm to nucleus by promoting the transport of preintegrative complex. VPR can also make the cell cycle of host cells remain in G 2 / M phase. Results the easy apoptosis and even the mitotic cell apoptosis. Vif could inhibit the activity of antiviral factor APOBEC3G and enhance the infection of virus. Vif could also make the cell cycle stay in G 2 / M phase. In this study, 61 patients with HIV-1 / AIDS and 10 healthy controls with negative HIV antibody were selected as subjects. CD4 cell count, viral load detection and general clinical data were collected. A total of 142 peptide segments covering the HIV-1 BU C subtype C subsidiary protein, Nef-Vpu-Vpr and Vif-, were used as antigens to stimulate the production of interferon 緯 by CTL from the study subjects. Elisa assay was used to detect quantitatively the specific CD8 T cell response of HIV-1 satellite protein. The response of HIV-1 dependent protein specific CD8 T cells in Chinese population was studied. In this study, we found that both HIV-1B subtype and HIV-1C subtype adjunct protein can produce specific CTL response. In particular, the response frequency and cumulative response intensity of Nef protein were higher than that of P0.001C subtype. There was no significant difference in the response frequency and cumulative response intensity between the two subtypes, and the immune dominant region was similar, and the immune dominant region of the accessory protein region was screened out. The specific cumulative CTL response intensity of accessory protein was nearly 21% of the total response. These results suggest that although the sequence of HIV-1 satellite proteins is short, they play an important role in inducing specific CTL responses. In conclusion, we preliminarily studied the CTL response characteristics of HIV-1 satellite protein, evaluated the role of HIV-1 accessory protein specific CTL response in CTL response induced by HIV-1, and determined the dominant region of CD8 T cell response in HIV-1 accessory protein region. It lays a foundation for further screening of CTL epitopes and preparation of safe and effective HIV-1 vaccine.
【學(xué)位授予單位】：第四軍醫(yī)大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2007
【分類(lèi)號(hào)】：R392

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中國(guó)期刊全文數(shù)據(jù)庫(kù) 前2條

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本文編號(hào)：1908456