尚紅

中國醫(yī)科大學(xué)附屬第一醫(yī)院檢驗(yàn)科，國家衛(wèi)生和計(jì)劃生育委員會(huì)艾滋病免疫學(xué)重點(diǎn)實(shí)驗(yàn)室，沈陽 110001

目前我國人類免疫缺陷病毒(human immunodeficiency virus，HIV)感染疫情總體處于低流行水平，全人群HIV感染率為0.058%，但全國報(bào)告的HIV/艾滋病(acquired immunodeficiency syndrome，AIDS)病例中經(jīng)男男性行為(men who have sex with men，MSM)途徑感染者所占比例增長迅速，1985～2005年MSM所占比例僅為0.3%，2006年為2.5%，2012年上升至19.1%。影響我國MSM人群中HIV感染疫情上升的因素很多，包括人口流動(dòng)大、梅毒螺旋體感染率高、HIV檢測比例低、傳統(tǒng)生育觀所致的MSM人群與異性婚育現(xiàn)象嚴(yán)重，以及社會(huì)大眾對(duì)同性性行為的歧視現(xiàn)象等[1]，這些因素直接影響了艾滋病防控策略和措施的實(shí)施效果?，F(xiàn)就我國MSM人群中HIV感染疫情特點(diǎn)和防治策略作一綜述。

1 MSM人群中HIV感染流行病學(xué)特征

本團(tuán)隊(duì)近年來對(duì)上海、南京、沈陽、昆明、重慶等7個(gè)大中城市MSM人群開展的橫斷面系列調(diào)查研究發(fā)現(xiàn)，2012年HIV感染率為9.6%，顯著高于2009年的6.8%，也顯著高于2008年全國61個(gè)大中城市MSM人群平均4.9%的HIV感染率。2009年至今，對(duì)北京、沈陽、昆明等10個(gè)大中城市6 132名高危MSM人群的大規(guī)模前瞻性隊(duì)列研究發(fā)現(xiàn)，HIV新發(fā)感染率為5.5/100人年(person year，PY)，高于同期我國女性性工作者(1.4/100 PY)和注射吸毒者(0.7/100 PY)[1,2]，提示MSM人群已成為我國HIV新發(fā)感染的主體人群。

2 MSM人群中HIV分子流行病學(xué)傳播特征

截至2005年，我國MSM人群中流行的主要HIV毒株為歐美B亞型(占71.1%)，CRF_AE亞型僅占24.4%[3]。近年來隨著MSM人群中HIV感染人數(shù)快速增長，流行亞型也呈現(xiàn)出新特征。至2012年，CRF_AE亞型已成為我國MSM人群中占主導(dǎo)地位的HIV毒株[4-8]，并明顯分為2個(gè)獨(dú)立的傳播簇，其中一簇在我國南部、東南沿海及遼寧等地區(qū)廣泛傳播，另一簇則主要在北京及遼寧地區(qū)傳播[9]。同時(shí)，在我國MSM人群中還發(fā)現(xiàn)了新型HIV重組株CRF55_01B和CRF59_01B，其中CRF55_01B在華南和中南地區(qū)某些城市流行率已達(dá)10%，CRF59_01B也散在分布于全國多個(gè)省份[10,11]。此外，我國MSM人群中HIV流行株的原發(fā)耐藥比例亦明顯高于其他途徑的HIV感染人群[12-15]。新型HIV病毒株的出現(xiàn)和快速上升的原發(fā)HIV耐藥率等因素加大了在MSM人群中控制HIV傳播的難度，人們迫切需要探索適合我國的可有效降低MSM人群HIV新發(fā)感染水平的綜合防治模式。

3 MSM人群中HIV急性感染者的早期發(fā)現(xiàn)

HIV感染早期病毒復(fù)制水平高，傳染性強(qiáng)。及早發(fā)現(xiàn)感染者，對(duì)其早期進(jìn)行干預(yù)，可有效降低HIV在急性感染期的二代傳播，對(duì)HIV防控具有重要意義。以往常用第3代酶聯(lián)免疫吸附試驗(yàn)(enzyme-linked immunosorbent assay，ELISA)進(jìn)行HIV抗體檢測，用于HIV感染篩查。由于HIV感染人體后有一段窗口期，病毒抗體不能被檢出，可導(dǎo)致早期感染者的漏檢。在窗口期進(jìn)行P24抗原或病毒核酸檢測，是HIV感染早期輔助診斷和進(jìn)一步縮短窗口期的一種方法。使用多樣品集合方法，對(duì)采供血機(jī)構(gòu)和HIV抗體陰性的高危人群樣品進(jìn)行集合核酸檢測，可及時(shí)發(fā)現(xiàn)窗口期感染。本團(tuán)隊(duì)研究顯示，在以MSM人群為主的HIV高危人群中，通過高密度隨訪和第3代ELISA+集合核酸檢測方法進(jìn)行急性感染者的篩查，投入與產(chǎn)出比是1∶16.9，可節(jié)省醫(yī)療資源，有助于艾滋病防治的可持續(xù)發(fā)展[16]。此外，應(yīng)用化學(xué)發(fā)光或第4代ELISA可同時(shí)檢測HIV抗體及P24抗原，有利于窗口期感染者的發(fā)現(xiàn)。

4 MSM人群中HIV急性感染者的疾病進(jìn)展及相關(guān)因素

HIV感染后疾病進(jìn)展速度不同。70%～80%的個(gè)體感染后6～10年進(jìn)入艾滋病期(典型HIV感染者)，僅10%～15%的HIV感染者3年內(nèi)CD4+T細(xì)胞迅速下降(快速進(jìn)展者)[17]。本團(tuán)隊(duì)通過對(duì)遼寧、北京及云南地區(qū)HIV新發(fā)感染者隊(duì)列隨訪，發(fā)現(xiàn)約37%的新發(fā)感染者1年內(nèi)CD4+T細(xì)胞數(shù)降至350個(gè)/μ l以下，疾病進(jìn)展速度快于其他感染途徑人群，且CD4+T細(xì)胞下降及病毒載量上升速度均高于歐洲等國MSM人群新發(fā)感染者[18]。早期發(fā)現(xiàn)并評(píng)估疾病進(jìn)展速度，對(duì)快速進(jìn)展者及早干預(yù)，對(duì)降低MSM人群的HIV感染病死率至關(guān)重要。國外研究顯示，早期出現(xiàn)CXCR4嗜性毒株，感染多藥耐藥毒株或多重感染，白細(xì)胞介素7受體(interleukin 7 receptor，IL-7R)、蛋白精氨酸甲基轉(zhuǎn)移酶6 (protein arginine methyltransferase 6, PRMT6)、CX3C趨化因子受體1(CX3C chemokine receptor 1，CX3CR1)、Toll樣受體(Toll-like receptor，TLR)單核苷酸多態(tài)性、HIV特異性T細(xì)胞應(yīng)答和漿細(xì)胞樣樹突細(xì)胞(plasmacytoid dendritic cell，pDC)數(shù)量下降，以及血漿γ 干擾素誘導(dǎo)蛋白10(interferon-γ -inducible protein 10，IP-10)、人類白細(xì)胞抗原G(human leukocyte antigen G，HLA-G)水平較高等，與疾病快速進(jìn)展相關(guān)[19-29]。本團(tuán)隊(duì)對(duì)我國MSM人群中HIV感染者micro-RNA表達(dá)水平進(jìn)行了研究，首次發(fā)現(xiàn)快速進(jìn)展者microRNA明顯低于非快速進(jìn)展者，可預(yù)測疾病進(jìn)展，功能研究發(fā)現(xiàn)其可能通過影響細(xì)胞凋亡信號(hào)通路發(fā)揮作用[30]。這組與疾病快速進(jìn)展相關(guān)micro-RNA的發(fā)現(xiàn)，對(duì)開發(fā)HIV感染早期預(yù)測疾病進(jìn)展的分子標(biāo)記、實(shí)施早期干預(yù)具有重要意義。

5 MSM人群中HIV急性感染者的治療前景

20世紀(jì)90年代以來，抗反轉(zhuǎn)錄病毒治療(anti-retroviral therapy，ART)在全球廣泛應(yīng)用，明顯降低了艾滋病的發(fā)病率及病死率。但ART不能徹底清除病毒，停藥后病毒即反彈，患者需終身服藥，其毒副作用及耐藥等問題難以避免，成為艾滋病防控的瓶頸[31]。2013年，法國巴斯德研究所及美國霍普金斯大學(xué)研究人員報(bào)道了2個(gè)令人振奮的艾滋病“功能性治愈”信息。美國“密西西比州嬰兒”出生時(shí)攜帶HIV，接受18個(gè)月ART，停藥半年后檢測不到具有復(fù)制能力的HIV[32]。法國14例早期HIV感染者接受平均36.5個(gè)月的ART，停藥后平均隨訪89個(gè)月病毒亦未反彈，提示早期有效的ART可能使小部分HIV感染者實(shí)現(xiàn)功能性治愈(5%～15%)[33]。近期，《新英格蘭雜志》報(bào)道了2項(xiàng)HIV感染早期抗病毒治療隊(duì)列的研究結(jié)果，均提示早期治療有助于CD4+T細(xì)胞恢復(fù)[34,35]。但是，這2項(xiàng)研究并未探索早期治療后臨床癥狀是否得到改善，且均在感染早期病毒達(dá)到峰值后開始治療，HIV可能已經(jīng)導(dǎo)致人體廣泛損傷[36]。因此，早期發(fā)現(xiàn)MSM人群中的HIV急性感染者，實(shí)施抗病毒治療，探索其對(duì)病毒儲(chǔ)存庫清除、免疫重建及改善臨床癥狀的效果，同時(shí)降低HIV二代傳播，已成為HIV感染預(yù)防及治療領(lǐng)域急需深入研究的重要課題。

6 MSM高危人群暴露前的預(yù)防策略

傳統(tǒng)行為干預(yù)策略，如禁欲、保持單一性伴、100%使用安全套，以及擴(kuò)大檢測及時(shí)發(fā)現(xiàn)HIV感染者等，曾為降低MSM人群中HIV新發(fā)感染率發(fā)揮一定的積極作用。但該人群難以做到禁欲和保持單一性伴，且“信-知-行”分離現(xiàn)象較為突出，單純開展健康教育和咨詢已不能有效控制其無保護(hù)性肛交的發(fā)生率。因此，除行為干預(yù)措施外，生物醫(yī)學(xué)防控策略已成為探索HIV感染預(yù)防的熱點(diǎn)。一項(xiàng)在美國、泰國、南非等國家開展的國際多中心研究顯示，采用暴露前預(yù)防用藥(pre-exposure prophylaxis，PrEP)，MSM人群的HIV感染率降低44%[37]。針對(duì)異性性行為人群的研究結(jié)果顯示，在肯尼亞和烏干達(dá)對(duì)HIV單陽配偶家庭實(shí)施PrEP，保護(hù)率達(dá)67%～75%[38]。Gomez等對(duì)預(yù)防HIV感染的衛(wèi)生經(jīng)濟(jì)學(xué)分析顯示，在高危人群中開展PrEP預(yù)防是一項(xiàng)具有較好收益的投資，但PrEP的經(jīng)濟(jì)有效性還取決于藥物費(fèi)用、流行狀況、暴露前預(yù)防方案的覆蓋和優(yōu)先級(jí)策略，以及個(gè)體依從性和對(duì)PrEP效力的評(píng)估[39]。大規(guī)模服用PrEP藥物，價(jià)格高昂，發(fā)展中國家難以承擔(dān)，且目前PrEP需每天進(jìn)行，可能存在HIV耐藥的風(fēng)險(xiǎn)；長期常規(guī)采用PrEP者中，約70%出現(xiàn)頭痛、腹瀉、抑郁等不良反應(yīng)[37]，7%出現(xiàn)嚴(yán)重藥物不良反應(yīng)[38]，且部分接受PrEP的高危人群易發(fā)生更多的無保護(hù)性行為，感染HIV的風(fēng)險(xiǎn)反而增加。PrEP對(duì)預(yù)防我國MSM人群中HIV新發(fā)感染的預(yù)防作用尚處于研究評(píng)估階段。

7 HIV疫苗研究任重道遠(yuǎn)

2007年，被科學(xué)界廣泛寄予厚望的艾滋病候選疫苗——復(fù)制缺陷型Ad5腺病毒載體疫苗Ⅱb期臨床試驗(yàn)宣告失敗，給艾滋病疫苗研究帶來重創(chuàng)[40]。目前唯一顯示有效性的艾滋病疫苗試驗(yàn)為RV144試驗(yàn)，其采用重組金絲雀痘病毒載體疫苗ALVAC初次免疫，重組gp120亞單位疫苗AIDSVAX加強(qiáng)，可將HIV感染率降低31.2%[41]。盡管RV144的有效性有限，但為HIV疫苗研究帶來了曙光，對(duì)HIV疫苗研究具有重要意義。近年來，從HIV感染者體內(nèi)分離并鑒定出具有廣泛中和活性的抗體，成為艾滋病研究領(lǐng)域中的主要突破之一[42]。動(dòng)物模型研究顯示，廣譜中和抗體能有效阻止HIV感染或在感染動(dòng)物中抑制病毒復(fù)制[43,44]，但目前為止尚無有效疫苗能在人體中誘導(dǎo)產(chǎn)生這些抗體[45]。CD8+T細(xì)胞應(yīng)答對(duì)控制病毒的重要作用使其在疫苗研發(fā)中仍具有重要意義[46]。近期，Picker團(tuán)隊(duì)研究發(fā)現(xiàn)，一種對(duì)猴免疫缺陷病毒(simian immunodeficiency virus，SIV)感染具有保護(hù)作用的SIV基因重組巨細(xì)胞病毒載體，可誘導(dǎo)識(shí)別由主要組織相容性復(fù)合體(major histocompatibility complex，MHC)Ⅰ及Ⅱ呈遞廣譜多肽的CD8+T細(xì)胞，對(duì)基于細(xì)胞免疫的疫苗研制具有重要意義[47]。此外，科學(xué)家也在積極研究探討能否使天然免疫應(yīng)答成為疫苗策略的一部分[48]。2013年4月，處于Ⅱb期的基于DNA/Ad5的HVTN505 HIV疫苗臨床試驗(yàn)由于其不能降低HIV感染而被叫停，使HIV疫苗研究又遭挫折，HIV疫苗的研究任重而道遠(yuǎn)。

綜上所述，MSM人群已成為我國HIV新發(fā)感染的主體，系統(tǒng)研究MSM人群中HIV新發(fā)感染特點(diǎn)、疾病進(jìn)展速度及關(guān)鍵影響因素，有針對(duì)性地實(shí)施綜合干預(yù)，探索早期治療療效，對(duì)降低我國艾滋病的發(fā)病率及病死率具有重要意義。

[1] Shang H, Xu J, Han X, Spero Li J, Arledge KC, Zhang L. HIV prevention: Bring safe sex to China [J]. Nature, 2012, 485(7400):576-577.

[2] Xu J, Han X, Reilly KH，Shang H. New features of the HIV epidemic among men who have sex with men in China [J]. Emerg Microbes Infect, 2013, 2(7): e45. doi: 10.1038/emi.2013.45.

[3] Zhang X, Li S, Li X, Li X, Xu J, Li D, Ruan Y, Xing H, Zhang X, Shao Y. Characterization of HIV-1 subtypes and viral antiretroviral drug resistance in men who have sex with men in Beijing, China [J]. AIDS, 2007, 21(Suppl 8): S59-S65.

[4] Wang W, Jiang S, Li S, Yang K, Ma L, Zhang F, Zhang X, Shao Y. Identification of subtype B, multiple circulating recombinant forms and unique recombinants of HIV type 1 in an MSM cohort in China [J]. AIDS Res Hum Retroviruses, 2008, 24(10): 1245-1254.

[5] Wang W, Xu J, Jiang S, Yang K, Meng Z, Ma Y, Li M, Zhang X, Shao Y, Zhang F, Zhang X. The dynamic face of HIV-1 subtypes among men who have sex with men in Beijing, China [J]. Curr HIV Res, 2011, 9(2): 136-139.

[6] Han X, Dai D, Zhao B, Liu J, Ding H, Zhang M, Hu Q, Lu C, Goldin M, Takebe Y, Zhang L, Shang H. Genetic and epidemiologic characterization of HIV-1 infection in Liaoning Province, China [J]. J Acquir Immune Defic Syndr, 2010, 53(Suppl 1): S27-S33.

[7] Zhao B, Han X, Dai D, Liu J, Ding H, Xu J, Chu Z, Bice T, Diao Y, Shang H. New trends of primary drug resistance among HIV type 1-infected men who have sex with men in Liaoning Province, China [J]. AIDS Res Hum Retroviruses, 2011, 27(10): 1047-1053.

[8] Li L, Lu X, Li H, Chen L, Wang Z, Liu Y, Bao Z, Li T, Tian C, Liu H, Zhuang D, Liu S, Li J. High genetic diversity of HIV-1 was found in men who have sex with men in Shijiazhuang, China [J]. Infect Genet Evol, 2011, 11(6): 1487-1492.

[9] An M, Han X, Xu J, Chu Z, Jia M, Wu H, Lu L, Takebe Y, Shang H. Reconstituting the epidemic history of HIV strain CRF01_AE among men who have sex with men (MSM) in Liaoning, Northeastern China: Implications for the expanding epidemic among MSM in China [J]. J Virol, 2012, 86(22):12402-12406.

[10] Han X, An M, Zhang W, Cai W, Chen X, Takebe Y, Shang H. Genome sequences of a novel HIV-1 circulating recombinant form, CRF55_01B, identified in China [J]. Genome Announc, 2013, 1(1) e00050-12. doi: 10.1128/genomeA.00050-12.

[11] Han X, An M, Zhang W, Zhao B, Chu Z, Takebe Y, Shang H. Genome sequences of a novel HIV-1 circulating recombinant form (CRF59_01B) identified among men who have sex with men in Northeastern China [J]. Genome Announc, 2013, 1(3) e00315-13. doi: 10.1128/genomeA.00315-13.

[12] Liao L, Xing H, Dong Y, Qin G, Ma Y, Lu H, Chen L, Zhang L, Osborne C, Seguy N, Wei D, Sun F, Yang J, Ruan Y, Shao Y. Surveys of transmitted HIV drug resistance in 7 geographic regions in China, 2008-2009 [J]. Clin Infect Dis, 2012, 54 (Suppl 4): S320-S323.

[13] Chen M, Ma Y, Duan S, Xing H, Yao S, Su Y, Luo H, Yang L, Chen H, Fu L, Qu A, Ou CY, Jia M, Lu L. Genetic diversity and drug resistance among newly diagnosed and antiretroviral treatment-naive HIV-infected individuals in western Yunnan: a hot area of viral recombination in China [J]. BMC Infect Dis, 2012, 12: 382.

[14] Yang C, Liu S, Zhang T, Hou Y, Liu X, Gao Y, Yang G, Wang Z, Chen H, Li M, Zhu Z. Transmitted antiretroviral drug resistance and thumb subdomain polymorphisms among newly HIV type 1 diagnosed patients infected with CRF01_AE and CRF07_BC virus in Guangdong Province, China [J].AIDS Res Hum Retroviruses, 2012, 28(12):1723-1728.

[15] Yang J, Xing H, Niu J, Liao L, Ruan Y, He X, Feng Y, Li Z, Shao Y. The emergence of HIV-1 primary drug resistance genotypes among treatment-na?ve men who have sex with men in high-prevalence areas in China [J]. Arch Virol, 2013:158(4):839-844.

[16] Han X, Xu J, Chu Z, Dai D, Lu C, Wang X, Zhao L, Zhang C, Ji Y, Zhang H, Shang H. Screening acute HIV infections among Chinese men who have sex with men from voluntary counseling & testing centers [J]. PLoS One, 2011, 6(12): e28792.

[17] Langford SE, Ananworanich J, Cooper DA. Predictors of disease progression in HIV infection: a review [J]. AIDS Res Ther, 2007, 4: 11.

[18] Huang X, Lodi S, Fox Z, Li W, Phillips A, Porter K, Lutsar I, Kelleher A, Li N, Xu X, Wu H, Johnson AM, Beijing PRIMO cohort study, CASCADE Collaboration in EuroCoord. Rate of CD4 decline and HIV-RNA change following HIV seroconversion in men who have sex with men: a comparison between the Beijing PRIMO and CASCADE cohorts [J]. J Acquir Immune Defic Syndr, 2013, 62(4):441-446.

[19] Jiao Y, Zhang T, Wang R, Zhang H, Huang X, Yin J, Zhang L, Xu X, Wu H. Plasma IP-10 is associated with rapid disease progression in early HIV-1 infection [J]. Viral Immunol, 2012, 25(4):333-337.

[20] Limou S, Melica G, Coulonges C, Lelièvre JD, Do H, McGinn S, Gut IG, Lévy Y, Zagury JF. Identification of IL7RA risk alleles for rapid progression during HIV-1 infection: a comprehensive study in the GRIV cohort [J]. Curr HIV Res, 2012, 10(2): 143-150.

[21] Sucupira MC, Sanabani S, Cortes RM, Giret MT, Tomiyama H, Sauer MM, Sabino EC, Janini LM, Kallas EG, Diaz RS. Faster HIV-1 disease progression among Brazilian individuals recently infected with CXCR4-utilizing strains [J]. PLoS One, 2012, 7(1): e30292.

[22] Freguja R, Gianesin K, Del Bianco P, Malacrida S, Rampon O, Zanchetta M, Giaquinto C, De Rossi A. Polymorphisms of innate immunity genes influence disease progression in HIV-1-infected children [J]. AIDS, 2012, 26(6): 765-768.

[23] Socías ME, Sued O, Laufer N, Lázaro ME, Mingrone H, Pryluka D, Remondegui C, Figueroa MI, Cesar C, Gun A, Turk G, Bouzas MB, Kavasery R, Krolewiecki A, Pérez H, Salomón H, Cahn P, Grupo Argentino de Seroconversión Study Group. Acute retroviral syndrome and high baseline viral load are predictors of rapid HIV progression among untreated Argentinean seroconverters [J]. J Int AIDS Soc, 2011, 14(1): 40.

[24] Le Clerc S, Limou S, Coulonges C, Carpentier W, Dina C, Taing L, Delaneau O, Labib T, Sladek R, ANRS Genomic Group, Deveau C, Guillemain H, Ratsimandresy R, Montes M, Spadoni JL, Therwath A, Sch?chter F, Matsuda F, Gut I, Lelièvre JD, Lévy Y, Froguel P, Delfraissy JF, Hercberg S, Zagury JF. Genomewide association study of a rapid progression cohort identifies new susceptibility alleles for AIDS (ANRS Genomewide Association Study 03) [J]. J Infect Dis, 2009, 200(8): 1194-1201.

[25] Lajoie J, Fontaine J, Tremblay C, Routy JP, Poudrier J, Roger M. Persistence of high levels of blood soluble human leukocyte antigen-G is associated with rapid progression of HIV infection [J]. AIDS, 2009, 23(11): 1437-1440.

[26] Streeck H, Schweighardt B, Jessen H, Allgaier RL, Wrin T, Stawiski EW, Jessen AB, Allen TM, Walker BD, Altfeld M. Loss of HIV-1-specific T-cell responses associated with very rapid HIV-1 disease progression [J]. AIDS, 2007, 21(7): 889-891.

[27] Blick G, Kagan RM, Coakley E, Petropoulos C, Maroldo L, Greiger-Zanlungo P, Gretz S, Garton T. The probable source of both the primary multidrug-resistant (MDR) HIV-1 strain found in a patient with rapid progression to AIDS and a second recombinant MDR strain found in a chronically HIV-1-infected patient [J]. J Infect Dis, 2007, 195(9): 1250-1259.

[28] Faure S, Meyer L, Costagliola D, Vaneensberghe C, Genin E, Autran B, Delfraissy JF, McDermott DH, Murphy PM, Debré P, Théodorou I, Combadière C. Rapid progression to AIDS in HIV+individuals with a structural variant of the chemokine receptor CX3CR1 [J]. Science, 2000, 287(5461): 2274-2277.

[29] Cornelissen M, Pasternak AO, Grijsen ML, Zorgdrager F, Bakker M, Blom P, Prins JM, Jurriaans S, van der Kuyl AC. HIV-1 dual infection is associated with faster CD4+T-cell decline in a cohort of men with primary HIV infection [J]. Clin Infect Dis, 2012, 54(4): 539-547.

[30] Zhang ZN, Xu JJ, Fu YJ, Liu J, Jiang YJ, Cui HL, Zhao B, Sun H, He YW, Li QJ, Shang H. Transcriptomic analysis of peripheral blood mononuclear cells in rapid progressors in early HIV infection identifies a signature closely correlated with disease progression [J]. Clin Chem, 2013, 59(8): 1175-1186.

[31] Wong JK, Hezareh M, Günthard HF, Havlir DV, Ignacio CC, Spina CA, Richman DD. Recovery of replication-competent HIV despite prolonged suppression of plasma viremia [J]. Science, 1997, 278(5341): 1291-1295.

[32] Persaud D, Gay H, Ziemniak C, Chen YH, Piatak M Jr, Chun TW, Strain M, Richman D, Luzuriaga K. Absence of detectable HIV-1 viremia after treatment cessation in an infant [J]. N Engl J Med, 2013, 369 (19): 1828-1835.

[33] Sáez-Cirión A, Bacchus C, Hocqueloux L, Avettand-Fenoel V, Girault I, Lecuroux C, Potard V, Versmisse P, Melard A, Prazuck T, Descours B, Guergnon J, Viard JP, Boufassa F, Lambotte O, Goujard C, Meyer L, Costagliola D, Venet A, Pancino G, Autran B, Rouzioux C, ANRS VISCONTI Study Group. Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study [J]. PLoS Pathog, 2013, 9(3): e1003211.

[34] Le T, Wright EJ, Smith DM, He W, Catano G, Okulicz JF, Young JA, Clark RA, Richman DD, Little SJ, Ahuja SK. Enhanced CD4+T-cell recovery with earlier HIV-1 antiretroviral therapy [J]. N Engl J Med, 2013, 368(3): 218-230.

[35] SPARTAC Trial Investigators, Fidler S, Porter K, Ewings F, Frater J, Ramjee G, Cooper D, Rees H, Fisher M, Schechter M, Kaleebu P, Tambussi G, Kinloch S, Miro JM, Kelleher A, McClure M, Kaye S, Gabriel M, Phillips R, Weber J, Babiker A. Short-course antiretroviral therapy in primary HIV infection [J]. N Engl J Med, 2013, 368(3): 207-217.

[36] Walker BD, Hirsch MS. Antiretroviral therapy in early HIV infection [J]. N Engl J Med, 2013, 368(3): 279-281.

[37] Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, Goicochea P, Casapía M, Guanira-Carranza JV, Ramirez-Cardich ME, Montoya-Herrera O, Fernández T, Veloso VG, Buchbinder SP, Chariyalertsak S, Schechter M, Bekker LG, Mayer KH, Kallás EG, Amico KR, Mulligan K, Bushman LR, Hance RJ, Ganoza C, Defechereux P, Postle B, Wang F, McConnell JJ, Zheng JH, Lee J, Rooney JF, Jaffe HS, Martinez AI, Burns DN, Glidden DV, iPrEx Study Team. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men [J]. N Engl J Med, 2010, 363(27): 2587-2599.

[38] Baeten JM, Donnell D, Ndase P, Mugo NR, Campbell JD, Wangisi J, Tappero JW, Bukusi EA, Cohen CR, Katabira E, Ronald A, Tumwesigye E, Were E, Fife KH, Kiarie J, Farquhar C, John-Stewart G, Kakia A, Odoyo J, Mucunguzi A, Nakku-Joloba E, Twesigye R, Ngure K, Apaka C, Tamooh H, Gabona F, Mujugira A, Panteleeff D, Thomas KK, Kidoguchi L, Krows M, Revall J, Morrison S, Haugen H, Emmanuel-Ogier M, Ondrejcek L, Coombs RW, Frenkel L, Hendrix C, Bumpus NN, Bangsberg D, Haberer JE, Stevens WS, Lingappa JR, Celum C, Partners PrEP Study Team. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women [J]. N Engl J Med, 2012, 367(5): 399-410.

[39] Gomez GB, Borquez A, Case KK, Wheelock A, Vassall A, Hankins C. The cost and impact of scaling up pre-exposure prophylaxis for HIV prevention: a systematic review of cost-effectiveness modelling studies [J]. PLoS Med, 2013, 10(3): e1001401.

[40] Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kaewkungwal J, Chiu J, Paris R, Premsri N, Namwat C, de Souza M, Adams E, Benenson M, Gurunathan S, Tartaglia J, McNeil JG, Francis DP, Stablein D, Birx DL, Chunsuttiwat S, Khamboonruang C, Thongcharoen P, Robb ML, Michael NL, Kunasol P, Kim JH, MOPH-TAVEG Investigators. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand [J]. N Engl J Med, 2009, 361(23): 2209-2220.

[41] Haynes BF, Gilbert PB, McElrath MJ, Zolla-Pazner S, Tomaras GD, Alam SM, Evans DT, Montefiori DC, Karnasuta C, Sutthent R, Liao HX, DeVico AL, Lewis GK, Williams C, Pinter A, Fong Y, Janes H, DeCamp A, Huang Y, Rao M, Billings E, Karasavvas N, Robb ML, Ngauy V, de Souza MS, Paris R, Ferrari G, Bailer RT, Soderberg KA, Andrews C, Berman PW, Frahm N, De Rosa SC, Alpert MD, Yates NL, Shen X, Koup RA, Pitisuttithum P, Kaewkungwal J, Nitayaphan S, Rerks-Ngarm S, Michael NL, Kim JH. Immune-correlates analysis of an HIV-1 vaccine efficacy trial [J]. N Engl J Med, 2012, 366(14): 1275-1286.

[42] Picker LJ, Deeks SG. HIV: Antibodies advance the search for a cure [J]. Nature, 2013, 503(7475): 207-208.

[43] Klein F, Mouquet H, Dosenovic P, Scheid JF, Scharf L, Nussenzweig MC. Antibodies in HIV-1 vaccine development and therapy [J]. Science, 2013, 341(6151): 1199-1204.

[44] Tomaras GD, Ferrari G, Shen X, Alam SM, Liao HX, Pollara J, Bonsignori M, Moody MA, Fong Y, Chen X, Poling B, Nicholson CO, Zhang R, Lu X, Parks R, Kaewkungwal J, Nitayaphan S, Pitisuttithum P, Rerks-Ngarm S, Gilbert PB, Kim JH, Michael NL, Montefiori DC, Haynes BF. Vaccine-induced plasma IgA specific for the C1 region of the HIV-1 envelope blocks binding and effector function of IgG [J].Proc Natl Acad Sci USA, 2013, 110(22): 9019-9024.

[45] McCoy LE, Weiss RA. Neutralizing antibodies to HIV-1 induced by immunization [J]. J Exp Med, 2013, 210(2): 209-223.

[46] McElrath MJ, Walker BD. Is an HIV vaccine possible [J]? J Acquir Immune Defic Syndr, 2012, 60(Suppl 2): S41-S43.

[47] Hansen SG, Sacha JB, Hughes CM, Ford JC, Burwitz BJ, Scholz I, Gilbride RM, Lewis MS, Gilliam AN, Ventura AB, Malouli D, Xu G, Richards R, Whizin N, Reed JS, Hammond KB, Fischer M, Turner JM, Legasse AW, Axthelm MK, Edlefsen PT, Nelson JA, Lifson JD, Früh K, Picker LJ. Cytomegalovirus vectors violate CD8+T cell epitope recognition paradigms [J]. Science, 2013, 340(6135): 1237874.

[48] Fauci AS, Marston HD. Achieving an AIDS-free world: science and implementation [J]. Lancet, 2013, 382(9903):1461-1462.