近日,，佛羅里達(dá)大學(xué)科研人員發(fā)現(xiàn)了艾滋?。℉IV）病毒在人體內(nèi)的進(jìn)化歷程，此項(xiàng)發(fā)現(xiàn)為確定早期HIV病毒形式,，研究新型治療措施,，開發(fā)新型治療藥物找到了新方向。該項(xiàng)科研成果發(fā)表在美國《公共科學(xué)圖書館·綜合》（PLoS ONE）期刊上,。
研究人員跟蹤觀察了4個(gè)出生時(shí)感染HIV的兒童,。他們一出生就被采了血液樣本，并對(duì)患者進(jìn)行終生跟蹤研究,。被研究的HIV病毒分為CCR5（R5）和CXCR4（X4）兩種,。研究人員發(fā)現(xiàn)，在早期感染階段,，R5病毒數(shù)量較多,，而X4病毒的出現(xiàn)則標(biāo)志著HIV感染已經(jīng)進(jìn)入了晚期。
佛羅里達(dá)醫(yī)學(xué)院病理免疫與試驗(yàn)醫(yī)學(xué)助理教授馬可·塞爾米說,，此前我們只知道,，HIV病毒一旦變異,，就會(huì)很快發(fā)展成艾滋病。但從開始感染到死亡整個(gè)過程中,，病毒是如何變異的,，變異發(fā)生在什么部位，還沒有人知道,。
通過觀察,，研究人員發(fā)現(xiàn)胸腺是病毒定居和復(fù)制的場所，胸腺位于胸骨后面,，也是T細(xì)胞分化與成熟的場所,，具有免疫調(diào)節(jié)功能，大部分的病毒變異發(fā)生在胸腺,，到了感染晚期,，病毒X4已經(jīng)控制了胸腺。
研究人員還發(fā)現(xiàn),，X4病毒并非一直存在于人體中,，而是在艾滋病發(fā)作之前由R5病毒直接進(jìn)化而來，X4病毒比R5病毒的致病性更強(qiáng),。但事實(shí)上,，病人致死是由于R5病毒所造成的，但X4病毒的某些進(jìn)化機(jī)理真正起到了促進(jìn)作用,。如果我們能了解這種機(jī)制或者干擾病毒發(fā)展到胸腺的能力,，就可以為相關(guān)治療藥物的研發(fā)找到一條新路。
牛津大學(xué)動(dòng)物系研究人員奧立佛·派巴斯表示,，這項(xiàng)研究準(zhǔn)確地揭示了感染過程中HIV病毒的進(jìn)化和生長變異以及身體免疫細(xì)胞在病毒進(jìn)化過程中的行為,，這可以作為臨床感染結(jié)果的測定手段。(科技日?qǐng)?bào))
原始出處:
Received: April 6, 2007; Accepted: September 6, 2007; Published: September 26, 2007
Phylodynamics of HIV-1 in Lymphoid and Non-Lymphoid Tissues Reveals a Central Role for the Thymus in Emergence of CXCR4-Using Quasispecies
Marco Salemi1*#, Brant R. Burkhardt1¤#, Rebecca R. Gray1,2, Guity Ghaffari1,3, John W. Sleasman4, Maureen M. Goodenow1,3*
1 Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, Florida, United States of America, 2 Department of Anthropology, University of Florida, Gainesville, Florida, United States of America, 3 Department of Pediatrics, Division of Immunology, Rheumatology, and Infectious Diseases, University of Florida, Gainesville, Florida, United States of America, 4 Department of Pediatrics, Division of Allergy, Immunology, and Rheumatology, University of South Florida and All Children's Hospital, St. Petersburg, Florida, United States of America
Abstract
Background
During HIV-1 infection coreceptor switch from CCR5- (R5)- to CXCR4 (X4)-using viruses is associated with disease progression. X4 strains of HIV-1 are highly cytopathic to immature thymocytes. Virtually no studies have evaluated the HIV-1 quasispecies present in vivo within thymic and lymphoid tissues or the evolutionary relationship between R5 and X4 viruses in tissues and peripheral blood.
Methodology/Principal Findings
High-resolution phylodynamic analysis was applied to virus envelope quasispecies in longitudinal peripheral blood mononuclear cells (PBMCs) and lymphoid and non-lymphoid tissues collected post mortem from therapy naïve children with AIDS. There were three major findings. First, continued evolution of R5 viruses in PBMCs, spleen and lymph nodes involved multiple bottlenecks, independent of coreceptor switch, resulting in fitter quasispecies driven by positive selection. Second, evolution of X4 strains appeared to be a sequential process requiring the initial fixation of positively selected mutations in V1-V2 and C2 domains of R5 variants before the emergence of high charge V3 X4 variants. Third, R5 viruses persisted after the emergence of CXCR4-using strains, which were found predominantly but not exclusively in the thymus.
Conclusions/Significance
Our data indicate that the evolution of X4 strains is a multi-step, temporally structured process and that the thymus may play an important role in the evolution/amplification of coreceptor variants. Development of new therapeutic protocols targeting virus in the thymus could be important to control HIV-1 infection prior to advanced disease.
全文鏈接：http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0000950
