美國科學家近日通過研究,，揭示了HIV病毒在人的一生中發(fā)展成致命艾滋病（AIDS）病毒的過程,。這一發(fā)現(xiàn)將有助于開發(fā)針對早期HIV病毒的藥靶,。相關論文9月份發(fā)表在《公共科學圖書館.綜合》（PLoS ONE）上。
此次研究由美國佛羅里達大學醫(yī)學院的Marco Salemi領導完成,。他表示,，之前人們所知道的僅僅是HIV會發(fā)生變異，而一旦變異發(fā)生,，人體就開始發(fā)展AIDS,。但人們對其中的機制卻所知甚少。
在最新的研究中,，研究人員提取了四個天生帶有HIV病毒兒童的血液和組織樣本,，這些樣本的提取時間分別在剛出生時、貫穿生命期間以及剛死亡后不久,。應用一種高分辨計算技術,，研究人員監(jiān)控了一種幫助HIV感染人類細胞的蛋白的變異情況，并將病毒分成了兩個族群,，R5和X4,。R5通常在感染的早期階段大量出現(xiàn)，而X4則在AIDS即將真正形成之前開始出現(xiàn),。此次實驗的目的即是要找出X4最初出現(xiàn)的時間和地點,。
結果發(fā)現(xiàn)，X4病毒主要分布在胸腺里,。這表明這些病毒是在胸腺里進行進化,，或者至少是在這里進行停留和復制。研究人員同時揭示出,，X4病毒并不是一直存在于身體里,，而是在AIDS開始發(fā)作前由R5直接進化而來。此外，研究人員還發(fā)現(xiàn),，雖然各個兒童的病史存在差異,，但是HIV在每個兒童體內的進化路徑卻很相似。
Goodenow認為,，這表明HIV病毒的進化路徑可能并不是完全隨機的,，它可能遵循一種設計好的發(fā)展程序。
英國牛津大學動物學系的Oliver Pybus表示,，這是一項卓越的研究,，它表明了感染過程中HIV精密的進化和改編模式，并且第一次揭示了機體免疫細胞的運作與病毒進化之間的聯(lián)系,。
Goodenow表示,，下一步的研究將是追蹤成人體內HIV病毒在治療前后的變化情況。他同時希望此次發(fā)現(xiàn)能夠有助于開發(fā)出一種新的藥物,，以干擾HIV在胸腺里的進化,。（科學網(wǎng) 梅進/編譯）
原始出處:
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.
Received: April 6, 2007; Accepted: September 6, 2007; Published: September 26, 2007
