Bartosch Birke, Stefanidis Dimitrios, Myers Richard, Weiss Robin, Patience Clive, Takeuchi Yasuhiro
Wohl Virion Centre, Division of Infection of Immunity, University College London, 46 Cleveland St., London W1T 4JF, United Kingdom.
J Virol. 2004 Dec;78(24):13880-90. doi: 10.1128/JVI.78.24.13880-13890.2004.
The genetic nature and biological effects of recombination between porcine endogenous retroviruses (PERV) were studied. An infectious molecular clone was generated from a high-titer, human-tropic PERV isolate, PERV-A 14/220 (B. A. Oldmixon, et al. J. Virol. 76:3045-3048, 2002; T. A. Ericsson et al. Proc. Natl. Acad. Sci. USA 100:6759-6764, 2003). To analyze this sequence and 15 available full-length PERV nucleotide sequences, we developed a sequence comparison program, LOHA(TM) to calculate local sequence homology between two sequences. This analysis determined that PERV-A 14/220 arose by homologous recombination of a PERV-C genome replacing an 850-bp region around the pol-env junction with that of a PERV-A sequence. This 850-bp PERV-A sequence encompasses the env receptor binding domain, thereby conferring a wide host range including human cells. In addition, we determined that multiple regions derived from PERV-C are responsible for the increased infectious titer of PERV-A 14/220. Thus, a single recombination event may be a fast and effective way to generate high-titer, potentially harmful PERV. Further, local homology and phylogenetic analyses between 16 full-length sequences revealed evidence for other recombination events in the past that give rise to other PERV genomes that possess the PERV-A, but not the PERV-B, env gene. These results indicate that PERV-A env is more prone to recombination with heterogeneous backbone genomes than PERV-B env. Such recombination events that generate more active PERV-A appear to occur in pigs rather frequently, which increases the potential risk of zoonotic PERV transmission. In this context, pigs lacking non-human-tropic PERV-C would be more suitable as donor animals for clinical xenotransplantation.
对猪内源性逆转录病毒（PERV）之间重组的遗传本质和生物学效应进行了研究。从一株高滴度、嗜人PERV分离株PERV-A 14/220构建了一个感染性分子克隆（B.A. Oldmixon等人，《病毒学杂志》76:3045 - 3048，2002；T.A. Ericsson等人，《美国国家科学院院刊》100:6759 - 6764，2003）。为了分析该序列以及15个可用的全长PERV核苷酸序列，我们开发了一个序列比较程序LOHA(TM)，用于计算两个序列之间的局部序列同源性。该分析确定PERV-A 14/220是由PERV-C基因组的同源重组产生的，其在pol-env连接区周围用一个PERV-A序列替换了一个850 bp的区域。这个850 bp的PERV-A序列包含env受体结合结构域，从而赋予了包括人类细胞在内的广泛宿主范围。此外，我们确定源自PERV-C的多个区域导致了PERV-A 14/220感染滴度的增加。因此，单次重组事件可能是产生高滴度、潜在有害PERV的快速有效方式。此外，16个全长序列之间的局部同源性和系统发育分析揭示了过去其他重组事件的证据，这些事件产生了其他拥有PERV-A但不拥有PERV-B env基因的PERV基因组。这些结果表明，与PERV-B env相比，PERV-A env更容易与异源主干基因组发生重组。产生更活跃的PERV-A的此类重组事件似乎在猪中相当频繁地发生，这增加了人兽共患PERV传播 的潜在风险。在这种情况下，缺乏非嗜人PERV-C的猪作为临床异种移植的供体动物会更合适。
