Geographic, Genetic and functional diversity of antiretroviral host factor TRIMCyp in cynomolgus macaque (Macaca fascicularis).

Saito A, Kono K, Nomaguchi M, Yasutomi Y, Adachi A, Shioda T, Akari H, Nakayama EE.

近年の研究で、既知の獲得免疫や自然免疫とは異なる第三の宿主内因性抗ウイルス因子TRIM5の存在が明らかにされてきた。カニクイザルには野生型アリルTRIM5αのみでなく、TRIM5αの3’末端側に外来遺伝子サイクロフィリンAの一部がレトロトランスポゾンにより挿入された変異型アリルTRIMCypが存在することが報告されている。本研究において、我々はカニクイザルにおけるTRIM5αおよびTRIMCypのアリル頻度がその産地により大きく異なること、またそのコード領域に多様なSNPが存在することを見出した。さらに、このようなTRIM5の遺伝的多様性は、霊長類免疫不全ウイルスに対する抗ウイルス作用に大きく影響を及ぼすことが明らかとなった。本研究結果は、カニクイザルに対する何らかの環境要因がTRIM5遺伝子の選択的多様性を生じさせた可能性を示すものである。

Journal of General Virology, Nov 23, 2011

The antiretroviral factor TRIM5 gene-derived isoform, TRIMCyp, was found in at least three species of Old World monkey, rhesus (Macaca mulatta), pig-tailed (Macaca nemestrina), and cynomolgus macaques (Macaca fascicularis). Although the frequency of TRIMCyp has been well studied in rhesus and pig-tailed macaques, the frequency and prevalence of TRIMCyp in the cynomolgus macaque remain to be definitively elucidated. Here, we studied the geographic and genetic diversity of TRIM5α/TRIMCyp in cynomolgus macaques in comparison with their anti-lentiviral activity. We found that the frequency of TRIMCyp in the population in the Philippines was significantly higher than those in Indonesian and Malaysian populations. We also found major and minor haplotypes of cynomolgus macaque TRIMCyp with single nucleotide polymorphisms in the cyclophilin A domain. We then examined the functional significance of the polymorphism in TRIMCyp and demonstrated that the major haplotype of the TRIMCyp suppressed HIV-1 but not HIV-2, while the minor haplotype of TRIMCyp suppressed HIV-2 but not HIV-1. The major haplotype of TRIMCyp did not restrict a monkey-tropic HIV-1 clone NL-DT5R, which contains a capsid with the simian immunodeficiency virus-derived loop between α-helices 4 and 5 and the entire vif gene. These results indicate that the polymorphisms of TRIMCyp affect its anti-lentiviral activity. In total, our results in this study will help understanding the genetic background of cynomolgus macaque TRIMCyp and also the host factors composing species barrier of primate lentiviruses.

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