de Rozìeres Sohela, Thompson Jesse, Sundstrom Magnus, Gruber Julia, Stump Debora S, de Parseval Aymeric P, VandeWoude Sue, Elder John H
Department of Molecular Biology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
J Virol. 2008 Aug;82(16):7953-63. doi: 10.1128/JVI.00337-08. Epub 2008 Jun 11.
Feline immunodeficiency virus (FIV) causes progressive immunodeficiency in domestic cats, with clinical course dependent on virus strain. For example, clade A FIV-PPR is predominantly neurotropic and causes a mild disease in the periphery, whereas clade C FIV-C36 causes fulminant disease with CD4(+) T-cell depletion and neutropenia but no significant pathology in the central nervous system. In order to map pathogenic determinants, chimeric viruses were prepared between FIV-C36 and FIV-PPR, with reciprocal exchanges involving (i) the 3' halves of the viruses, including the Vif, OrfA, and Env genes; (ii) the 5' end extending from the 5' long terminal repeat (LTR) to the beginning of the capsid (CA)-coding region; and (iii) the 3' LTR and Rev2-coding regions. Ex vivo replication rates and in vivo replication and pathologies were then assessed and compared to those of the parental viruses. The results show that FIV-C36 replicates ex vivo and in vivo to levels approximately 20-fold greater than those of FIV-PPR. None of the chimeric FIVs recapitulated the replication rate of FIV-C36, although most replicated to levels similar to those of FIV-PPR. The rates of chloramphenicol acetyltransferase gene transcription driven by the FIV-C36 and FIV-PPR LTRs were identical. Furthermore, the ratios of surface glycoprotein (SU) to capsid protein (CA) in the released particles were essentially the same in the wild-type and chimeric FIVs. Tests were performed in vivo on the wild-type FIVs and chimeras carrying the 3' half of FIV-C36 or the 3' LTR and Rev2 regions of FIV-C36 on the PPR background. Both chimeras were infectious in vivo, although replication levels were lower than for the parental viruses. The chimera carrying the 3' half of FIV-C36 demonstrated an intermediate disease course with a delayed peak viral load but ultimately resulted in significant reductions in neutrophil and CD4(+) T cells, suggesting potential adaptation in vivo. Taken together, the findings suggest that the rapid-growth phenotype and pathogenicity of FIV-C36 are the result of evolutionary fine tuning throughout the viral genome, rather than being properties of any one constituent.
猫免疫缺陷病毒（FIV）可导致家猫出现进行性免疫缺陷，其临床病程取决于病毒株。例如，A亚型FIV-PPR主要嗜神经，在外周引起轻度疾病，而C亚型FIV-C36则导致暴发性疾病，伴有CD4(+) T细胞耗竭和中性粒细胞减少，但中枢神经系统无明显病变。为了确定致病决定因素，制备了FIV-C36和FIV-PPR之间的嵌合病毒，进行了相互交换，包括：（i）病毒的3' 半段，包括Vif、OrfA和Env基因；（ii）从5' 长末端重复序列（LTR）延伸至衣壳（CA）编码区起始处的5' 端；以及（iii）3' LTR和Rev2编码区。然后评估并比较了体外复制率、体内复制情况和病理学表现与亲代病毒的差异。结果表明，FIV-C36在体外和体内的复制水平比FIV-PPR高约20倍。尽管大多数嵌合FIV的复制水平与FIV-PPR相似，但没有一个嵌合FIV能重现FIV-C36的复制率。由FIV-C36和FIV-PPR LTR驱动的氯霉素乙酰转移酶基因转录率相同。此外，野生型和嵌合FIV释放颗粒中表面糖蛋白（SU）与衣壳蛋白（CA）的比例基本相同。对携带FIV-C36的3' 半段或PPR背景下FIV-C36的3' LTR和Rev2区域的野生型FIV和嵌合体进行了体内试验。两种嵌合体在体内均具有传染性，尽管复制水平低于亲代病毒。携带FIV-C36的3' 半段的嵌合体表现出中间病程，病毒载量峰值延迟，但最终导致中性粒细胞和CD4(+) T细胞显著减少，提示在体内可能发生了适应性变化。综上所述，这些发现表明，FIV-C36的快速生长表型和致病性是整个病毒基因组进化精细调节的结果，而不是任何一个组成部分的特性。
