Owens Christopher M, Song Byeongwoon, Perron Michel J, Yang Peter C, Stremlau Matthew, Sodroski Joseph
Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
J Virol. 2004 May;78(10):5423-37. doi: 10.1128/jvi.78.10.5423-5437.2004.
In cells of Old World and some New World monkeys, dominant factors restrict human immunodeficiency virus type 1 (HIV-1) infections after virus entry. The simian immunodeficiency virus SIV(mac) is less susceptible to these restrictions, a property that is determined largely by the viral capsid protein. For this study, we altered exposed amino acid residues on the surface of the HIV-1 capsid, changing them to the corresponding residues found on the SIV(mac) capsid. We identified two distinct pathways of escape from early, postentry restriction in monkey cells. One set of mutants that were altered near the base of the cyclophilin A-binding loop of the N-terminal capsid domain or in the interdomain linker exhibited a decreased ability to bind the restricting factor(s). Consistent with the location of this putative factor-binding site, cyclophilin A and the restricting factor(s) cooperated to achieve the postentry block. A second set of mutants that were altered in the ridge formed by helices 3 and 6 of the N-terminal capsid domain efficiently bound the restricting factor(s) but were resistant to the consequences of factor binding. These results imply that binding of the simian restricting factor(s) is not sufficient to mediate the postentry block to HIV-1 and that SIV(mac) capsids escape the block by decreases in both factor binding and susceptibility to the effects of the factor(s).
在旧世界猴和一些新世界猴的细胞中,显性因子在病毒进入后限制1型人类免疫缺陷病毒(HIV-1)感染。猿猴免疫缺陷病毒SIV(mac)对这些限制的敏感性较低,这一特性在很大程度上由病毒衣壳蛋白决定。在本研究中,我们改变了HIV-1衣壳表面暴露的氨基酸残基,将它们替换为SIV(mac)衣壳上相应的残基。我们确定了两条从猴细胞早期进入后限制中逃逸的不同途径。一组在N端衣壳结构域亲环素A结合环基部附近或结构域间连接区发生改变的突变体,与限制因子结合的能力降低。与这个假定的因子结合位点的位置一致,亲环素A和限制因子协同作用以实现进入后阻断。第二组在N端衣壳结构域由螺旋3和6形成的脊中发生改变的突变体,能有效地结合限制因子,但对因子结合的后果具有抗性。这些结果表明,猿猴限制因子的结合不足以介导对HIV-1的进入后阻断,并且SIV(mac)衣壳通过降低因子结合和对因子作用的敏感性来逃避阻断。