Heinzinger N K, Bukrinsky M I, Haggerty S A, Ragland A M, Kewalramani V, Lee M A, Gendelman H E, Ratner L, Stevenson M, Emerman M
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha 68198-5120.
Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):7311-5. doi: 10.1073/pnas.91.15.7311.
The replication of human immunodeficiency virus type 1 (HIV-1) in nondividing host cells such as those of macrophage lineage is an important feature of AIDS pathogenesis. The pattern of HIV-1 replication is dictated, in part, by the nucleophilic property of the viral gag matrix (MA) protein, a component of the viral preintegration complex that facilitates nuclear localization of viral nucleic acids in the absence of mitosis. We now identify the accessory viral protein Vpr, as a second nucleophilic component that influences nuclear localization of viral nucleic acids in nondividing cells. Reverse transcription and nuclear localization of viral nucleic acids following infection of cells by viruses lacking Vpr or viruses containing mutations in a gag MA nuclear localization sequence were indistinguishable from the pattern observed in cells infected by wild-type HIV-1. These viruses retained the ability to replicate in both dividing and nondividing host cells including monocyte-derived macrophages. In contrast, introduction of both gag MA and Vpr mutations in HIV-1 attenuated nuclear localization of viral nucleic acids in nondividing cells and virus replication in monocyte-derived macrophages. These studies demonstrate redundant nucleophilic determinants of HIV-1 that independently permit nuclear localization of viral nucleic acids and virus replication in nondividing cells such as monocyte-derived macrophages. In addition, these studies provide a defined function for an accessory gene product of HIV-1.
1型人类免疫缺陷病毒（HIV-1）在诸如巨噬细胞系的非分裂宿主细胞中的复制是艾滋病发病机制的一个重要特征。HIV-1的复制模式部分由病毒gag基质（MA）蛋白的亲核特性决定，该蛋白是病毒整合前复合物的一个组成部分，在无有丝分裂的情况下促进病毒核酸的核定位。我们现在确定辅助病毒蛋白Vpr是影响非分裂细胞中病毒核酸核定位的第二个亲核成分。缺乏Vpr的病毒或gag MA核定位序列中含有突变的病毒感染细胞后，病毒核酸的逆转录和核定位与野生型HIV-1感染细胞中观察到的模式没有区别。这些病毒保留了在包括单核细胞衍生巨噬细胞在内的分裂和非分裂宿主细胞中复制的能力。相比之下，HIV-1中同时引入gag MA和Vpr突变会减弱非分裂细胞中病毒核酸的核定位以及单核细胞衍生巨噬细胞中的病毒复制。这些研究证明了HIV-1的冗余亲核决定因素，它们独立地允许病毒核酸在诸如单核细胞衍生巨噬细胞等非分裂细胞中的核定位和病毒复制。此外，这些研究为HIV-1的一个辅助基因产物提供了明确的功能。
