THE ROLE OF INTRACELLULAR TRAFFIC IN HIV INFECTION

通过核膜的运输是细胞的必要组成部分

Transport across the nuclear membrane is a necessary component of the life cycle of the human immunodeficiency virus (HIV). Once in the cytoplasm, HIV RNA is reverse-transcribed into double-stranded DNA which then must enter the nucleus. A growing amount of evidence points to the viral matrix protein of HIV as a mediator of this transport event. Efforts are underway to determine how the matrix protein may be involved in nuclear transport of the DNA-RNA-protein complex. In addition, other retroviral regulatory proteins also enter the nucleus, and viral transcripts are exported out to the cytoplasm. The viral proteins, rev and tat, have been identified as a key regulators of the transcription and transport of HIV envelope mRNA out of the nucleus. These proteins contain sequences that are necessary and sufficient for targeting to the nucleolus. An in Vitro system using permeabilized cells has been developed to look at the nucleolar targeting of proteins bearing such targeting signals. This nucleolar localization is blocked by reducing the temperature to 4 degrees C or by omitting ATP. This suggests that transport to the nucleolus is an active process. Recently, it has been demonstrated that a reduction in cellular GTP levels induced by inhibitors of IMP-dehydrogenase reduce the nucleolar accumulation of other nucleolar proteins. However, these inhibitors, which include ribavirin and mycophenolic acid, did not affect nucleolar accumulation of the model protein in permeabilized cells. Moreover, an 100-fold reduction of GTP levels in the in vitro assay did not affect nucleolar accumulation of the model protein. Our studies suggest that the loss of a protein with a rapid turnover rate may be responsible for the observed effect of IMP dehydrogenase inhibitors on nucleolar targeting. In other studies, the structure of the nuclear pore has been examined. Nuclei have been reconstituted from Xenopus laevis egg extracts with exogenous DNA. The reconstituted nuclei mimic interphase nuclei in many ways and carry out active nuclear transport, and also contain structures resembling nucleoli. The nuclear pore requires glycoprotein components for proper morphology and function.