HIV regulatory and accessory genes

In addition to the usual three retroviral structural genes, the HIV-1 genome includes six further genes encoding regulatory and accessory proteins translated from various mutiply-spliced HIV RNAs. The three genes regulating virus replication are tat, rev and ncf. Two of these genes, tat and rev, are nuclear proteins which are absolutely essential for virus replication. Proviruses defective in these genes fail to replicate. The two exons of the tat gene code for a 14 kDa diffusable effector protein which binds directly to specific responsive sequences (the trans-activating responsive region, TAR) within the LTR. In so doing, the synthesis of both structural and regu latory viral proteins is either directly or indirectly increased at the level of transcription initiation, elongation or both.

Viral structural protein synthesis is additionally controlled by the action of the rev gene, the 19 kDa phosphorylated product of which is located within the nucleolus and binds to Rev response elements (RRE) located within the env gene. The functional expression of the Rev nuclear protein acts to facilitate the transport from the nucleus to the cytoplasm of multiply-spliced transcripts encoding regulatory proteins (Tat, Rev, Nef, Vpr) early in infection, or unspliced or partially spliced mRNA from which the Gag and Env proteins are translated.

The nef gene encodes a 27 kDa myristylated protein which is highly conserved in all immunodeficiency virus genomes (HIV-1, HIV-2 and the SIVs), yet is not essential for replication of the virus in vitro. Its importance would appear to be connected to its role in pathogenesis in vivo, since macaques infected with nef-deleted mutants fail to develop simian AIDS.

The remaining accessory genes, vif, vpr, vpu and vpx, which arc dispensible for in vitro replication of the virus are, nevertheless, highly conserved in HIV and SIV strains, suggesting that, like nef, these genes have an important role in vivo, either in contributing to the efficiency of virus replication or to the pathogenic effect of the virus in the infected host. The vif and vpu genes contribute to virus replication by increasing the efficiency of infection of cell-free virus (vif) and in facilitating the assembly, binding and release of mature virus particles (vpu). In the absence of Vif, the 23 kDa cytoplasmic gene product which associates strongly with the cell membrane, virions have an abnormal morphology and a reduccd capacity to synthesize proviral DNA when they infect new cells. Only the HIV-1 genome and that of the closely related chimpanzee immunodeficiency virus, SIVcp,, contain the vpu gene,the 16 kDa phosphoryl-ated gene product of which is located outside the nucleus, close to the endoplasmic reticulum (ER) and Golgi apparatus. It appears to direct the transport of envelope proteins to the cell surface by mediating degradation of CD4 molecules in the ER. Mutant virus deficient in vpu replicates in vitro at reduced titer due to the accumulation of virus particles in intracytoplasmic vesicles.

The vpr gene induces subtle increases in the kinetics of virus infection. It appears to enhance virus production in primary macrophages and, to a lesser extent, in some T lymphocyte cell lines. The vpx gene is present in HIV-2 and the SIVs, but not in HIV-1 and, like vpr is packaged within the virion. Its function is ill-defined.

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