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Integration

In order for integration to occur in non replicating cells, the HIV preintegration complex must be transported into the nucleus. A nuclear localization signal (NLS) on the HIV matrix protein (p17) as well as other interactions have been reported to facilitate transport of the HIV preintegration complex into the nucleus (1). A more recent paper, however, indicates that the proposed NLS on p17 is not involved in nuclear transport but in gag processing (2). Viral protein R (VPR), an accessory protein that appears to be incorporated in the virion, has also been reported to facilitate targeting of HIV preintegration complex to the nucleus (3). Inhibitors of HIV preintegration complex nuclear transport have been reported to have potential as anti-HIV agents (4).


After entry into the nucleus, the double stranded HIV DNA of the preintegration complex undergoes specific cleavages at the 5' and 3' termini and is integrated into the host DNA through the action of the HIV viral integrase. High throughput assays for integration have led to many compounds which are potent inhibitors of the enzymatic integrase reaction. Many of these compounds, however, have shown either little anti-viral activity or activity that could also be attributed to other targets. HIV integrase, however, remains an important target in HIV drug development (4-6).



Protein Synthesis

Newly synthesized viral RNA is transported out of the nucleus and translated, in the case of mRNA, or incorporated into new virions, in the case of genomic RNA. The gag and pol genes are encoded out of a frame on a single mRNA. Frameshifting during the translation of the viral gag-pol messenger RNA, therefore, is essential for the production of pol gene products (protease, reverse transcriptase, and integrase) (1). RNA secondary structure located downstream (3') from the gag/pol frameshift has been shown to be important for wild-type levels of frameshifting to occur (2). Compounds that either inhibit or alter viral mRNA frameshifting are potentially effective antiviral agents.



References

  1. JACKS, T.; POWER, M.D.; MASIARZ, F.R.; LUCIW, P.A.; BARR, P.J.; VARMUS, H.E., CHARACTERIZATION OF RIBOSOMAL FRAMESHIFTING IN HIV-1 GAG-POL EXPRESSION. NATURE (LONDON) 331:280-283 (1988).
  2. PARKIN, N.T.; CHAMORRO, M., VARMUS, H.E., HUMAN IMMUNODEFICIENCY VIRUS TYPE 1 GAG-POL FRAMESHIFTING IS DEPENDENT ON DOWNSTREAM MRNA SECONDARY STRUCTURE: DEMONSTRATION BY EXPRESSION IN VIVO. J VIROL 66(8):5147-5151 (1992).



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