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HIV Life Cycle

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).

References

  1. BUKRINSKY, M.I.; HAGGERTY, S.; DEMPSEY, M.P.; SHAROVA, N.; ADZHUBEL, A.; SPITZ, L.; LEWIS, P.; GOLDFARB, D.; EMERMAN, M.; STEVENSON, M., A nuclear localization signal within HIV-1 matrix protein that governs infection of non-dividing cells. NATURE 365:666-669 (1993).
  2. FOUCHIER R.A.; MEYER B.E.; SIMON J.H.; FISCHER U.; MALIM M.H., HIV-1 Infection of non-dividing cells: evidence that the amino-terminal basic region of the viral matrix protein is important for gag processing but not for post-entry nuclear import. EMBO J 16(15):4531-4539 (1997).
  3. BUKRINSKY M.I.; HAFFAR O.K., HIV-1 Nuclear import: In search of a leader. FRONT BIOSCI 1;2:D578-D587 (1997).
  4. BUSHMAN, F.D., CRAIGIE, R. Activities of human immunodeficiency virus (HIV) integration protein in vitro: specific cleavage and integration of hiv dna. PROC NATL ACAD SCI USA 88:1339-1343 (1991).
  5. FARNET CM; BUSHMAN FD, HIV CDNA integration: molecular biology and inhibitor development. AIDS. 10 SUPPL A:S3-11(1996).
  6. HONG H.; NEAMATI N.; WANG S.; NICKLAUS MC.; MAZUMDER A.; ZHAO H.; BURKE TR JR.; POMMIER Y.; MILNE G.W., Discovery of hiv-1 integrase inhibitors by pharmacophore searching J MED CHEM 40(6):930-936 (1997).




  
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