NIAID HIV/OI Searchable Chemical Database

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).

Viral Latency

Although HIV replicates extensively throughout all stages of infection (1-2), latently infected cells do exist (3) and if viral eradication is to be achieved it is essential to develop agents to target these cells. The advent of potent anti-viral therapy has demonstrated that the vast majority of HIV viral production is due to newly infected cells and not the activation of latently infected cells (1-2). Although there may still be important therapeutic roles for compounds capable of inducing viral latency (4), potent anti-HIV therapies have raised the prospect of viral eradication, a goal inconsistent with the induction of viral latency. Since HIV expression in nearly all primary cells appears to be cytopathic, compounds capable of inducing viral activation or preventing latency combined with potent anti-HIV therapies may represent a strategy capable of eradicating HIV.

References

1. WEI, X; GHOSH, S.K.; TAYLOR, M.E.; JOHNSON, V.A.; EMINI ,E.A.; DEUTSCH, P.; LIFSON, J.D.; BONHOEFFER, J.D. NOWAK, M.A.; HAHN, B.H.; ET AL. VIRAL DYNAMICS IN HUMAN IMMUNODEFICIENCY VIRUS TYPE I INFECTION. NATURE 373:117-122 (1995).
2. HO, D.D.; NEUMANN A.U.; PERELSON A.S.; CHEN, W.; LEONARD J.M.; MARKOWITZ M., RAPID TURNOVER OF PLASMA VIRIONS AND CD4 LYMPHOCYTES IN HIV-1 INFECTION. NATURE 373:123-126 (1995).
3. LI X.D.; MOORE B.; CLOYD M.W., GRADUAL SHUTDOWN OF VIRUS PRODUCTION RESULTING IN LATENCY IS THE NORM DURING THE CHRONIC PHASE OF HUMAN IMMUNODEFICIENCY VIRUS REPLICATION AND DIFFERENTIAL RATES AND MECHANISMS OF SHUTDOWN ARE DETERMINED BY VIRAL SEQUENCES. VIROLOGY 225(1):196-212 (1996).
4. BUTERA S.T.; FOLKS T.M., APPLICATION OF LATENT HIV-1 INFECTED CELLULAR MODELS TO THERAPEUTIC INTERVENTION. AIDS RES HUMRETROVIRUSES 8:991-999 (1992).