Multiple Effects of an Anti-human Immunodeficiency Virus Nucleocapsid Inhibitor on Virus Morphology and Replication

Overview

Journal J Virol

Publisher American Society for Microbiology

Date 1999 Nov 13

PMID 10559314

Citations 12

Authors

L Berthoux

C Pechoux

J L Darlix

Affiliations

Soon will be listed here.

Abstract

Human immunodeficiency virus type 1 nucleocapsid protein is a major structural component of the virion core and a key factor involved in proviral DNA synthesis and virus formation. 2,2'-Dithiobenzamides (DIBA-1) and related compounds that are inhibitors of NCp7 are thought to eject zinc ions from NCp7 zinc fingers, inhibiting the maturation of virion proteins. Here, we show that the presence of DIBA-1 at the time of virus formation causes morphological malformations of the virus and reduces proviral DNA synthesis. Thus, it seems that DIBA-1 is responsible for a "core-freezing effect," as shown by electron microscopy analyses. DIBA-1 can also directly interfere with the fate of the newly made proviral DNA in a manner independent of its effects on virion core formation. These data strongly suggest that nucleocapsid protein is a prime target for new compounds aimed at inhibiting human immunodeficiency virus and other retroviruses.

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References

Vandevelde M, Witvrouw M, Schmit J, Sprecher S, De Clercq E, Tassignon J . ADA, a potential anti-HIV drug. AIDS Res Hum Retroviruses. 1996; 12(7):567-8. DOI: 10.1089/aid.1996.12.567. View

Larder B . Viral resistance and the selection of antiretroviral combinations. J Acquir Immune Defic Syndr Hum Retrovirol. 1995; 10 Suppl 1:S28-33. View

Poon D, Wu J, Aldovini A . Charged amino acid residues of human immunodeficiency virus type 1 nucleocapsid p7 protein involved in RNA packaging and infectivity. J Virol. 1996; 70(10):6607-16. PMC: 190701. DOI: 10.1128/JVI.70.10.6607-6616.1996. View

Rice W, Baker D, Schaeffer C, Graham L, Bu M, Terpening S . Inhibition of multiple phases of human immunodeficiency virus type 1 replication by a dithiane compound that attacks the conserved zinc fingers of retroviral nucleocapsid proteins. Antimicrob Agents Chemother. 1997; 41(2):419-26. PMC: 163723. DOI: 10.1128/AAC.41.2.419. View

Rice W, Turpin J, Huang M, Clanton D, Buckheit Jr R, Covell D . Azodicarbonamide inhibits HIV-1 replication by targeting the nucleocapsid protein. Nat Med. 1997; 3(3):341-5. DOI: 10.1038/nm0397-341. View

Gervaix A, West D, Leoni L, Richman D, Wong-Staal F, Corbeil J . A new reporter cell line to monitor HIV infection and drug susceptibility in vitro. Proc Natl Acad Sci U S A. 1997; 94(9):4653-8. PMC: 20779. DOI: 10.1073/pnas.94.9.4653. View

Lamarre D, Croteau G, Wardrop E, Bourgon L, Thibeault D, Clouette C . Antiviral properties of palinavir, a potent inhibitor of the human immunodeficiency virus type 1 protease. Antimicrob Agents Chemother. 1997; 41(5):965-71. PMC: 163834. DOI: 10.1128/AAC.41.5.965. View

Zhang Y, Imamichi H, Imamichi T, Lane H, Falloon J, Vasudevachari M . Drug resistance during indinavir therapy is caused by mutations in the protease gene and in its Gag substrate cleavage sites. J Virol. 1997; 71(9):6662-70. PMC: 191944. DOI: 10.1128/JVI.71.9.6662-6670.1997. View

Zhang Y, Barklis E . Effects of nucleocapsid mutations on human immunodeficiency virus assembly and RNA encapsidation. J Virol. 1997; 71(9):6765-76. PMC: 191957. DOI: 10.1128/JVI.71.9.6765-6776.1997. View

10.

Berthoux L, Pechoux C, Ottmann M, Morel G, Darlix J . Mutations in the N-terminal domain of human immunodeficiency virus type 1 nucleocapsid protein affect virion core structure and proviral DNA synthesis. J Virol. 1997; 71(9):6973-81. PMC: 191982. DOI: 10.1128/JVI.71.9.6973-6981.1997. View

11.

Gallay P, Hope T, Chin D, Trono D . HIV-1 infection of nondividing cells through the recognition of integrase by the importin/karyopherin pathway. Proc Natl Acad Sci U S A. 1997; 94(18):9825-30. PMC: 23276. DOI: 10.1073/pnas.94.18.9825. View

12.

De Guzman R, Wu Z, Stalling C, Pappalardo L, Borer P, Summers M . Structure of the HIV-1 nucleocapsid protein bound to the SL3 psi-RNA recognition element. Science. 1998; 279(5349):384-8. DOI: 10.1126/science.279.5349.384. View

13.

Gunthard H, Wong J, Ignacio C, Guatelli J, Riggs N, Havlir D . Human immunodeficiency virus replication and genotypic resistance in blood and lymph nodes after a year of potent antiretroviral therapy. J Virol. 1998; 72(3):2422-8. PMC: 109542. DOI: 10.1128/JVI.72.3.2422-2428.1998. View

14.

Tanchou V, Decimo D, Pechoux C, Lener D, Rogemond V, Berthoux L . Role of the N-terminal zinc finger of human immunodeficiency virus type 1 nucleocapsid protein in virus structure and replication. J Virol. 1998; 72(5):4442-7. PMC: 109678. DOI: 10.1128/JVI.72.5.4442-4447.1998. View

15.

Huang M, Maynard A, Turpin J, Graham L, Janini G, Covell D . Anti-HIV agents that selectively target retroviral nucleocapsid protein zinc fingers without affecting cellular zinc finger proteins. J Med Chem. 1998; 41(9):1371-81. DOI: 10.1021/jm9708543. View

16.

Finzi D, Siliciano R . Viral dynamics in HIV-1 infection. Cell. 1998; 93(5):665-71. DOI: 10.1016/s0092-8674(00)81427-0. View

17.

Rein A, Henderson L, LEVIN J . Nucleic-acid-chaperone activity of retroviral nucleocapsid proteins: significance for viral replication. Trends Biochem Sci. 1998; 23(8):297-301. DOI: 10.1016/s0968-0004(98)01256-0. View

18.

Freed E . HIV-1 gag proteins: diverse functions in the virus life cycle. Virology. 1998; 251(1):1-15. DOI: 10.1006/viro.1998.9398. View

19.

Lener D, Tanchou V, Roques B, Le Grice S, Darlix J . Involvement of HIV-I nucleocapsid protein in the recruitment of reverse transcriptase into nucleoprotein complexes formed in vitro. J Biol Chem. 1998; 273(50):33781-6. DOI: 10.1074/jbc.273.50.33781. View

20.

Turpin J, Song Y, INMAN J, Huang M, Wallqvist A, Maynard A . Synthesis and biological properties of novel pyridinioalkanoyl thiolesters (PATE) as anti-HIV-1 agents that target the viral nucleocapsid protein zinc fingers. J Med Chem. 1999; 42(1):67-86. DOI: 10.1021/jm9802517. View