Role of Gag in HIV Resistance to Protease Inhibitors

Overview

Journal Viruses

Publisher MDPI

Specialty Microbiology

Date 2011 Oct 14

PMID 21994687

Citations 29

Authors

Francois Clavel

Fabrizio Mammano

Affiliations

Soon will be listed here.

Abstract

Cleavage of Gag and Gag-Pol precursors by the viral protease is an essential step in the replication cycle of HIV. Protease inhibitors, which compete with natural cleavage sites, strongly impair viral infectivity and have proven to be highly valuable in the treatment of HIV-infected subjects. However, as with all other antiretroviral drugs, the clinical benefit of protease inhibitors can be compromised by resistance. One key feature of HIV resistance to protease inhibitors is that the mutations that promote resistance are not only located in the protease itself, but also in some of its natural substrates. The best documented resistance-associated substrate mutations are located in, or near, the cleavage sites in the NC/SP2/p6 region of Gag. These mutations improve interactions between the substrate and the mutated enzyme and correspondingly increase cleavage. Initially described as compensatory mutations able to partially correct the loss of viral fitness that results from protease mutations, changes in Gag are now recognized as being directly involved in resistance. Besides NC/SP2/p6 mutations, polymorphisms in other regions of Gag have been found to exert various effects on viral fitness and or resistance, but their importance deserves further evaluation.

Citing Articles

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HIV-1 envelope facilitates the development of protease inhibitor resistance through acquiring mutations associated with viral entry and immune escape.

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References

Verheyen J, Litau E, Sing T, Daumer M, Balduin M, Oette M . Compensatory mutations at the HIV cleavage sites p7/p1 and p1/p6-gag in therapy-naive and therapy-experienced patients. Antivir Ther. 2007; 11(7):879-87. View

Coren L, Thomas J, Chertova E, Sowder 2nd R, Gagliardi T, Gorelick R . Mutational analysis of the C-terminal gag cleavage sites in human immunodeficiency virus type 1. J Virol. 2007; 81(18):10047-54. PMC: 2045408. DOI: 10.1128/JVI.02496-06. View

Moore M, Bryan W, Fakhoury S, Magaard V, Huffman W, Dayton B . Peptide substrates and inhibitors of the HIV-1 protease. Biochem Biophys Res Commun. 1989; 159(2):420-5. DOI: 10.1016/0006-291x(89)90008-9. View

Gallego O, de Mendoza C, Corral A, Soriano V . Changes in the human immunodeficiency virus p7-p1-p6 gag gene in drug-naive and pretreated patients. J Clin Microbiol. 2003; 41(3):1245-7. PMC: 150303. DOI: 10.1128/JCM.41.3.1245-1247.2003. View

Dam E, Quercia R, Glass B, Descamps D, Launay O, Duval X . Gag mutations strongly contribute to HIV-1 resistance to protease inhibitors in highly drug-experienced patients besides compensating for fitness loss. PLoS Pathog. 2009; 5(3):e1000345. PMC: 2652074. DOI: 10.1371/journal.ppat.1000345. View

Bleiber G, Munoz M, Ciuffi A, Meylan P, Telenti A . Individual contributions of mutant protease and reverse transcriptase to viral infectivity, replication, and protein maturation of antiretroviral drug-resistant human immunodeficiency virus type 1. J Virol. 2001; 75(7):3291-300. PMC: 114122. DOI: 10.1128/JVI.75.7.3291-3300.2001. View

Zennou V, Mammano F, Paulous S, Mathez D, Clavel F . Loss of viral fitness associated with multiple Gag and Gag-Pol processing defects in human immunodeficiency virus type 1 variants selected for resistance to protease inhibitors in vivo. J Virol. 1998; 72(4):3300-6. PMC: 109806. DOI: 10.1128/JVI.72.4.3300-3306.1998. View

Myint L, Matsuda M, Matsuda Z, Yokomaku Y, Chiba T, Okano A . Gag non-cleavage site mutations contribute to full recovery of viral fitness in protease inhibitor-resistant human immunodeficiency virus type 1. Antimicrob Agents Chemother. 2004; 48(2):444-52. PMC: 321554. DOI: 10.1128/AAC.48.2.444-452.2004. View

Nijhuis M, van Maarseveen N, Lastere S, Schipper P, Coakley E, Glass B . A novel substrate-based HIV-1 protease inhibitor drug resistance mechanism. PLoS Med. 2007; 4(1):e36. PMC: 1769415. DOI: 10.1371/journal.pmed.0040036. View

10.

Krausslich H, Facke M, Heuser A, Konvalinka J, Zentgraf H . The spacer peptide between human immunodeficiency virus capsid and nucleocapsid proteins is essential for ordered assembly and viral infectivity. J Virol. 1995; 69(6):3407-19. PMC: 189053. DOI: 10.1128/JVI.69.6.3407-3419.1995. View

11.

Shehu-Xhilaga M, Kraeusslich H, Pettit S, Swanstrom R, Lee J, Marshall J . Proteolytic processing of the p2/nucleocapsid cleavage site is critical for human immunodeficiency virus type 1 RNA dimer maturation. J Virol. 2001; 75(19):9156-64. PMC: 114484. DOI: 10.1128/JVI.75.19.9156-9164.2001. View

12.

Malet I, Roquebert B, Dalban C, Wirden M, Amellal B, Agher R . Association of Gag cleavage sites to protease mutations and to virological response in HIV-1 treated patients. J Infect. 2006; 54(4):367-74. DOI: 10.1016/j.jinf.2006.06.012. View

13.

Girnary R, King L, Robinson L, Elston R, Brierley I . Structure-function analysis of the ribosomal frameshifting signal of two human immunodeficiency virus type 1 isolates with increased resistance to viral protease inhibitors. J Gen Virol. 2006; 88(Pt 1):226-235. DOI: 10.1099/vir.0.82064-0. View

14.

Mammano F, Petit C, Clavel F . Resistance-associated loss of viral fitness in human immunodeficiency virus type 1: phenotypic analysis of protease and gag coevolution in protease inhibitor-treated patients. J Virol. 1998; 72(9):7632-7. PMC: 110025. DOI: 10.1128/JVI.72.9.7632-7637.1998. View

15.

Verheyen J, Knops E, Kupfer B, Hamouda O, Somogyi S, Schuldenzucker U . Prevalence of C-terminal gag cleavage site mutations in HIV from therapy-naïve patients. J Infect. 2008; 58(1):61-7. DOI: 10.1016/j.jinf.2008.11.009. View

16.

Pettit S, Lindquist J, Kaplan A, Swanstrom R . Processing sites in the human immunodeficiency virus type 1 (HIV-1) Gag-Pro-Pol precursor are cleaved by the viral protease at different rates. Retrovirology. 2005; 2:66. PMC: 1291402. DOI: 10.1186/1742-4690-2-66. View

17.

Brumme Z, Chan K, Dong W, Wynhoven B, Mo T, Hogg R . Prevalence and clinical implications of insertions in the HIV-1 p6Gag N-terminal region in drug-naive individuals initiating antiretroviral therapy. Antivir Ther. 2003; 8(2):91-6. View

18.

Molla A, Korneyeva M, Gao Q, Vasavanonda S, Schipper P, Mo H . Ordered accumulation of mutations in HIV protease confers resistance to ritonavir. Nat Med. 1996; 2(7):760-6. DOI: 10.1038/nm0796-760. View

19.

Launay O, Duval X, Dalban C, Descamps D, Peytavin G, Certain A . Lamivudine and indinavir/ritonavir maintenance therapy in highly pretreated HIV-infected patients (Vista ANRS 109). Antivir Ther. 2007; 11(7):889-99. View

20.

Pettit S, Clemente J, Jeung J, Dunn B, Kaplan A . Ordered processing of the human immunodeficiency virus type 1 GagPol precursor is influenced by the context of the embedded viral protease. J Virol. 2005; 79(16):10601-7. PMC: 1182631. DOI: 10.1128/JVI.79.16.10601-10607.2005. View