Article

Human Immunodeficiency Virus Gag and protease: partners in resistance

Department of Virology, Medical Microbiology, University Medical Center Utrecht, HP G04,614, Heidelberglaan 100, Utrecht, 3584 CX, The Netherlands.
Retrovirology (Impact Factor: 4.19). 08/2012; 9(1):63. DOI: 10.1186/1742-4690-9-63
Source: PubMed

ABSTRACT

Human Immunodeficiency Virus (HIV) maturation plays an essential role in the viral life cycle by enabling the generation of mature infectious virus particles through proteolytic processing of the viral Gag and GagPol precursor proteins. An impaired polyprotein processing results in the production of non-infectious virus particles. Consequently, particle maturation is an excellent drug target as exemplified by inhibitors specifically targeting the viral protease (protease inhibitors; PIs) and the experimental class of maturation inhibitors that target the precursor Gag and GagPol polyproteins. Considering the different target sites of the two drug classes, direct cross-resistance may seem unlikely. However, coevolution of protease and its substrate Gag during PI exposure has been observed both in vivo and in vitro. This review addresses in detail all mutations in Gag that are selected under PI pressure. We evaluate how polymorphisms and mutations in Gag affect PI therapy, an aspect of PI resistance that is currently not included in standard genotypic PI resistance testing. In addition, we consider the consequences of Gag mutations for the development and positioning of future maturation inhibitors.

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Available from: Annemarie M.J. Wensing
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    • "It is well documented that drug resistance exerted by mutations occur in active site or residues placing near binding site. Nevertheless these mutations lower enzyme affinity for inhibitors but they did not attenuate enzyme affinity for its natural substrates (Fun et al., 2012, Kolli et al., 2006, Prabu-Jeyabalan et al., 2006, Nalam et al., 2010). It should be noted that In vitro studies as site directed mutagenesis confirmed that the major or drug resistant mutations for HIV-1 protease are as follow: D30N, V32I, M46L, M46I, I47V, I47A, G48V, I50L, I50V, I54M, Q58E, T74P, L76V, V82A, V82F, V82T, V82S, V82L, N83D, I84V, N88S (Johnson et al., 2010). "
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    • "One of the therapeutic approaches has been inhibition of the virally encoded enzymatic proteins necessary for viral replication and maturation. Human Immunodeficiency Virus Type 1 Protease (HIV-1 PR) is one of the vital enzymes of HIV-1 retrovirus, which cleaves viral gag and pol polyproteins and releases structural and enzymatic proteins for its maturation and proliferation inside infected host (Fun et al., 2012). The inhibition of HIV PR activity can lead to disruption of the viral protein maturation and replication, thus making HIV protease a potential target for AIDS therapy (Heal et al., 2012). "
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    • "More detailed structural analyses of virus mutants indicated that not the presence of the spacer peptide itself, but possibly the proper kinetics of cleavages in this region is relevant (de Marco et al., 2012). This interpretation is in agreement with the observation that mutations in the NC-SP2 region are characteristically observed as tertiary resistance mutations restoring fitness to HIV-1 variants carrying resistance mutations in PR, which affect the catalytic activity of the enzyme (reviewed in (Clavel and Mammano, 2010; Fun et al., 2012)). Furthermore, NC-SP2-p6, NC-SP2 and NC display different abilities to condense nucleic acid ((Mirambeau et al., 2010) and references therein) suggesting that successive processing steps in this region regulate the dynamics of nucleocapsid core formation. "
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