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


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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    • "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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    ABSTRACT: Proteolytic processing of viral polyproteins is essential for retrovirus infectivity. Retroviral proteases (PR) become activated during or after assembly of the immature, non-infectious virion. They cleave viral polyproteins at specific sites, inducing major structural rearrangements termed maturation. Maturation converts retroviral enzymes into their functional form, transforms the immature shell into a metastable state primed for early replication events, and enhances viral entry competence. Not only cleavage at all PR recognition sites, but also an ordered sequence of cleavages is crucial. Proteolysis is tightly regulated, but the triggering mechanisms and kinetics and pathway of morphological transitions remain enigmatic. Here, we outline PR structures and substrate specificities focusing on HIV PR as a therapeutic target. We discuss design and clinical success of HIV PR inhibitors, as well as resistance development towards these drugs. Finally, we summarize data elucidating the role of proteolysis in maturation and highlight unsolved questions regarding retroviral maturation. Copyright © 2015 Elsevier Inc. All rights reserved.
    Virology 03/2015; 479-480. DOI:10.1016/j.virol.2015.03.021 · 3.32 Impact Factor
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    • "Thus, our data on CS conservation across HIV-1 variants could provide useful data to design potential targets for an effective vaccine development against HIV effective for all groups, subtypes and recombinants. Moreover, since mutations within CS have been associated with PI exposure and maturation inhibitor resistance [5], [32], our results could potentially provide a better understanding of the role of gag in antiretroviral resistance and in the development of future maturation inhibitors [4]. "
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    ABSTRACT: Polymorphisms at cleavage sites (CS) can influence Gag and Pol proteins processing by the viral protease (PR), restore viral fitness and influence the virological outcome of specific antiretroviral drugs. However, data of HIV-1 variant-associated CS variability is scarce. In this descriptive research, we examine the effect of HIV-1 variants on CS conservation using all 9,028 gag and 3,906 pol HIV-1 sequences deposited in GenBank, focusing on the 110 residues (10 per site) involved at 11 CS: P17/P24, P24/P2, P2/P7, P7/P1, P1/P6 (gag) , NC/TFP, TFP/P6 (pol), P6 (pol) /PR, PR/RT(p51), RT(p51)/RT(p66) and RT(p66)/IN. CS consensus amino acid sequences across HIV-1 groups (M, O, N, P), group M 9 subtypes and 51 circulating recombinant forms (CRF) were inferred from our alignments and compared to the HIV-1 consensus-of-consensuses sequence provided by GenBank. In all HIV-1 variants, the most conserved CS were PR/RT(p51), RT(p51)/RT(p66), P24/P2 and RT(p66)/IN and the least P2/P7 and P6 (pol) /PR. Conservation was significantly lower in subtypes vs. recombinants in P2/P7 and TFP/P6 (pol) and higher in P17/P24. We found a significantly higher conservation rate among Group M vs. non-M Groups HIV-1. The late processing sites at Gag (P7/P1) and GagPol precursors (PR/RT(p51)) presented a significantly higher conservation vs. the first CS (P2/P7) in the 4 HIV-1 groups. Here we show 52 highly conserved residues across HIV-1 variants in 11 CS and the amino acid consensus sequence in each HIV-1 group and HIV-1 group M variant for each 11 CS. This is the first study to describe the CS conservation level across all HIV-1 variants and 11 sites in one of the largest available sequence HIV-1 dataset. These results could help other researchers for the future design of both novel antiretroviral agents acting as maturation inhibitors as well as for vaccine targeting CS.
    PLoS ONE 02/2014; 9(2):e88099. DOI:10.1371/journal.pone.0088099 · 3.23 Impact Factor
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    • "In this regard, constantly evolving nature of viruses owing to their error prone polymerase often makes drug therapy a failure due to emergence of viral strains. This is further complicated by the presence of viral structural or regulatory proteins that can confer resistance to both anti-viral and anti-cancer drugs which makes the removal of affected cells difficult [10] [11]. Problems of drug resistance in the HBV-related tumours have been reported [12] but the molecular mechanism behind it still remains unexplained. "

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