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Mutations in Both Env and Gag Genes Are Required for HIV-1 Resistance to the Polysulfonic Dendrimer SPL2923, As Corroborated by Chimeric Virus Technology

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Mutations in Both Env and Gag Genes Are Required for HIV-1 Resistance to the Polysulfonic Dendrimer SPL2923, As Corroborated by Chimeric Virus Technology Antiviral Chemistry & Chemotherapy 16:253–266 Mutations in both env and gag genes are required for HIV-1 resistance to the polysulfonic dendrimer SPL2923, as corroborated by chimeric virus technology Anke Hantson1,†, Valery Fikkert1,†, Barbara Van Remoortel1, Chistophe Pannecouque3, Peter Cherepanov1, Barry Matthews2, George Holan2, Erik De Clercq3, Anne-Mieke Vandamme3, Zeger Debyser1 and Myriam Witvrouw1* 1Laboratory for Molecular Virology, Molecular Medicine, Katholieke Universiteit Leuven and KULAK, Flanders, Belgium 2Starpharma Limited, Melbourne, Victoria, Australia 3Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium *Corresponding author: Tel: +32 1633 2170; Fax: +32 1633 6336; E-mail: [email protected] †Anke Hantson and Valery Fikkert contributed equally to this paper A drug-resistant NL4.3/SPL2923 strain has previ- NL4.3/SPL2923 were sufficient to reproduce the ously been generated by in vitro selection of HIV- cross resistance to enfuvirtide. Unexpectedly, the 1(NL4.3) in the presence of the polysulfonic reduced sensitivity towards SPL2923 was not fully dendrimer SPL2923 and mutations were reported reproduced after gp160-recombination. The search in its gp120 gene (Witvrouw et al., 2000). Here, we for mutations in NL4.3/SPL2923 in viral genes further analysed the (cross) resistance profile of other than env revealed several mutations in the NL4.3/SPL2923. NL4.3/SPL2923 was found to gene encoding the HIV p17 matrix protein (MA) contain additional mutations in gp41 and showed and one mutation in the gene encoding the p24 reduced susceptibility to SPL2923, dextran sulfate capsid protein (CA). In order to analyse the impact (DS) and enfuvirtide. To delineate to what extent of the gag mutations alone and in combination the mutations in each env gene were accountable with the mutations in env on the phenotypic resis- for the phenotypic (cross) resistance of tance towards SPL2923, we developed a novel NL4.3/SPL2923, the gp120-, gp41- and gp160- p17- and p17/gp160-CVT. Phenotypic analysis of sequences derived from this strain were placed the NL4.3/SPL2923 p17- and p17/gp160-recom- into a wild-type background using env chimeric bined strains indicated that the mutations in both virus technology (CVT). The cross resistance of env and gag have to be present to fully reproduce NL4.3/SPL2923 towards DS was fully reproduced the resistance of NL4.3/SPL2923 towards SPL2923. following gp160-recombination, while it was only partially reproduced following gp120- or gp41- Key words: HIV, entry, bicyclams, gag, env, recombination. The mutations in gp41 of resistance Introduction Current treatments for human immunodeficiency virus entry into its target cells involves the interaction of the viral type 1 (HIV-1) infection are based on drug combination protein gp120 with the CD4 receptor on the cell surface regimens, consisting of drugs that target reverse transcrip- and the successive interaction of gp120 with the coreceptor. tase (RT) and protease (PR) (Richman, 2001). Due to toxi- This results in a conformational change to the prehairpin city and the emergence of virus strains resistant to the intermediate, in which the fusion peptide of gp41 pene- antiretrovirals, the development of drugs preferentially trates the cell membrane. The prehairpin intermediate acting on new targets in the HIV replication cycle remains resolves to the fusion-active hairpin structure, resulting in crucial (Vandamme et al., 1999). An attractive new target the apposition of the viral envelope and the plasma for anti-HIV therapy is entry, since blocking entry should membrane and is followed by the fusion of the envelope lead to suppression of infectivity and replication. HIV with the cellular lipid bilayer (Chan & Kim, 1998). ©2005 International Medical Press 253 A Hantson et al. Numerous entry inhibitors acting at different stages of peptidic agents, for example, the polyphemusin T22, T134 the entry process have been reported, of which a growing and T140 (Arakaki et al., 1999; Murakami et al., 1997; number has recently been introduced into clinical trials or Tamamura et al., 1998a; Tamamura et al., 1998b), and the is in preclinical development. Typical polyanionic Tat protein analogues ALX40-4C (Doranz et al., 1997) compounds, like dextran sulfate (DS) inhibit HIV binding and CGP64222 (Daelemans et al., 2000). Also, low molec- to its target cells (Baba et al., 1988). They exert their anti- ular weight CXCR4 antagonists are the highly potent and HIV activity by shielding off the positively charged sites in selective bicyclams (De Clercq et al., 1992; De Vreese et al., the V3 loop of gp120, thereby blocking the attachment to 1996; Schols et al., 1997), represented by AMD3100, cell surface heparan sulfate (Witvrouw & De Clercq, which has been evaluated in Phase II clinical trials (Schols 1997). The dendrimer SPL2923 shares an analogous mode D, Claes S, De Clercq E, Hendrix C, Bridger G, Calandra of action due to its polysulfonated periphery. Dendrimers G, Henson GW, Fransen S, Huang W, Whitcomb JM & are highly branched macromolecules that are built up in Petropoulos CJ [2002] AMD3100 HIV study group. generations from a reactive core group by the use of AMD3100, a CXCR4 antagonist reduced HIV viral load branched building blocks to give spherical molecules. and X4 virus levels in humans. 9th Conference on SPL2923 consists of a fourth generation polyamidoamine Retroviruses & Opportunistic Infections. Seattle, WA, USA, (PAMAM) dendrimer scaffold built from an ammonia 24–28 February 2002. Oral Abstract 2.) but has not been core, which is fully capped on the surface with 24 naph- further pursued for the treatment of HIV infections thyldisulfonic acids (Witvrouw et al., 2000). PRO 542, an because of the lack of oral bioavailability. antibody-like fusion protein of the D1D2 domains of CD4 From the group of HIV entry inhibitors that interfere and IgG2, is a specific CD4 attachment inhibitor (Allaway with the hairpin formation and membrane fusion, enfuvir- et al., 1995; Jacobson et al., 2000). The conserved CD4- tide (T20), has recently been approved to be included in binding pocket on gp120 is a target for BMS-806, another anti-HIV combination regimens (Lalezari et al., 2003; HIV binding inhibitor. Preclinical development of this Lazzarin, 2003). T20 is a synthetic 36-amino acid peptide inhibitor is ongoing (Guo et al., 2003; Lin et al., 2003; segment corresponding to residues 127-162 of the Wang et al., 2003). ectodomain of gp41, that is, the envelope HR2 domain. In addition, co-receptor antagonists can inhibit replica- T20 binds to the N-terminal fusion peptide of the pre- tion. SCH-C is an orally bioavailable CCR5 antagonist hairpin intermediate and prevents the subsequent forma- (Strizki et al., 2001) which demonstrates good pharmaco- tion of the fusion-active hairpin conformation (Eckert & kinetics, safety and tolerability besides a clear decrease in Kin, 2001). A second generation fusion inhibitor, T1249, HIV RNA in Phase I/II clinical trials (Reynes J, Rouzier has already been identified (Sista P, Melby T, Dhingra U, R, Kanouni T, Baillet V, Baroudy B, Keung A, Hogan C, Cammack N, McKenna P, Dehertogh P & Matthews T Malowitz M & Laughlin [2002] SCH C. safety and [2001] The fusion inhibitors T20 and T1249 demonstrate antiviral effects of a CCR5 receptor antagonist in HIV-1 potent in vitro antiviral activity against clade B HIV-1 infected subjects. 9th Conference on Retroviruses & isolates resistant to reverse transcriptase and protease Opportunistic Infections. Seattle, WA, USA, 24–28 February inhibitors and non-B clades. 5th International Workshop on 2002. Oral Abstract 1.). SCH-D acts in a similar mode, but HIV Drug resistance & Treatment Strategies. Scottsdale, shows higher antiviral potency (Chen Z, Hu B, Huang W, Arizona, USA, 4–8 June 2001. Abstract 2.) and demon- He T, Huang Y, Strizki J, Xu S, Wojcik L, Whitcom J, strated a strong dose response in patients with multi-drug Zhang L, Petropoulos C, Baroudy B & Ho DD [2002] resistant strains (Miralles GD, DeMasi R, Sista P,Melby T, HIV-1 mutants less susceptible to SCH-D a novel small Duff F, Matthews T & the T1249-101 study group [2001] antagonist of CCR5. 9th Conference on Retroviruses & Baseline genotype and prior antiretroviral history do not Opportunistic Infections. 24–28 February, Seattle, WA, affect virologic response to T1249. 5th International USA. Abstract 396-T). PRO 140, an anti-CCR5 mono- Workshop on HIV Drug resistance & Treatment Strategies. clonal antibody, displayed anti-HIV activity in the thera- Scottsdale, Arizona, USA, 4–8 June 2001. Abstract 3.). peutic hu-PBMC-SCID mouse model (Franti M, O’Neill Most likely, more HIV entry inhibitors will follow. This Maddon P,Burton D, Poignard P & Olson W [2002] PRO makes the study of resistance towards inhibitors of viral 542 (CD4IgG2) has a profound impact on HIV-1 replica- entry and the development of phenotypic assays to evaluate tion in the Hu-PBL-SCID mouse model. 9th Conference on the susceptibility of clinical isolates towards HIV entry Retroviruses & Opportunistic Infections. Seattle, USA, 24–28 inhibitors mandatory. February 2002. Abstract 396-T.). A number of polycationic We previously reported the anti-HIV activity of polyan- molecules were found to interact electrostatically with the ionic dendrimers inhibiting the replication of HIV-1 in MT- negatively charged amino acid residues of CXCR4. The 4 cells in the nanomolar range (Witvrouw et al., 2000). In a majority of these compounds are high molecular weight time-of-addition experiment SPL2923 had to be present at 254 ©2005 International Medical Press HIV-1 resistance to entry inhibitors the moment of viral entry. However, at much higher concen- (Bethesda, MD, USA). NL4.3/SPL2923 has previously trations it was found to exert its anti-HIV activity by inter- been selected in our laboratory by serial passage of HIV-1 fering at a later stage in the replicative cycle, that is, at a step (NL4.3) in the presence of increasing concentrations of coinciding with the RT and/or integrase process.
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