Evaluation of antiretrovirals in animal models of HIV infection

Rompay, Koen K. A. Van

doi:10.1016/j.antiviral.2009.07.008

Cited by 50 publications

(55 citation statements)

References 244 publications

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“…Previous studies have shown that SIV and HIV share similar resistance patterns against different classes of ARVs (10,36,37). Additionally, tissue culture studies by our group demonstrated that SIV substitutions confer resistance against INSTIs in a similar fashion to HIV (12).…”

Section: Discussionmentioning

confidence: 60%

Characterization of the Drug Resistance Profiles of Integrase Strand Transfer Inhibitors in Simian Immunodeficiency Virus SIVmac239

Hassounah

Liu

Quashie

et al. 2015

J Virol

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We previously showed that the simian immunodeficiency virus SIVmac239 is susceptible to human immunodeficiency virus (HIV) integrase (IN) strand transfer inhibitors (INSTIs) and that the same IN drug resistance mutations result in similar phenotypes in both viruses. Now we wished to determine whether tissue culture drug selection studies with SIV would yield the same resistance mutations as in HIV. Tissue culture selection experiments were performed using rhesus macaque peripheral blood mononuclear cells (PBMCs) infected with SIVmac239 viruses in the presence of increasing concentrations of dolutegravir (DTG), elvitegravir (EVG), and raltegravir (RAL). We now show that 22 weeks of selection pressure with DTG yielded a mutation at position R263K in SIV, similar to what has been observed in HIV, and that selections with EVG led to emergence of the E92Q substitution, which is a primary INSTI resistance mutation in HIV associated with EVG treatment failure. To study this at a biochemical level, purified recombinant SIVmac239 wild-type (WT) and E92Q, T97A, G118R, Y143R, Q148R, N155H, R263K, E92Q T97A, E92Q Y143R, R263K H51Y, and G140S Q148R recombinant substitution-containing IN enzymes were produced, and each of the characteristics strand transfer, 3=-processing activity, and INSTI inhibitory constants was assessed in cell-free assays. The results show that the G118R and G140S Q148R substitutions decreased K m = and V max =/K m = for strand transfer compared to those of the WT. RAL and EVG showed reduced activity against both viruses and against enzymes containing Q148R, E92Q Y143R, and G140S Q148R. Both viruses and enzymes containing Q148R and G140S Q148R showed moderate levels of resistance against DTG. This study further confirms that the same mutations associated with drug resistance in HIV display similar profiles in SIV. IMPORTANCEOur goal was to definitively establish whether HIV and simian immunodeficiency virus (SIV) share similar resistance pathways under tissue culture drug selection pressure with integrase strand transfer inhibitors and to test the effect of HIV-1 integrase resistance-associated mutations on SIV integrase catalytic activity and resistance to integrase strand transfer inhibitors. Clinically relevant HIV integrase resistance-associated mutations were selected in SIV in our tissue culture experiments. Not only do we report on the characterization of SIV recombinant integrase enzyme catalytic activities, we also provide the first research anywhere on the effect of mutations within recombinant integrase SIV enzymes on drug resistance.T he limitations of current highly active antiretroviral therapy (HAART) include the incidence of drug resistance observed in patients, issues of drug adherence, and numbers of newly acquired infections. The emergence of drug-resistant viruses can lead to increases in viral load and treatment failure, and such viruses can be transmitted to both healthy individuals as well as to untreated HIV-positive individuals, therefore threatening the long-term effica...

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Section: Discussionmentioning

confidence: 60%

Characterization of the Drug Resistance Profiles of Integrase Strand Transfer Inhibitors in Simian Immunodeficiency Virus SIVmac239

Hassounah

Liu

Quashie

et al. 2015

J Virol

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“…Sustained contact between humans and other species increases the likelihood of the emergence of a virus adapted to infect and replicate in humans either directly or through intermediate hosts (2). Identification and characterization of animal virus homologs provide new insights into pathogenesis of human viruses, and, in some instances, models for investigating prevention and treatment of human disease must be pursued with related animal viruses (3)(4)(5). Comparative genetic analysis of closely related viruses can also identify genomic regions (RNA structures, amino acid motifs, and residues) important for virus receptor binding, entry, replication, immunity, and other biological functions (6)(7)(8)(9)(10).…”

mentioning

confidence: 99%

Characterization of a canine homolog of hepatitis C virus

Kapoor

Simmonds

Qaisar

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

243

282

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An estimated 3% of the world's population is chronically infected with hepatitis C virus (HCV). Although HCV was discovered more than 20 y ago, its origin remains obscure largely because no closely related animal virus homolog has been identified; furthermore, efforts to understand HCV pathogenesis have been hampered by the absence of animal models other than chimpanzees for human disease. Here we report the identification in domestic dogs of a nonprimate hepacivirus. Comparative phylogenetic analysis of the canine hepacivirus (CHV) confirmed it to be the most genetically similar animal virus homolog of HCV. Bayesian Markov chains Monte Carlo and associated time to most recent common ancestor analyses suggest a mean recent divergence time of CHV and HCV clades within the past 500-1,000 y, well after the domestication of canines. The discovery of CHV may provide new insights into the origin and evolution of HCV and a tractable model system with which to probe the pathogenesis, prevention, and treatment of diseases caused by hepacivirus infection.flavivirus | zoonosis

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“…Many novel antiretroviral small molecule inhibitors have been characterized for efficacy against HIV, SIV, or SHIV in animal models, many leading to FDA approval or to more improved versions of the compounds (reviewed in Ambrose and KewalRamani, 2008;Van Rompay, 2010). For example, PMEA, a drug related to tenofovir, was found to inhibit SIV infection effectively in macaques (Balzarini et al, 1991).…”

Section: Efficacy In Viral Inhibitionmentioning

confidence: 99%

Use of Animal Models for Anti-HIV Drug Development

Ambrose¹

2012

Antiviral Drugs - Aspects of Clinical Use and Recent Advances

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Evaluation of antiretrovirals in animal models of HIV infection

Cited by 50 publications

References 244 publications

Characterization of the Drug Resistance Profiles of Integrase Strand Transfer Inhibitors in Simian Immunodeficiency Virus SIVmac239

Characterization of the Drug Resistance Profiles of Integrase Strand Transfer Inhibitors in Simian Immunodeficiency Virus SIVmac239

Characterization of a canine homolog of hepatitis C virus

Use of Animal Models for Anti-HIV Drug Development

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