Human immunodeficiency virus integrase inhibitors efficiently suppress feline immunodeficiency virus replication in vitro and provide a rationale to redesign antiretroviral treatment for feline AIDS

Savarino, Andrea; Pistello, Mauro; D'Ostilio, Daniela; Zabogli, Elisa; Taglia, Fabiana; Mancini, Fabiola; Ferro, Stefania; Matteucci, Donatella; Luca, Laura De; Barreca, Maria Letizia; Ciervo, Alessandra; Chimirri, Alba; Ciccozzi, Massimo; Bendinelli, Mauro

doi:10.1186/1742-4690-4-79

Cited by 38 publications

(31 citation statements)

References 38 publications

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“…It is clear that the CTD is the least conserved domain and that the CCD is the most conserved. Thus, the similarity of the SIV resistance profile to INSTIs to that of HIV-1 is probably due to the high degree of conservation of the CCD (57). All of the residues studied here are located within the CCD with the exception of R263 that is found within the CTD.…”

Section: Discussionmentioning

confidence: 76%

Effect of HIV-1 Integrase Resistance Mutations When Introduced into SIVmac239 on Susceptibility to Integrase Strand Transfer Inhibitors

Hassounah

Mésplède

Quashie

et al. 2014

J Virol

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Studies on the in vitro susceptibility of SIV to integrase strand transfer inhibitors (INSTIs) have been rare. In order to determine the susceptibility of SIVmac239 to INSTIs and characterize the genetic pathways that might lead to drug resistance, we inserted various integrase (IN) mutations that had been selected with HIV under drug pressure with raltegravir (RAL), elvitegravir (EVG), and dolutegravir (DTG) into the IN gene of SIV. We evaluated the effects of these mutations on SIV susceptibility to INSTIs and on viral infectivity. Sequence alignments of SIVmac239 IN with various HIV-1 isolates showed a high degree of homology and conservation of each of the catalytic triad and the key residues involved in drug resistance. Each of the G118R, Y143R, Q148R, R263K, and G140S/Q148R mutations, when introduced into SIV, impaired infectiousness and replication fitness compared to wild-type virus. Using TZM-bl cells, we demonstrated that the Q148R and N155H mutational pathways conferred resistance to EVG (36-and 62-fold, respectively), whereas R263K also displayed moderate resistance to EVG (12-fold). In contrast, Y143R, Q148R, and N155H all yielded low levels of resistance to RAL. The combination of G140S/Q148R conferred highlevel resistance to both RAL and EVG (>300-and 286-fold, respectively). DTG remained fully effective against all site-directed mutants except G118R and R263K. Thus, HIV INSTI mutations, when inserted into SIV, resulted in a similar phenotype. These findings suggest that SIV and HIV may share similar resistance pathways profiles and that SIVmac239 could be a useful nonhuman primate model for studies of HIV resistance to INSTIs. IMPORTANCEThe goal of our project was to establish whether drug resistance against integrase inhibitors in SIV are likely to be the same as those responsible for drug resistance in HIV. Our data answer this question in the affirmative and show that SIV can probably serve as a good animal model for studies of INSTIs and as an early indicator for possible emergent mutations that may cause treatment failure. An SIV-primate model remains an invaluable tool for investigating questions related to the potential role of INSTIs in HIV therapy, transmission, and pathogenesis, and the present study will facilitate each of the above.

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Section: Discussionmentioning

confidence: 76%

Effect of HIV-1 Integrase Resistance Mutations When Introduced into SIVmac239 on Susceptibility to Integrase Strand Transfer Inhibitors

Hassounah

Mésplède

Quashie

et al. 2014

J Virol

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“…Drug classes that inhibit human immunodeficiency virus type 1 (HIV-1) have been tested on FIV, and the real effectiveness is still controversial (1). FIV is not inhibited by non-NRTIs and protease inhibitors but responds to NRTIs and, more recently, to integrase strand-transfer inhibitors (36). The emergence of drug resistance mutants in infected cats is believed to result in clinical failure of antiviral therapy, based on AIDS treatment knowledge (19).…”

mentioning

confidence: 99%

Phylogenetic and Genetic Analysis of Feline Immunodeficiency Virus gag , pol , and env Genes from Domestic Cats Undergoing Nucleoside Reverse Transcriptase Inhibitor Treatment or Treatment-Naïve Cats in Rio de Janeiro, Brazil

Martins

Medeiros

Simonetti

et al. 2008

J Virol

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Feline immunodeficiency virus (FIV) is the Lentivirus responsible for an immunodeficiency-like disease in domestic cats (Felis catus). FIV is divided into five phylogenetic subtypes (A, B, C, D, and E), based on genetic diversity. Knowledge of the geographical distribution of subtypes is relevant for understanding different disease progressions and for vaccine development. In this study, viral sequences of 26 infected cats from Rio de Janeiro, 8 undergoing treatment with zidovudine (AZT) for at least 5 years, were successfully amplified from blood specimens. gag capsid (CA), pol reverse transcriptase (RT), and env gp120 (V3-V4) regions were analyzed to determine subtypes and to evaluate potential mutations related to antiretroviral drug resistance among treated cats. Subtyping based on phylogenetic analysis was performed by the neighbor-joining and maximum likelihood methods. All of the sequences clustered with subtype B in the three regions, exhibiting low genetic variability. Additionally, we found evidence that the same virus is circulating in animals in close contact. The analysis of FIV RT sequences identified two new putative mutations related to drug resistance located in the RT "finger" domain, which has 60% identity to human immunodeficiency virus (HIV) sequence. Amino acid change K3R at codons 64 and 69 was found in 25% and 37.5% of the treated animals, respectively. These signatures were comparable to K65R and K70R thymidine-associated mutations found in the HIV-1 HXB2 counterpart. This finding strongly suggests a position correlation between the mutations found in FIV and the K65R and K70R substitutions from drug-resistant HIV-1 strains.

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“…The high sequence conservation between the IN CCD domains of FIV and HIV-1 (44% identity) suggested the FIV IN CCD structure and INSTIs binding site would be nearly the same as for HIV IN; a prediction that has been validated by the effective binding of INSTIs to FIV and the inhibition of FIV replication by INSTIs in vitro at concentrations comparable to those reported for HIV-1 (Savarino et al, 2007).…”

Section: Introductionmentioning

confidence: 79%

“…Modeling reveals that whereas the loop in the closed conformation would not clash with viral DNA ( Figure 3B), a conserved P144 residue (HIV-1 P142, PFV P211) would clash with host acceptor-DNA and inhibitors mandating loop movement to enable substrate binding ( Figure 3C). In FIV, the shallower cavity formed by the backbone of smaller G145 (Y212 in PFV and Y143 in HIV-1) apparently provides sufficient space for binding of INSTI because raltegravir binds and inhibits FIV IN at concentrations comparable to those used with HIV-1 IN (Savarino et al, 2007). Figure 4A).…”

Section: The Catalytic Loop Is Fully Structured In a ''Closed'' Confomentioning

confidence: 99%

Identification of Phe187 as a Crucial Dimerization Determinant Facilitates Crystallization of a Monomeric Retroviral Integrase Core Domain

Galilee

Alian

2014

Structure

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Retroviral DNA integration into the host genome is mediated by nucleoprotein assemblies containing tetramers of viral integrase (IN). Whereas the fully active form of IN comprises a dimer of dimers, the molecular basis of IN multimerization has not been fully characterized. IN has consistently been crystallized in an analogous dimeric form in all crystallographic structures and experimental evidence as to the level of similarity between IN monomeric and dimeric conformations is missing because of the lack of IN monomeric structures. Here we identify Phe187 as a critical dimerization determinant of IN from feline immunodeficiency virus (FIV), a nonprimate lentivirus that causes AIDS in the natural host, and report, in addition to a canonical dimeric structure of the FIV IN core-domain, a monomeric structure revealing the preservation of the backbone structure between the two multimeric forms and suggest a role for Phe187 in "hinging" the flexible IN dimer.

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Human immunodeficiency virus integrase inhibitors efficiently suppress feline immunodeficiency virus replication in vitro and provide a rationale to redesign antiretroviral treatment for feline AIDS

Cited by 38 publications

References 38 publications

Effect of HIV-1 Integrase Resistance Mutations When Introduced into SIVmac239 on Susceptibility to Integrase Strand Transfer Inhibitors

Effect of HIV-1 Integrase Resistance Mutations When Introduced into SIVmac239 on Susceptibility to Integrase Strand Transfer Inhibitors

Phylogenetic and Genetic Analysis of Feline Immunodeficiency Virus gag , pol , and env Genes from Domestic Cats Undergoing Nucleoside Reverse Transcriptase Inhibitor Treatment or Treatment-Naïve Cats in Rio de Janeiro, Brazil

Identification of Phe187 as a Crucial Dimerization Determinant Facilitates Crystallization of a Monomeric Retroviral Integrase Core Domain

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