Feline immunodeficiency virus, a model for reverse transcriptase-targeted chemotherapy for acquired immune deficiency syndrome

North, Thomas W.; North, Ginnie Lee T.; Pedersen, Niels C

doi:10.1128/aac.33.6.915

Cited by 94 publications

(80 citation statements)

References 19 publications

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“…Accordingly, a virus for which the FC in EC 50 was Յ5 was considered highly susceptible to the challenge compound, that for which the FC was Ͼ5 and Ͻ50, moderately drug sensitive, and that for which the FC was Ն50, relatively insensitive. As expected (28,31,35,39,46,47), AZT effectively inhibited all retroviruses, yielding FC values that ranged from a low of 0.4 for RSV to a high of 2.4 for FIV (Table 2). In contrast, relatively large FC spectra were determined for the INSTIs.…”

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confidence: 87%

Differential Sensitivities of Retroviruses to Integrase Strand Transfer Inhibitors

Koh

Matreyek

Engelman

2011

J Virol

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Integrase inhibitors are emerging anti-human immunodeficiency virus (HIV) drugs, and multiple retroviruses and transposable elements were evaluated here for susceptibilities to raltegravir (RAL) and elvitegravir (EVG). All viruses, including primate and nonprimate lentiviruses, a Betaretrovirus, a Gammaretrovirus, and the Alpharetrovirus Rous sarcoma virus (RSV), were susceptible to inhibition by RAL. EVG potently inhibited all lentiviruses and intermediately inhibited Betaretrovirus and Gammaretrovirus infections yet was basically ineffective against RSV. Substitutions based on HIV type 1 (HIV-1) resistance changes revealed that integrase residue Ser150 contributed significantly to the resistance of RSV. The drugs intermediately inhibited intracisternal A-particle retrotransposition but were inactive against Sleeping Beauty transposition and long interspersed nucleotide element 1 (LINE-1) retrotransposition.Reverse transcription of retroviral RNA yields linear viral DNA (vDNA) containing a copy of the long terminal repeat (LTR) at each end. Integrase (IN) is an essential retroviral enzyme that catalyzes two reactions to insert the vDNA into cellular chromosomal DNA. IN prepares the LTR ends by hydrolyzing phosphodiester bonds adjacent to invariant CA dinucleotides, yielding reactive 3Ј deoxyadenylate (dA OH ) termini. In the nucleus, IN catalyzes DNA strand transfer by using the 3Ј OHs to cut the chromosome in a staggered fashion, concomitantly joining the vDNA ends to 5Ј phosphates. Hostmediated repair of the resulting DNA recombination intermediate completes the integration process. See reference 8 for an overview of retroviral reverse transcription and integration.IN belongs to the polynucleotidyl transferase superfamily of nucleic acid-metabolizing enzymes (7). Conserved amino acid residues (typically Asp and Glu [32]) arranged commonly on an RNase H structural fold comprise active sites that coordinate divalent metal ions for in-line nucleophilic attack of phosphodiester bonds. Due to its critical role in replication, human immunodeficiency virus type 1 (HIV-1) IN has long been targeted for drug development, and the first-in-class inhibitor raltegravir (RAL) was licensed in 2007 (45). Because RAL and related compounds preferentially inhibit DNA strand transfer activity, the drugs are referred to as IN strand transfer inhibitors (INSTIs) (24). Elvitegravir (EVG) is another well-studied INSTI (41). Recently determined X-ray crystal structures revealed that the drugs work by ejecting the 3Ј dA and its associated OH nucleophile from the IN active site (10,

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confidence: 87%

Differential Sensitivities of Retroviruses to Integrase Strand Transfer Inhibitors

Koh

Matreyek

Engelman

2011

J Virol

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“…Although FIV's overall genomic organization is more closely related to that of nonprimate lentiviruses, the biology of FIV resembles that of HIV, as it is highly lymphotropic and causes an immunodeficiency syndrome. Molecular cloning and characterization of the gene and gene products encoded by FIV make it amenable to molecular manipulations for detailed studies of the lentivirus life cycle and development of intervention strategies (30,39).…”

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confidence: 99%

Inhibitory Activity of Synthetic Peptide Antibiotics on Feline Immunodeficiency Virus Infectivity In Vitro

Kennedy‐Stoskopf

Jaynes³

et al. 2002

J Virol

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for up to 7 days, The virions from the D4E1-treated culture had impaired infectivity, as measured by the 50% tissue culture infectious dose and nested PCR analysis of proviral DNA. However, these noninfectious virions were able to bind and internalize, suggesting a defect at some postentry step. After chronically infected CrFK cells were treated with D4E1 for 24 h, increased cell-associated mature p26 Gag and decreased extracellular virus-associated p26 Gag were observed by Western blot analysis, suggesting that virus assembly and/or release may be blocked by D4E1 treatment, whereas virus binding, penetration, RNA synthesis, and protein synthesis appear to be unaffected. Synthetic peptide antibiotics may be useful tools in the search for antiviral drugs having a wide therapeutic window for host cells.

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“…FIV RT has been shown to be as sensitive as HIV RT to inhibition by dideoxynucleoside analogues (North et al, 1989(North et al, , 1990. Feline macrophages can also be productively infected by FIV with in vitro maximum viral production at week two (data not shown).…”

Section: Discussionmentioning

confidence: 91%

Inhibition of HIV-1 and LP-BM5 Replication in Macrophages by Dideoxycytidine and Dideoxycytidine 5′-Triphosphate

Magnani

Casabianca

Rossi

et al. 1995

Antivir Chem Chemother

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The antiviral agent 2′,3′-dideoxycytidine (ddC) has been shown to be active against HIV-1 infectivity. However, conflicting results have been reported concerning its efficacy in macrophages. Because macrophages possess low levels of the kinase(s) responsible for ddC phosphorylation, we investigated the ability of ddC and 2′,3′-dideoxycytidine 5′-trisphosphate (ddCTP) to suppress HIV-1 and LP-BM5 replication in these cells. Retrovirus replication was only partially inhibited in the two systems investigated by a high (1 μM) ddC concentration. The direct administration of ddCTP, using autologous red blood cells as a delivery system, was found to inhibit HIV-1 and LP-BM5 replication by more than 90% in macrophages without affecting major cell functions. These data, together with those already reported for FIV [Magnani et al. (1994) AIDS Res Hum Retroviruses 10: 1179-1186], suggest that the anabolic phosphorylation of ddC is an important determinant of its anti-HIV activity and that pharmacological interventions that modulate ddC metabolism may be useful for improving its antiretroviral activity in macrophages.

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Feline immunodeficiency virus, a model for reverse transcriptase-targeted chemotherapy for acquired immune deficiency syndrome

Cited by 94 publications

References 19 publications

Differential Sensitivities of Retroviruses to Integrase Strand Transfer Inhibitors

Differential Sensitivities of Retroviruses to Integrase Strand Transfer Inhibitors

Inhibitory Activity of Synthetic Peptide Antibiotics on Feline Immunodeficiency Virus Infectivity In Vitro

Inhibition of HIV-1 and LP-BM5 Replication in Macrophages by Dideoxycytidine and Dideoxycytidine 5′-Triphosphate

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