Early onset of autoimmune disease by the retroviral integrase inhibitor raltegravir

Beck-Engeser, Gabriele; Eilat, Dan; Harrer, Thomas; Jäck, Hans‐Martin; Wabl, Matthias

doi:10.1073/pnas.0908074106

Cited by 38 publications

(32 citation statements)

References 53 publications

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“…We found that AZT inhibited XMRV replication, as recently reported by Sakuma et al and Hong et al (20,49) and consistent with previously reported inhibition of MLV replication (22,44,56). We also found that TDF inhibits XMRV replication, albeit with less potency than HIV-1, and that raltegravir, recently reported to inhibit MLV integration (1), is a potent inhibitor of XMRV. These antiviral agents may be useful for analysis of the kinetics of XMRV replication; such studies have provided great insights into the mechanisms of HIV-1 replication and pathogenesis (4,16,66).…”

Section: Discussionmentioning

confidence: 74%

Inhibition of Xenotropic Murine Leukemia Virus-Related Virus by APOBEC3 Proteins and Antiviral Drugs

Paprotka

Venkatachari

Chaipan

et al. 2010

J Virol

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Xenotropic murine leukemia virus-related virus (XMRV), a gammaretrovirus, has been isolated from human prostate cancer tissue and from activated CD4؉ T cells and B cells of patients with chronic fatigue syndrome, suggesting an association between XMRV infection and these two diseases. Since APOBEC3G (A3G) and APOBEC3F (A3F), which are potent inhibitors of murine leukemia virus and Vif-deficient human immunodeficiency virus type 1 (HIV-1), are expressed in human CD4؉ T cells and B cells, we sought to determine how XMRV evades suppression of replication by APOBEC3 proteins. We found that expression of A3G, A3F, or murine A3 in virus-producing cells resulted in their virion incorporation, inhibition of XMRV replication, and G-to-A hypermutation of the viral DNA with all three APOBEC3 proteins. Quantitation of A3G and A3F mRNAs indicated that, compared to the human T-cell lines CEM and H9, prostate cell lines LNCaP and DU145 exhibited 50% lower A3F mRNA levels, whereas A3G expression in 22Rv1, LNCaP, and DU145 cells was nearly undetectable. XMRV proviral genomes in LNCaP and DU145 cells were hypermutated at low frequency with mutation patterns consistent with A3F activity. XMRV proviral genomes were extensively hypermutated upon replication in A3G/A3F-positive T cells (CEM and H9), but not in A3G/A3F-negative cells (CEM-SS). We also observed that XMRV replication was susceptible to the nucleoside reverse transcriptase (RT) inhibitors zidovudine (AZT) and tenofovir and the integrase inhibitor raltegravir. In summary, the establishment of XMRV infection in patients may be dependent on infection of A3G/A3F-deficient cells, and cells expressing low levels of A3G/A3F, such as prostate cancer cells, may be ideal producers of infectious XMRV. Furthermore, the anti-HIV-1 drugs AZT, tenofovir, and raltegravir may be useful for treatment of XMRV infection.Gammaretroviruses infect a wide range of species and are associated with a variety of neurological and immunological disorders, as well as carcinomas and leukemias (9,11,21,30,58). In 2006, for the first time, a gammaretrovirus was isolated from human tissues and was named xenotropic murine leukemia virus-related virus (XMRV) (63). The virus was discovered to be prevalent in prostate cancer tissues derived from patients carrying a mutation in the RNASEL gene, an important player in the interferon-mediated suppression of viral infection in host target cells (48,53,54). A recent study found XMRV in several prostate cancer samples with the same prevalence for patients with and without the RNASEL mutation and suggested that XMRV infection may be associated with nearly 30% of all prostate cancers (51). However, two other studies could not confirm an association of XMRV with prostate cancer in Germany, suggesting that XMRV's geographic distribution may not extend to Europe (10,17). In addition to prostate cancers, XMRV was also recently isolated from chronic fatigue syndrome (CFS) patients, exhibiting a high prevalence of 67% in confirmed cases and a prevalence of 4% in healthy co...

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Section: Discussionmentioning

confidence: 74%

Inhibition of Xenotropic Murine Leukemia Virus-Related Virus by APOBEC3 Proteins and Antiviral Drugs

Paprotka

Venkatachari

Chaipan

et al. 2010

J Virol

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“…Protease inhibitors harbor an intermediate phenotype which is highly active against HIV-2/SIV (18) but ineffective against the Gammaretrovirus xenotropic murine leukemia virus-related virus (42). RAL and EVG were previously shown to be effective against HIV-2/SIV (21,38,40), gammaretroviruses (1,34,40,42,43), and the Spumavirus prototype foamy virus (PFV) (48), suggesting that they, like NRTIs, might harbor pantropic antiretroviral activities. To comprehensively address this question, we determined RAL and EVG concentrations required to inhibit infection by vectors derived from five different lentiviruses, the Betaretrovirus Mason-Pfizer monkey virus (MPMV), the Alpharetrovirus Rous sarcoma virus (RSV), and the Gammaretrovirus Moloney murine leukemia virus (MLV).…”

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confidence: 99%

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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“…However, subtle findings of nephrotoxicity were observed in the Raltegravir Switch clinical trial and in a retroviral mouse model. 4 The studies presented here do not support a direct nephrotoxic effect of integrase inhibitors in mice in the time frame examined. Serum creatinine levels of mice were reliably elevated after two weeks of RAL and DTG administration.…”

Section: Discussionmentioning

confidence: 49%

“…The concentration of RAL in water, dose administered, and route of administration follow a previously published RAL mouse model. 4 The concentration and dose for DTG were scaled to maintain a fourfold exposure as compared to the human daily dose. The two-week time point was selected as serum creatinine was reliably elevated at that time and modeled after a human study wherein two weeks of oral administration led to changes in creatinine secretion without affecting GFR.…”

Section: Methodsmentioning

confidence: 99%

“…In a mouse retroviral model, treatment with RAL led to increased autoimmunity manifested by hemolytic anemia and proteinuria. 4 Given these findings, we sought to determine whether a two-week regimen of 1 Division of Nephrology, Indiana University School of Medicine, Indianapolis, USA 2 Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, USA 3 Division of Infectious Diseases, Indiana University School of Medicine, Indianapolis, USA high-dose integrase inhibitor administration had a direct nephrotoxic effect in C57BL/6 mice.…”

Section: Introductionmentioning

confidence: 99%

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A two-week regimen of high-dose integrase inhibitors does not cause nephrotoxicity in mice

Eadon

Zhang

Skaar

et al. 2015

Antivir Chem Chemother

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Background: The integrase inhibitors, raltegravir and dolutegravir, are nucleoside reverse transcriptase inhibitor-sparing agents which may be used as part of first-line antiretroviral therapy for HIV. These drugs inhibit creatinine secretion through organic cation transporters, thus elevating serum creatinine without affecting glomerular filtration. We sought to determine whether subtle signs of nephrotoxicity could be observed in mice administered a two-week regimen of highdose integrase inhibitors. Methods: C57BL/6 mice were fed standard water (CTRL, n ¼ 6), raltegravir-containing water (40 mg/kg/day, n ¼ 6), or dolutegravir-containing water (2.7 mg/kg/day, n ¼ 6) for two weeks and sacrificed. Endpoints were assessed including urine microalbumin, kidney injury molecule-1 renal tissue gene expression, renal histopathology, serum creatinine, and blood urea nitrogen. Results: The results are NOT consistent with a direct nephrotoxic effect of the integrase inhibitors in mice. Serum creatinine was significantly elevated in raltegravir and dolutegravir mice (p < 0.05) compared to control (raltegravir ¼ 0.25 mg/dl, dolutegravir ¼ 0.30 mg/dl versus CTRL ¼ 0.17 mg/dl). Blood urea nitrogen, cystatin C, and urine microalbumin were unchanged. Kidney injury molecule-1 tissue expression in raltegravir and dolutegravir groups was nonsignificantly elevated compared to control (1.2-fold compared to control). Renal histopathology by periodic acid-Schiff staining failed to reveal glomerular or tubular renal injury in any group. Conclusion: These studies are consistent with integrase inhibitors competitively inhibiting creatinine secretion. While no evidence of direct nephrotoxicity was observed after two weeks of high-dose drug administration, additional studies may be performed to understand whether these drugs lead to chronic nephropathy.

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Early onset of autoimmune disease by the retroviral integrase inhibitor raltegravir

Cited by 38 publications

References 53 publications

Inhibition of Xenotropic Murine Leukemia Virus-Related Virus by APOBEC3 Proteins and Antiviral Drugs

Inhibition of Xenotropic Murine Leukemia Virus-Related Virus by APOBEC3 Proteins and Antiviral Drugs

Differential Sensitivities of Retroviruses to Integrase Strand Transfer Inhibitors

A two-week regimen of high-dose integrase inhibitors does not cause nephrotoxicity in mice

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