Abstract
Replication of retroviral and host genomes requires ribonucleotide reductase to convert rNTPs to dNTPs, which are then used as substrates for DNA synthesis. Inhibition of ribonucleotide reductase by hydroxyurea (HU) has been previously used to treat cancers as well as HIV. However, the use of HU as an antiretroviral is limited by its associated toxicities such as myelosuppression and hepatotoxicity. In this study, we examined the ribonucleotide reductase inhibitor, gemcitabine, both in cell culture and in C57Bl/6 mice infected with LP-BM5 murine leukemia virus (LP-BM5 MuLV, a murine AIDS model). Gemcitabine decreased infectivity of MuLV in cell culture with an EC50 in the low nanomolar range with no detectable cytotoxicity. Similarly, gemcitabine significantly decreased disease progression in mice infected with LP-BM5. Specifically, gemcitabine treatment decreased spleen size, plasma IgM, and provirus levels compared to LP-BM5 MuLV infected, untreated mice. Gemcitabine efficacy was observed at doses as low as 1 mg/kg/day in the absence of toxicity. Higher doses of gemcitabine (3 mg/kg/day and higher) were associated with toxicity as determined by a loss in body mass. In summary, our findings demonstrate that gemcitabine has antiretroviral activity ex vivo and in vivo in the LP-BM5 MuLV model. These observations together with a recent ex vivo study with HIV-1[1], suggest that gemcitabine has broad antiretroviral activity and could be particularly useful in vivo when used in combination drug therapy.
Highlights
Retroviruses are a significant source of morbidity and mortality worldwide
There are 33 million people infected with human immunodeficiency virus type 1 (HIV-1) whereas the retrovirus, xenotropic murine leukemia virus like-virus (XMRV), has recently been proposed to be linked to prostate cancer and chronic fatigue syndrome (CFS) [2,3]
We examined the ability of gemcitabine to inhibit replication of another retrovirus, murine leukemia virus in cell culture
Summary
Retroviruses are a significant source of morbidity and mortality worldwide. For example, there are 33 million people infected with human immunodeficiency virus type 1 (HIV-1) whereas the retrovirus, xenotropic murine leukemia virus like-virus (XMRV), has recently been proposed to be linked to prostate cancer and chronic fatigue syndrome (CFS) [2,3]. There are a number of drugs available for HIV-1 chemotherapy, the efficacy of these treatments is limited by the emergence of drug resistance, cost of treatment, and off-target effects. These limitations necessitate the development of new drugs and novel drug targets for HIV as well as other retroviruses. If XMRV is shown to be the etiological agent of either prostate cancer and/or CFS, the development of new drugs could reduce morbidity and mortality. Drugs that target host proteins could delay or prevent the emergence of drug resistance, there are significant side effects associated with inhibiting host proteins. While cellular deoxynucleoside triphosphates (dNTPs) are necessary for host cell function, even small changes in dNTP pools appear to affect viral replication without significant cellular toxicity [4]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
