ABSTRACT
5-aza-cytidine (5-aza-C) has been shown to be a potent human immunodeficiency virus type 1 (HIV-1) mutagen that induces G-to-C hypermutagenesis by incorporation of the reduced form (i.e., 5-aza-dC, 5-aza-dCTP). Evidence to date suggests that this lethal mutagenesis is the primary antiretroviral mechanism for 5-aza-C. To investigate the breadth of application of 5-aza-C as an antiretroviral mutagen, we have conducted a comparative, parallel analysis of the antiviral mechanism of 5-aza-C between HIV-1 and gammaretroviruses - i.e., murine leukemia virus (MuLV) and feline leukemia virus (FeLV). Intriguingly, in contrast to the hallmark G-to-C hypermutagenesis observed with HIV-1, MuLV and FeLV did not reveal the presence of a significant increase in mutational burden, particularly that of G-to-C transversion mutations. The effect of 5-aza-dCTP on DNA synthesis revealed that while HIV-1 RT was not inhibited by 5-aza-dCTP even at 100 µM, 5-aza-dCTP was incorporated and significantly inhibited MuLV RT, generating pause sites and reducing the fully extended product. 5-aza-dCTP was found to be incorporated into DNA by MuLV RT or HIV-1 RT, but only acted as a non-obligate chain terminator for MuLV RT. This biochemical data provides an independent line of experimental evidence in support of the conclusion that HIV-1 and MuLV have distinct primary mechanisms of antiretroviral action with 5-aza-C. Taken together, our data provides striking evidence that an antiretroviral mutagen can have strong potency via distinct mechanisms of action among closely related viruses, unlinking antiviral activity from antiviral mechanism of action.
Subject(s)
Antiviral Agents/pharmacology , Azacitidine/analogs & derivatives , Cytidine Triphosphate/analogs & derivatives , HIV Infections/drug therapy , Leukemia, Experimental/drug therapy , Mutation/drug effects , Retroviridae Infections/drug therapy , Tumor Virus Infections/drug therapy , Animals , Azacitidine/pharmacology , Cats , Cytidine Triphosphate/pharmacology , HIV/drug effects , HIV Infections/virology , Humans , Leukemia Virus, Feline/drug effects , Leukemia Virus, Murine/drug effects , Leukemia, Experimental/virology , Mice , Mutagenesis , Mutagens , Retroviridae Infections/virology , Tumor Virus Infections/virology , Virus ReplicationABSTRACT
Feline leukemia virus (FeLV) is a gammaretrovirus that is a significant cause of neoplastic-related disorders affecting cats worldwide. Treatment options for FeLV are limited, associated with serious side effects, and can be cost-prohibitive. The development of drugs used to treat a related retrovirus, human immunodeficiency virus type 1 (HIV-1), has been rapid, leading to the approval of five drug classes. Although structural differences affect the susceptibility of gammaretroviruses to anti-HIV drugs, the similarities in mechanism of replication suggest that some anti-HIV-1 drugs may also inhibit FeLV. This study demonstrates the anti-FeLV activity of four drugs approved by the US FDA (Food and Drug Administration) at non-toxic concentrations. Of these, tenofovir and raltegravir are anti-HIV-1 drugs, while decitabine and gemcitabine are approved to treat myelodysplastic syndromes and pancreatic cancer, respectively, but also have anti-HIV-1 activity in cell culture. Our results indicate that these drugs may be useful for FeLV treatment and should be investigated for mechanism of action and suitability for veterinary use.
Subject(s)
Antiviral Agents/therapeutic use , Cat Diseases/virology , Leukemia Virus, Feline/drug effects , Retroviridae Infections/veterinary , Tumor Virus Infections/veterinary , Adenine/analogs & derivatives , Adenine/therapeutic use , Animals , Azacitidine/analogs & derivatives , Azacitidine/therapeutic use , Cat Diseases/drug therapy , Cats , Decitabine , Deoxycytidine/analogs & derivatives , Deoxycytidine/therapeutic use , Dose-Response Relationship, Drug , Leukemia, Feline/drug therapy , Organophosphonates/therapeutic use , Pyrrolidinones/therapeutic use , Raltegravir Potassium , Retroviridae Infections/drug therapy , Tenofovir , Tumor Virus Infections/drug therapy , GemcitabineABSTRACT
Antiretroviral drugs have saved and extended the lives of millions of individuals infected with HIV. The major classes of anti-HIV drugs include reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, and entry/fusion inhibitors. While antiretroviral drug regimens are not commonly used to treat other types of retroviral infections, there are instances where there is a perceived need for re-evaluation of the benefits of antiretroviral therapy. One case in point is that of feline leukemia virus (FeLV), an infection of companion felines. While vaccines exist to prevent FeLV infection and spread, they have not eliminated FeLV infection. For FeLV-infected felines and their human companions, antiretroviral therapy would be desirable and of practical importance if good options were available. Here, we discuss FeLV biology and current treatment options, and propose that there is a need for antiretroviral treatment options for FeLV infection. The comparative use and analysis of antiretroviral therapy can provide new insights into the mechanism of antiretroviral drug action.