integrase

Xenotropic murine leukemia virus related virus (XMRV) has been implicated in prostate cancer and chronic fatigue syndrome (CFS). Because XMRV is a retrovirus, it has been suggested that it might be susceptible to some of the many drugs available for treatment of AIDS. Of ten licensed compounds evaluated for activity against XMRV, just one, AZT (azidothymidine), was found to inhibit viral replication.

Compounds used to treat HIV-1 infection fall into distinct classes: protease inhibitors (Ritonavir, Saquinavir, or Indinavir), nucleoside reverse transcriptase inhibitors (NRTI, AZT, 3TC, Tenofovir, D4T), non-nucleoside reverse transcriptase inhibitors (NNRTI, Efavirenz, Nevirapine), integrase inhibitors (118-D-24), and fusion inhibitors (Maraviroc). None of the HIV-1 protease inhibitors, NNRTI, or integrase inhibitors blocked XMRV replication.  Of the NRTIs, only AZT significantly inhibited viral replication. Fusion inhibitors were not examined in this study.

AZT was the first drug licensed to treat AIDS. It is phosphorylated to the active form by cellular enzymes. Phosphorylated AZT is an inhibitor of viral reverse transcriptase because it acts as a chain terminator when incorporated into DNA:

Because AZT has a N3 (azido) group on the ribose instead of a hydrogen, the next base cannot be added to the DNA chain and synthesis stops.

The relative selectivity of this drug depends on the fact that reverse transcription takes place in the cytoplasm, where the drug appears first and in the highest concentration. But the presence of AZT monophosphate causes depletion of the intracellular pool of ribosylthymine 5′-triphosphate (TTP). Therefore AZT has substantial side effects which include muscle wasting, nausea, and severe headaches. AZT treatment can also damage bone marrow, which requires multiple transfusions of red blood cells. The drug was used extensively because there was no alternative until other antivirals were developed.

AZT can be taken orally but it is degraded rapidly by liver enzymes. Patients must take the drug two or three times a day to maintain an effective antiviral concentration. The drug is modestly effective in infected adults, leading to a transient increase in CD4+ T-cell counts.

Much effort has been devoted to discovering alternatives to AZT, and several nucleoside analogs that have therapeutic value, such as 3TC, are available. However 3TC does not inhibit XMRV replication.

It is not known if treatment with AZT will effect either prostate cancer or CFS. If prostate cancer is triggered when XMRV inserts into chromosomal DNA, then the drug will not likely block progression of the disease because the drug does not eliminate infected cells. Whether reduction of viral loads by AZT treatment has a positive therapeutic outcome remains to be determined. Because AZT is approved for use in humans, such studies can proceed immediately, without the need for extensive toxicity studies in animals.

Sakuma R, Sakuma T, Ohmine S, Silverman RH, & Ikeda Y (2009). Xenotropic murine leukemia virus-related virus is susceptible to AZT. Virology PMID: 19959199