Re: Re: Drug found effective against XMRV virus in study

[Guest guest]

AZT inhibits XMRV

by Racaniello on 8 December 2009

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, Tnofovir, 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 ï¬rst 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 ï¬rst 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