All antiretroviral drugs work by stopping replication of new virus that can spread and infect uninfected cells. Currently, we have entry inhibitors (block HIV from binding or entering the CD4 cell), reverse transcriptase inhibitors (two classes of drugs: nucleoside and non-nucleoside), integrase inhibitors (block integration of viral DNA into the DNA of the cell) and protease inhibitors. HIV enters a CD4 cell, uses reverse transcriptase to convert single stranded viral RNA into double stranded DNA, uses integrase to integrate viral DNA into the cell genome, thus that cell now has integrated proviral DNA. When cell replication is turned on and viral polypeptides are manufactured from the integrated viral DNA, the viral protease cleaves the large peptide into smaller pieces of protein which are then assembled into a new virus that will then bud off the cell. Thus, new virus is produced and will seek out another cell to infect. Blockade at any of these enzymatic steps stops the process and that cell likely undergoes apoptosis.
We know from treating AIDS for 20 years, that inhibiting virus at several steps in its life cycle, using multiple drugs, is the way to go. HIV replicates quickly and has a high copy error rate resulting in mutations most of which do not convey an advantage. But when a mutation is superior, for example conveying drug resistance, the other drugs in the protocol, by keeping the copy rate low, prevent replication of that mutation. Experience has taught that combination therapy is definitely the way to go for HIV.
At this point, we have three studies (see links to Sakuma, Paprotka , Singh papers in Essential Reading). All three show that AZT inhibits XMRV in vitro. Two studies also show that raltegravir and tenofovir are inhibitory. In addition, the Singh study showed that all three 2 drug combinations of the three effective drugs are synergistic in vitro. HIV drug combinations can produce positive or negative synergies, so knowledge of likely combination synergies is very important. Unfortunately, the three available drugs that should work have not been tested together in vitro to see if further synergy occurs. Current starting HAART protocol is usually a triple cocktail, most commonly 2 NRTIs + a PI/NNRTI. We only have 3 drugs available, so we don’t have to think about the subtleties of which combinations are effective for HIV.
There is evidence that the virus is stable compared to HIV. It is possible that drug resistance will not be as much of a problem as it is with HIV. Because of the high prevalence of drug sensitivity in this patient population, I have heard of people thinking of taking doses of drugs that are not therapeutic for HIV. The Singh study showed that the drug concentrations to inhibit XMRV in vitro are somewhat higher than for HIV. Therefore, my personal decision is not to experiment with the doses. Also, the relatively slow progression of the disease should not lull us into complacency in my opinion. It’s a bad bug and should not be underestimated. We don’t know if the viral load may not be high in some tissues.
We don’t have a measure of viral load available to us, but nobody is thinking of treating anyone for XMRV who isn’t very sick. Current guidelines for HIV are to treat all symptomatic individuals. Asymptomatic individuals with a high viral load are left to physician discretion. The early credo of hit it early, hit it hard has given way to a more moderate approach to HIV infection, waiting for a certain viral load to be reached before treating, though I don’t know how much of this trend is financial.
I would like to add as a caution, that rapid suppression of HIV can produce an inflammatory immune reconstitution syndrome (IRIS). We have no way of knowing what will happen with treatment of XMRV. There has been some reasonable criticism of my letter on the CFS boards. I would like to state publicly that I am not advocating that anyone who is XMRV positive try HAART. That is a decision for an individual to reach with a prescribing doctor. I am only reporting my decision and the science and medicine that are informing my decisions.
There is also a rumor circulating that raltegravir will cause autoimmune problems to increase. The only evidence for this is that it causes autoimmunity in genetically susceptible MLV infected mice (see Beck-Engeser paper). If there were other drug choices that might have given me pause, but under the circumstances, raltegravir is the most potent inhibitor of XMRV that we have.
I started tenofovir this morning.