Day 55: Maintaning resistance

One of the fascinating aspects of HIV (and really all virology and microbiology) is the relationship between viral evolution and the selective pressures on the virus. HIV, like living creatures, adapts to its environment. If conditions are very harsh or not harsh at all, the viral population tends to be very uniform. In a very harsh environment, only viral particles with a very specific make-up may be able to spread; in the absence of these pressures, the viral particles that can replicate the fastest end up dominating the population. Somewhere in the middle, the viral population becomes diverse, with a number of different quasispecies or genetic variants. This is a key concept for antiviral therapy. Antiviral therapy needs to be stringent enough to place extremely harsh conditions on the virus. That’s why anti-HIV therapy needs to include three active drugs. 

Now, if the selective pressure on the virus during antiviral therapy lessens, which can happen for several reasons (not the least of which is non-adherence to a regimen), the virus can replicate and a viral variant will emerge that can replicate in the less harsh environment. In common terms, this is called resistance development. For useful drugs, there are usually only a few viral variants that can survive in these conditions. These viral variants may have to sacrifice certain advantages they would normally have to replicate under a moderate selective pressure. Often, they don’t replicate as well as normal virus (called wild-type) does in the absence of selective pressure. So, you get a scenario where it is believed that a resistant virus replicates alright when the drug is around, but not quite as well as a wild-type virus does in the absence of drug. 

This may have clinical importance. If the rate a viral variant replicates (called the replicative capacity) is slower, does that mean that a person carrying this variant as the predominant quasispecies will have a slower disease progression? Well, several studies have suggested that this is the case, but unfortunately it is difficult to determine how fast a viral variant replicates in the body. Outside of the body, yes, you can determine this rate, but no one knows if what happens outside the body is true in the body. Now, if the answer to the above question is “yes”, it would argue that for certain antiretrovirals, the development of resistance should not necessarily mean that drug is no longer a useful component of ant-HIV therapy. The idea is to maintain selective pressure on the virus and keep the predominant variant a person carries less fit than the wild-type virus, hopefully delaying disease progression. 

Recently in the Journal of Medical Virology, Gianotti and colleagues looked at the replicative capacity of HIV from people on lamivudine (3TC) monotherapy who have 3TC-associated resistance mutations (the methionine-to-valine switch at position 184 in reverse transcriptase, noted as M184V). Now, since you can’t measure the replicative capacity in the body, the authors looked at ex vivo samples from patients with the M184V mutation, comparing variants at 24 and 48 weeks from patients on 3TC monotherapy to patients who had stopped all therapy. What the authors found was that virus from patients who maintained their resistance mutations had reduced replicative capacity compared with those who “lost” these mutations (note: you don’t really lose these mutations, they just become a minority population while another variant takes over the majority role). Furthermore, those patients who lost the mutations had greater reductions in their CD4/CD8 T cell ratio. 

The study is important because it helps tie the reduced fitness hypothesis to what is observed in the clinic. This strategy of maintaining drugs to keep the viral replicative capacity down may help extend the options for patients who have been through several treatment options or those who have difficulty with adherence (provided they already have the M184V mutation). Of course drug companies also love this stuff because it suggests that some patients should stay on their meds, even after the development of resistance. There are necessary questions to answer; such as, is it really worth staying on these drugs for the reduced replicative capacity? Antiviral therapy is not without side effects and cost. However, now that there has been at least a preliminary link between reduced viral fitness and an immunologic parameter, the answer appears to be headed in the affirmative. Whether this holds for drugs other than 3TC remains to be determined. 

M. Linde