A cautiously optimistic essay about HIV drug resistance

From Pleuni Pennings:

… overall, drug resistance is not as big a problem as one may think. Treatments have become very good, which means that the rate of evolution of drug resistance is low. At the same time, many new drugs have become available so that when drug resistance evolves, the patient can be switched to another set of drugs. However, in poor countries, where viral genotyping, viral load monitoring and many new drugs are not available, drug resistance still poses a serious threat to people’s health.

The blog post is here, and the paper (on arXiv, soon to be published at Infectious Disease Reports) is here.

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Looking at HIV’s genome tells us how to fight drug resistance

HIV infection in macrophages (from http://www.flickr.com/photos/thejcb/4037334339/ -- CC by-nc-sa 3.0 license)

I learned a couple of cool things about HIV recombination recently:

1) There are recombination hotspots in the HIV genome.  When two viral genomes cohabit in the same virus capsid, their “offspring” virus will inherit a bit from each parent.  A hotspot is a likely location for genetic crossover: If the offspring has genetic material from parent “A” upstream of a hotspot, then it is particularly likely to have genetic material from parent “B” downstream of a hotspot.  I learned about this issue from Atila Iamarino, whose team in São Paulo has been chasing down new recombinant strains in Brazil, which seem to be popping up despite the spread of antiretroviral therapy.

The existence of hotspots in HIV is not surprising, as recombination hotspots show up in many species when people have searched for them…

2) … But knowing about these hotspots might give us some clues about ways to slow down the evolution of resistance.  Many people discuss drug resistance as if it were an on-or-off switch — either a bug is resistant or it ain’t.  This hasty approximation has caught on because of its clinical convenience: if you are a doctor treating a patient, then you want to know, simply: Do I use this drug or not?  Yes or no?  At the point of care, a complicated or nuanced answer is not helpful.  But one of the benefits of being a non-clinical researcher is that I can take a step back from the point of care and think about the broader picture, which includes viral evolution.  Imagine a drug where resistance is a sliding scale: a single mutation may confer weak resistance, but as the number of mutations increases, it becomes harder to use the drug successfully (e.g., a patient will need to be very careful about taking 100% of their pills, or will need to switch drugs).  Say that one lucky virus within a treated person has just evolved three resistance mutations; this bug is now a major threat to continued treatment success.  If the three mutations are far apart on the genome — especially if recombination hotspots lie between them — then it is quite likely for recombination to break up those resistance mutations when the virus pairs with the typical, nonresistant virus, and so its viral offspring will have fewer resistance mutations.  Recombination hotspots can actually prevent the growth of resistance, so it is a good idea to choose drugs (or combinations of drugs) in which the “killer” resistance mutations are spread far apart on the genome and have hotspots separating them.

There are caveats — and there are cases where recombination could work in the opposite direction, causing strongly drug-resistant viruses to persist in a patient for a long time, after they have spread widely — but the above story is the one best supported by the modeling literature so far.