Tag Archives: HIV

Fitness cost paper on bioRxiv

27 Jun

A little while ago we published a new manuscript on fitness costs on the bioRxiv. I’m very excited about this paper, because it is on a new topic for me (fitness costs) and we found some exciting results (for example, I never expected to find that CpG sites were so costly for HIV).

I am also excited about the paper because it is the first paper from my lab at SFSU and it is the first paper that resulted from our collaboration with Adi Stern in Tel Aviv.

The work was done by Marion Hartl (SFSU), Kristof Theys (University of Leuven and SFSU), Alison Feder (Stanford), Maoz Gelbart (University of Tel Aviv), Adi Stern (University of Tel Aviv) and myself.

F2-modeled_sels

Fig 2 from the manuscript. Selection coefficients for transitions at every nucleotide site in the pol sequence show that CpG-forming mutations are more costly than non-CpG-forming mutations and that mutations that involve a drastic amino acid change are more costly than mutations that do not.
Selection coefficients were estimated using a generalized linear model and sequence data from 160 HIV-infected patients. Shown are predicted selection coefficients for synonymous (left) and non-synonymous (right) mutations that do not involve a drastic amino acid change and either create CpG sites (green) or do not (orange). For non-synonymous mutations, predictions are also shown for mutations that do involve drastic amino acid changes and either create CpG sites (pink) or do not (blue).

 

 

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eLife paper and video on how HIV treatments affect selective sweeps

15 Feb

Very happy to announce that we have a new paper out and an accompanying video! The paper is about how effective treatments lead to (few) hard selective sweeps and bad treatments lead to soft selective sweeps.

The paper can be found here on the eLife website, but I suggest starting with the video that Alison Feder made.

 

Paper details

Title: More effective drugs lead to harder selective sweeps in the evolution of drug resistance in HIV-1.

Authors: Alison F Feder, Soo-Yon Rhee, Susan P Holmes, Robert W Shafer, Dmitri A Petrov, Pleuni S Pennings

DOI: http://dx.doi.org/10.7554/eLife.10670

Abstract: In the early days of HIV treatment, drug resistance occurred rapidly and predictably in all patients, but under modern treatments, resistance arises slowly, if at all. The probability of resistance should be controlled by the rate of generation of resistance mutations. If many adaptive mutations arise simultaneously, then adaptation proceeds by soft selective sweeps in which multiple adaptive mutations spread concomitantly, but if adaptive mutations occur rarely in the population, then a single adaptive mutation should spread alone in a hard selective sweep. Here, we use 6717 HIV-1 consensus sequences from patients treated with first-line therapies between 1989 and 2013 to confirm that the transition from fast to slow evolution of drug resistance was indeed accompanied with the expected transition from soft to hard selective sweeps. This suggests more generally that evolution proceeds via hard sweeps if resistance is unlikely and via soft sweeps if it is likely.

 

New paper, new videos!

31 Dec

With Ben Wilson, Nandita Garud, Alison Feder and Zoe Assaf, I wrote a review paper about population genetics and drug resistance. It was a lot of fun to write this paper and I feel like I learned a lot during the process.

We wrote about drug resistance in influenza, malaria, TB, MRSA and HIV. It turns out that each of these case studies have something unique to teach us about evolution.

The paper is now out in Molecular Ecology. You can also download it here: 2015Wilson_et_al-Molecular_Ecology.

We made five short movies about the paper. Have a look at the one you are most interested in!

Nandita Garud on using genome scans to find resistance loci in malaria

MolEcolNandita from Pleuni Pennings on Vimeo.

Ben Wilson on the role of epistasis in resistance in Influenza

BenMolEcol from Pleuni Pennings on Vimeo.

Pleuni Pennings on standing genetic variation in HIV

MolEcol from Pleuni Pennings on Vimeo.

Alison Feder on clonal interference in TB

MolEcolAlison from Pleuni Pennings on Vimeo.

Zoe Assaf on the origins of the SCCmec element that causes methicillin resistance

MolEcolZoe from Pleuni Pennings on Vimeo.

Review paper on HIV drug resistance is out

17 Jun

My review paper on HIV drug resistance for Infectious Disease Reports is out (see here). It is part of a special issue entitled “Current perspectives in HIV/AIDS“. You can download the paper here: Pennings2013IDR

Abstract: Access to combination antiretroviral treatment (ART) has improved greatly over recent years. At the end of 2011, more than eight million HIV-infected people were receiving ART in low-income and middle-income countries. ART generally works well in keeping the virus suppressed and the patient healthy. However, treatment only works as long as the virus is not resistant against the drugs used. In the last decades, HIV treatments have become better and better at slowing down the evolution of drug resistance, so that some patients are treated for many years without having any resistance problems. However, for some patients, especially in low-income countries, drug resistance is still a serious threat to their health. This essay will review what is known about transmitted and acquired drug resistance, multi-class drug resistance, resistance to newer drugs, resistance due to treatment for the prevention of mother-to-child transmission, the role of minority variants (low-frequency drug-resistance mutations), and resistance due to pre-exposure prophylaxis.

IDRpaper

Essay on HIV drug resistance published on the arXiv

26 Nov

A few days ago, I submitted a review paper to Infectious Disease Reports. The review is an invited essay for the special issue they are planning around the World AIDS Day (December 1st).

I was pleasantly surprised to see that the author guidelines of Infectious Disease Reports said: “Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work.” So, I decided to upload the manuscript to the arXiv.

The essay describes the current situation of drug resistance in HIV. The main conclusion is that, 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.

In the essay, I explain that transmitted drug resistance occurs, but at a level that is lower than many would have expected. Roughly 10% of newly infected patients are infected with an HIV strain with at least one major drug-resistance mutation. If the virus is genotyped before treatment is started (as is standard in rich, but not in poor, countries), then treatment success is very high for these patients.

Acquired drug resistance (when resistance evolves during treatment) is more common than transmitted drug resistance, and resistance can evolve even after many years of successful treatment. It can also happen that the virus becomes resistant against multiple drugs. Nowadays, there are many different drugs available, so that even patients with multi-class drug resistance can often be treated successfully, although this is not the case in poor countries, simply because the newer drugs are expensive.

I also describe what is known about resistance due to treatment for the prevention of mother-to-child-transmission (which is a big problem) and resistance due to pre-exposure prophylaxis (which occurs, but is uncommon). I also discuss the issue of low-frequency resistance mutations and their clinical relevance. Throughout the essay, I explain how certain effects are expected or surprising from an evolutionary perspective.

I thank my collaborators Daniel Rosenbloom and Alison Hill (both at Harvard) for useful comments on an earlier version of the manuscript.

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