HIV has a high mutation rate, a generation time of about two days, and different viruses within a patient recombine their genetic material frequently. This combination of factors allows HIV to evolve very rapidly and evade the human immune system to establish a persistent infection. If treated with antiviral drugs, resistance can emerge rapidly. The diversity of the viral population within a single patient reaches a few percent in certain parts of the HIV genome, which exceeds the divergence between human and chimp. Understanding the evolution of the virus is central to developing vaccines and to minimize drug resistant. In addition, HIV provides an ideal model system in which fundamental questions of evolution can be addressed. In contrast to most other model systems of evolution, time series data is available for HIV evolution which is much more informative about the evolutionary process than the snap shot typical of less rapidly evolving populations.
Whole-genome deep sequencing of HIV-1
We performed whole-genome deep sequencing of HIV-1 populations in 9 untreated patients, with 6-12 longitudinal samples per patient spanning 5-8 years of infection. This work was led by Fabio and is the product of a fantastic collaboration with the group of Jan Albert at the Karolinska Institute in Stockholm.
We show that one third of common mutations are reversions towards the ancestral HIV-1 sequence which occur throughout infection with a rate that increases with conservation. Patterns of minor diversity are reproducible between patients and mirror global HIV-1 diversity, suggesting a universal landscape of fitness costs that control diversity. Frequent recombination limits linkage disequilibrium to about 100bp. However, hitch-hiking due to the remaining short range linkage causes levels of synonymous diversity to be inversely related to the speed of evolution.
Population genomics of intrapatient HIV-1 evolution.
Fabio Zanini, Johanna Brodin, Lina Thebo, Christa Lanz, Göran Bratt, Jan Albert, Richard A. Neher
In the arms raise with the immune system, the viral proteins evolve rapidly to avoid recognition by T-cells and antibodies. Synonymous mutations, on the other hand, do not change the amino acid sequence of the viral proteins and are often assumed to be of no evolutionary consequence. In this article, we show that many synonymous mutations incur a slight fitness cost for the virus; this cost is partly due to disruption of RNA structures in the HIV genome. We show that these deleterious mutations “hitch-hike” to high frequency with beneficial mutations before being pruned by selection. We infer the strength of selection against synonymous mutations as well as the frequency, strength and nature of selection by the immune system.
The evolution of non-coding features of the HIV genome (translation efficiency, RNA structures etc) is rather poorly understand — mainly because we do not know what to look for. There is much to be discovered.
Quantifying selection against synonymous mutations in HIV-1 env evolution.
Fabio Zanini, Richard A. Neher. Journal of Virology
HIV evading the immune system: CTL escape
In the early stages of infection, HIV is under relentless attack by cytotoxic T lymphocytes (CTLs), which induce apoptosis in infected CD4+ cells that express viral protein fragments on their surfaces. The virus therefore experiences strong selective pressure favoring mutations that reduce the ability of CTLs to recognize infected cells. Accurate estimates of the “escape rate” of such mutations, a parameter that characterizes the advantage they convey in evading CTLs, are therefore important in describing the strength and ferocity of the early immune response. To this end, we have developed a model for estimating escape rates. Whereas previous methods assumed that many escape mutations could sweep simultaneously, we model clonal interference between different escape mutations. This results in substantially higher escape rate estimates. The method is remarkably robust under a variety of parameter ranges and produces results consistent with simulations. It should also be applicable to experimental evolution or studies of cancer evolution.
Mathematical modeling of escape of HIV from cytotoxic T lymphocyte responses
Vitaly Ganusov, Richard Neher, Alan Perelson. JSTAT 2013 (01), P01010
Inferring HIV escape rates from multi-locus genotype data
Taylor A. Kessinger, Alan S. Perelson and Richard A. Neher. Front. Immunol. 4:252. doi: 10.3389/fimmu.2013.00252
HIV recombination rate
Evolution, in viruses and other organisms, is the result of random genetic diversification by mutation or recombination and selection for survival. HIV evolves rapidly enough that substantial evolution is observable during a chronic HIV infection within single patients. Using such time series data of evolution, we estimate the effective recombination rate of HIV (the rate of viral sex) to be similar to the mutation rate, rather than much larger as previously reported. The key idea of our estimate is to observe how rapidly double mutants between sites at different distance on the genome (see sketch on the left). The distance dependence is unique to recombination and allows us to disentangle the contribution of recombination from that of recurrent mutation. Knowledge of the recombination rate and the strength of selection is essential for quantitative modeling and understanding of HIV evolution. Our estimate from 2010 has since been confirmed in several experimental and theoretical studies from the Coffin lab.
Recombination Rate and Selection Strength in HIV Intra-patient Evolution
Richard Neher and Thomas Leitner. PLoS Comput Biol 6, no. 1: e1000660.