Abstract
Analysis of HIV-1 gene sequences sampled longitudinally from infected individuals can reveal the evolutionary dynamics that underlie associations between disease outcome and viral genetic diversity and divergence. Here we extend a statistical framework to estimate rates of viral molecular adaptation by considering sampling error when computing nucleotide site-frequencies. This is particularly beneficial when analyzing viral sequences from within-host viral infections if the number of sequences per time point is limited. To demonstrate the utility of this approach, we apply our method to a cohort of 24 patients infected with HIV-1 at birth. Our approach finds that viral adaptation arising from recurrent positive natural selection is associated with the rate of HIV-1 disease progression, in contrast to previous analyses of these data that found no significant association. Most surprisingly, we discover a strong negative correlation between viral population size and the rate of viral adaptation, the opposite of that predicted by standard molecular evolutionary theory. We argue that this observation is most likely due to the existence of a confounding third variable, namely variation in selective pressure among hosts. A conceptual non-linear model of virus adaptation that incorporates the two opposing effects of host immunity on the virus population can explain this counterintuitive result.
Highlights
The molecular evolution and adaptation of the human immunodeficiency virus (HIV) within infected individuals is exceptionally fast
Positive natural selection during HIV infection has been typically inferred using dN/dS ratios [6, 7], as well as by methods based on allele frequency changes [7, 8], and these studies sometimes suggest that viral adaptation is associated with the time taken for disease symptoms to progress to AIDS [7, 8] or rate of immune escape [9]
The estimated rates varied significantly among patients, ranging from >0.03 adaptations/codon/year in two patients to zero in six patients. These rates are similar in magnitude to comparable estimates for nine adult HIV-1 infections, obtained from a 300 nt stretch of the C2-V3 region of the HIV-1 env gene [12]
Summary
The molecular evolution and adaptation of the human immunodeficiency virus (HIV) within infected individuals is exceptionally fast. This evolution is generated by a combination of high rates of mutation and recombination, large population sizes and short generation times, and has important consequences for the outcome and treatment of HIV infection [1]. Positive natural selection during HIV infection has been typically inferred using dN/dS ratios [6, 7], as well as by methods based on allele frequency changes [7, 8], and these studies sometimes suggest that viral adaptation is associated with the time taken for disease symptoms to progress to AIDS [7, 8] or rate of immune escape [9]. Williamson [12] introduced a method to estimate an absolute rate of viral molecular adaptation, and reported that the C2-V5 region of the HIV env gene undergoes approximately 3 adaptive fixations per year during infection
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