Within-host evolution of HIV and population genetics of rapid adaptation


Richard Neher
Biozentrum, University of Basel


slides at neherlab.org/201802_IST.html

Evolution of HIV


  • Chimp → human transmission around 1900 gave rise to HIV-1 group M
  • ~100 million infected people since
  • subtypes differ at 10-20% of their genome
  • HIV-1 evolves ~0.1% per year
image: Sharp and Hahn, CSH Persp. Med.

HIV infection

  • $10^8$ cells are infected every day
  • the virus repeatedly escapes immune recognition
  • integrates into T-cells as latent provirus
image: wikipedia

HIV-1 evolution within one individual



silouhette: clipartfest.com, Zanini at al, 2015. Collaboration with Jan Albert and his group


Population sequencing to track all mutations above 1%

Zanini et al, eLife, 2015; antibody data from Richman et al, 2003

Diversity and hitchhiking

  • envelope changes fastest, enzymes lowest
  • identical rate of synonymous evolution
  • diversity saturates where evolution is fast
  • synonymous mutations stay at low frequency
Zanini et al, eLife, 2015

Mutation rates and diversity at neutral sites

Zanini et al, Virus Evolution, 2017

Frequent reversion of previously beneficial mutations

  • HIV escapes immune systems
  • most mutations are costly
  • humans selects for different mutations
  • compensation or reversion?
Zanini et al, eLife, 2015

Inference of fitness costs

  • mutation away from preferred state with rate $\mu$
  • selection against non-preferred state with strength $s$
  • variant frequency dynamics: $\frac{d x}{dt} = \mu -s x $
  • equilibrium frequency: $\bar{x} = \mu/s $
  • fitness cost: $s = \mu/\bar{x}$

Inference of fitness costs

  • Frequencies of costly mutations decorrelate fast $\frac{d x}{dt} = \mu -s x $
  • $\Rightarrow$ average many samples to obtain accurate estimates
  • Assumption: The global consensus is the preferred state
  • Only use sites that initially agree with consensus
  • Only use sites that don't chance majority nucleotide

Fitness landscape of HIV-1

Zanini et al, Virus Evolution, 2017

Selection on RNA structures and regulatory sites

Zanini et al, Virus Evolution, 2017

The distribution of fitness costs

Zanini et al, Virus Evolution, 2017

Fitness variation in rapidly adapting populations

RN, Annual Reviews, 2013; Desai & Fisher; Brunet & Derride; Kessler & Levine

Neutral/Kingman coalescent

strong selection

Bolthausen-Sznitman Coalescent

RN, Hallatschek, PNAS, 2013; see also Brunet and Derrida, PRE, 2007; Desai, Walczak, Fisher, Genetics, 2013

Traveling waves and the Bolthausen-Snitman coalescent

  • Branching process approximation: $P(n_i, t|x_i)$
  • Does a sample (blue dots) have a common ancestor $\tau$ generations ago?
    $\quad Q_b = \langle \sum_i \left(\frac{n_i}{\sum_j n_j}\right)^b\rangle \approx \frac{\tau-T_c}{T_c(b-1)} $
  • All other merger rates are also consistent with the Bolthausen-Sznitman coalescent:
    $\quad\lambda_{b,k} = \frac{(k-2)!(b-k)!}{T_c (b-1)!}$
RN, Hallatschek, PNAS, 2013; see also Brunet and Derrida, PRE, 2007

U-shaped polarized site frequency spectra



RN, Hallatschek, PNAS, 2013

Universality -- adaptation and deleterious mutations




RN, Hallatschek, PNAS, 2013
Zanini et al, eLife, 2016

Extension to sexual populations


  • $T_{MRCA}$ determined by $\sigma_b$
  • Block length $\zeta_b$ is determined by $T_{MRCA}$
  • Fitness variation $\sigma_b$ is determined by block length
→ self-consistent solution required
RN, Kessinger, Shraiman PNAS, 2013

$T_{MRCA}$ and SFS



RN, Kessinger, Shraiman PNAS, 2013
  • Fitness diversity in block: $\sigma_b = \frac{\mu \langle s^2\rangle}{2\rho}$
  • Qualitative change behavior around $N\sigma_b$
  • Total rate of adaptation: $\sim L\sqrt{\rho \mu \langle s^2\rangle \log N}$

Bursts in a tree ↔ high fitness genotypes

Can we read fitness of a tree?



  • Influenza virus evolves to avoid human immunity
  • Vaccines need frequent updates

Predicting evolution

Given the branching pattern:

  • can we predict fitness?
  • pick the closest relative of the future?
RN, Russell, Shraiman, eLife, 2014

Fitness inference from trees

$$P(\mathbf{x}|T) = \frac{1}{Z(T)} p_0(x_0) \prod_{i=0}^{n_{int}} g(x_{i_1}, t_{i_1}| x_i, t_i)g(x_{i_2}, t_{i_2}| x_i, t_i)$$
RN, Russell, Shraiman, eLife, 2014

Validate on simulation data

  • simulate evolution
  • sample sequences
  • reconstruct trees
  • infer fitness
  • predict ancestor of future
  • compare to truth
RN, Russell, Shraiman, eLife, 2014

Validation on simulated data

RN, Russell, Shraiman, eLife, 2014

Prediction of the dominating H3N2 influenza strain

  • no influenza specific input
  • how can the model be improved? (see model by Luksza & Laessig)
  • what other context might this apply?
 RN, Russell, Shraiman, eLife, 2014

Summary

  • RNA virus evolution can be observed directly
  • Extensive reversion to preferred amino acid sequence
  • Rapidly adapting population require new population genetic models
  • Those model can be used to infer fit clades
  • Future influenza population can be anticipated
  • Automated real-time analysis can help fight the spread of disease

HIV acknowledgments

  • Fabio Zanini
  • Jan Albert
  • Johanna Brodin
  • Christa Lanz
  • Göran Bratt
  • Lina Thebo
  • Vadim Puller

Influenza and Theory acknowledgments

  • Boris Shraiman
  • Colin Russell
  • Trevor Bedford
  • Oskar Hallatschek

nextstrain.org

  • Trevor Bedford
  • Colin Megill
  • Pavel Sagulenko
  • Sidney Bell
  • James Hadfield
  • Wei Ding