Virus evolution and the spread of infectious disease


Richard Neher
Biozentrum, University of Basel


slides at neherlab.org/201812_Virology.html

Human Influenza A viruses

slide by Trevor Bedford

Weekly numbers of positive influenza tests in the US by subtype

Data by the US CDC

Influenza virus

  • Surface proteins hemagglutinin (HA) and neuraminidase (NA)
  • Influenza A virus
    • Common in birds and mammals
    • Many different subtypes defined by surface proteins
    • H3N2, H1N1, H7N9, H5N1
  • Influenza B virus
    • infects mainly humans
    • two lineages that split 30-40y ago
    • B/Victoria vs B/Yamagata


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

Vaccine selection time line


Slide by Trevor Bedford

Tracking virus spread and evolution by sequencing

A/Brisbane/100/2014
GGATAATTCTATTAACCATGAAGACTATCATTGCTTT...

A/Brisbane/1000/2015
GGATAATTCTATTAACCATGAAGACTATTATTGCTTT...

A/Brisbane/1/2017
GGATAATTCTATTAACCATGAAGACTATCATTGCTTT...

... thousands of sequences...

Phylogenetic analysis of viral sequences

RNA viruses have a high mutation rate. New mutations arise every few weeks.

nextflu.org

joint work with Trevor Bedford & his lab

Hemagglutination Inhibition assays

Slide by Trevor Bedford

HI data sets

  • Long list of distances between sera and viruses
  • Tables are sparse, only close by pairs
  • Structure of space is not immediately clear
  • MDS in 2 or 3 dimensions
Smith et al, Science 2002
Slide by Trevor Bedford

Antigenic evolution

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-SIV phylogeny

wikipedia.org

What makes these viruses so good at evolving?

High mutation rates


viralzone.expasy.org

Large population sizes

  • Within a chronically infected person, HIV infects $10^8$ cells a day
  • Influenza viruses infects $10^8$ humans a year
  • every infected cell produces 1000s of virions
  • → every possible mutation is produced many times every day

Recombination

Influenza Virus

viralzone.expasy.org
HIV

HIV-1 evolution within one individual


  • Viruses rapidly diversify
    swarm or quasi-species
  • Different tissues can harbor different viral variants
  • diversity depends on duration of infection
  • number of founder variants
  • immune selection
silouhette: clipartfest.com

Drug resistance evolution

Drug targets
  • Reverse transcriptase (NRTI and NNRTI)
  • Protease inhibitors
  • Integrase inhibitors
  • Entry inhibitors
Resistance evolution
  • Every mutations pre-exists → mono-therapy fails
  • Combination therapy requires multiple mutations to become resistant
  • Sufficiently high 'barrier to resistance' results in long-term suppressive therapy
Hedgkog et al, PLOS One, 2010

Sequence evolution vs phenotypic evolution

  • RNA viruses change rapidly under consistent selection pressure
  • Rapid immune escape or drug resistance in HIV or influenza
  • BUT: most mutations are deleterious
  • AND: most observed changes have no clear phenotype

Case in point: "the microcephaly mutation" in Zika

  • Weak evidence that a particular mutation facilitates spread of Zika virus in mouse brains
  • Media trumpets: "microcephaly causing mutation" found
  • Zika virus strains in India lack this mutations
    → authorities claim: Zika not a problem
  • see Open-Ed by Nathan Grubaugh for a good discussion

Development of sequencing technologies

We can now sequence...
  • thousands of bacterial isolates
  • thousands of single cells
  • populations of pathogens, metagenomics
Sequences allow us to reconstruct at great detail how viruses change and spread
But the link between genotype and phenotype is far from being understood.