Virus Evolution & Evolutionary Medicine

1. Virus Evolution & Evolutionary Medicine Jamaica Evolution Workshop November/December 2013

2. Evolutionary (Darwinian) Medicine • Diseases are not shaped by selection • But traits that leave the body vulnerable to disease are shaped by selection • From diseases to traits  Evolutionary Medicine • Since 1990 Nesseet al., 2012 & Ruhli and Henneberg 2013

3. …For traits that make bodies vulnerable to diseases Possible evolutionary explanations… • Constraints on what natural selection can do • Mismatch with environments • Trade-offs that leave traits suboptimal • Co-evolution with fast-evolving pathogens Nesseet al., 2012

4. Why we still remain vulnerable to infections? • Microbes evolve faster than primates do • They can have a generation every few hours • Our generation time is 40,000 times longer • Microorganisms can exchange genetic material • Approx. 8% of our genome is composed of viruses  cancers ?

5. What is a virus ? It is an agent that reproduces inside living cells

6. Central dogma DNA RNA Protein Genomes

7. Retrovirus Virus and disease: • HIV  AIDS • HTLV  Adult T-cell leukemia Characteristics: • Dimeric and single strand RNA • 7,000 – 11,000 bp • Reverse transcriptase

8. Structure of a typical retrovirus Genome(RNA) Capsid proteins Envelope proteins Nucleocapsid proteins Integrase Matrix protein Reverse transcriptase Protease Genome gag pro pol env

9. Endogenous RetroVirus (ERV) • Integrated into germ line • Provirus can be transmitted vertically from one host • generation to the next Vertical Horizontal Adapted from Weiss, 2006

10. Endogenous RetroVirus (ERV) • Integrated into germ line • Provirus can be transmitted vertically from one host • generation to the next • Distributed in a wide range of vertebrates

11. Integrated DNA provirus Accessory genes Accessory genes Accessory genes Accessory genes env gag pol pro LTR LTR ~ 7 – 12 kb Host genomic DNA Adapted from Gifford & Tristem, 2003

12. Jernet al. 2005

13. ERVs: on Good and Evil Dupressoiret al. 2012

14. ERVs: on Good and Evil Positive side: Expression of viral gene products as useful new genes Negative side: Potential for gene disruption or misexpression resulting from ERV integration Somatic spread of replicating virus leading to pathogenic consequences

15. Porcine Endogenous RetroVirus(PERV) • ERVs in the pig genome • Multiple copies in the genome • PERV-A, -B, -C and -E • Tissue types  expression of PERV mRNA

16. Concern for xenotransplantation But what is xenotransplantation ?

17. Transplantation The transplant of living organs or tissues from one part of the body to another or from one individual to another http://www.organtransplants.org/ http://optn.transplant.hrsa.gov/

18. Allotransplantation

19. The issue with allotransplantation http://optn.transplant.hrsa.gov/

20. Solution ? Xenotransplantation

21. Xenotransplantation Any procedure that involves the transplantation, implantation, or infusion into a human recipient of either Live cells, tissues, or organs from a nonhuman animal source or Human body fluids, cells, tissues or organs that have ex vivo contact with live nonhuman animal cells, tissues, or organs U.S. Food and Drug Administration, 2001

22. Xenotransplantation could solve the shortage of organ donors. Pigs are considered the first choice for xenografts.

23. Why use pigs ? (Why not monkeys ?) • Attain sexual maturity within 9 months • Slow to attain breeding maturity • Short gestation periods • Long gestation periods • Large litters of between 6-16 piglets • Usually have only a single offspring • Large-scale pig-breeding is highly feasible • Large-scale farming is difficult • Domestic pigs are not endangered • Chimpanzees are considered endangered • Adult pig organ size is compatible with adult humans

24. Difficulties … • Immunological rejection • Infection (zoonosis) The risk of Zoonosis… Any disease or infection that is naturally transmissible from vertebrate animals to humans and vice-versa

25. Zoonotic agent … • Virus can be efficiently transmitted with viable cellular grafts • Virus may be non-pathogenic in their animal host • But virus could cause serious disease in humans

26. So pigs harbor PERVs in their genomes … …Will PERVs jump to human genomes ? Pathogen-free conditions X vertically inherited pathogens

27. No evidence of PERV infection in humans H O W E V E R … Xenotransplantation requires immunosuppression Cross-species ? Influenza virus HIV

28. Do PERVs jump between the pig species ? 5 genera  18 species  Eurasia and Africa Desert warthog Domestic pig Bearded pig

29. What and how to test? Phylogenetic analyses: DNA of host and parasite Check if they are cospeciating Evidence of cross-species ?

30. The host phylogeny Common warthog Desert warthog Forest Hog Bush-pig Red river hog Javan warty pig Bearded pig Sulawesi warty pig Domestic pig Babirusa Gongoraet al., 2011

31. PERVs – The parasite phylogeny Sus African Eurasian Nascimento et al., 2011

32. Conclusions • Host and viral phylogenies are congruent  coevolution • This implies that horizontal transmission (cross-species) across these very different host species (African and Eurasian pigs) has not occurred and does not seem likely to occur. • Evolutionary analysis suggests that it is unlikely these viruses will cross over to the human genome.

33. Questions ?