Lecture 15 & 16. Case study in Evolution: HIV

1. Lecture 15 & 16. Case study in Evolution: HIV 1. Biology of HIV 2. Why do HIV treatments fail? 3. Why is HIV fatal? A. Natural selection within hosts B. Transmission rate hypothesis C. Evolved resistance?

2. Google: Toronto public health Host is largely asymptomatic during chronic phase, but immune system is very active Immune system collapses Specialized blood tests CAN detect HIV at this stage But HIV testing of blood is NOT a routine part of physical exams

3. (Fig. 1.5) 1 2. HIV gp120 binds to host cell membrane at CD-4 protein 1. HIV virion (extracellular stage) 3. HIV’s RNA, reverse transcriptase, protease & integrase enter host cell 2 3 4. Reverse transcription: HIV DNA from HIV RNA Co-receptor (host membrane) 4 5. HIV’s integrase splices HIV DNA into host genome. Host’s RNA polymerase transcribes HIV mRNA. CD-4 protein (host membrane) 5 6 6. HIV mRNA translated by host ribosomes to HIV protein, HIV protease modifies proteins 7 7. New virions assemble in host cell 8. New virions bud from host cell membrane 8

4. 2. Why do HIV treatments fail? • e.g., AZT (azidothymidine) • ‘fools’ reverse transcriptase into • using AZT instead of thymidine • AZT ends reverse transcription After about 6 months of using AZT, patients stop responding to treatment… Why?

5. Why do HIV treatments fail? HIV evolves resistance to AZT within the body of a single host. Usually within ~ 6 months Fig 1.12

6. Why do HIV treatments fail? See fig 1.14 HIV evolves resistance to AZT 1. Mutant form of HIV reverse transcriptase arises = less likely to mistake AZT for thymidine 2. Virions with mutant reverse transcriptase reproduce at higher rate than normal virions (natural selection) 3. Eventually, most virions present in the body are resistant to AZT This occurs within the body of one host

7. Mutations affect active site of reverse transcriptase Why do HIV treatments fail? Gene sequencing shows viral strains present late in treatment are genetically different from those present early in treatment (Fig. 1.13)

8. Resistance after 6 months Why do HIV treatments fail? Fig 1.12

9. Why do HIV treatments fail? HIV evolves resistance to most drugs A) Considerable heritable variation • Highest mutation rate of any known virus/organism • No reverse transcription error-correcting enzymes • >50% DNA transcripts carry at least 1 mutation Fig 1.17A Change in epitopes 8% divergence (chronic phase) 0 2 4 6 8 10 12 Years since patient became HIV positive

10. Why do HIV treatments fail? HIV evolves resistance to most drugs A) Considerable heritable variation • Highest mutation rate of any known virus/organism • No reverse transcription error-correcting enzymes • >50% DNA transcripts carry at least 1 mutation • 2. Many virus generations/host generation • 300 viral generations per year • during chronic infection, 10 – 100 million new virions/day B) Drug is an agent of selection Increased Probability of mutations beneficial to HIV in short time periods Any variant that is resistant to an anti-viral drug produces more copies of itself than others (fig 1.14)

11. Why do HIV treatments fail? What about a vaccine? 24 Sept 2009 HIV Vaccine ‘reduces infection’ Combo vaccine reduces risk of HIV infection, researchers say **HIV constantly generates NEW epitopes 20 October 2009 Researchers Say Thailand AIDS Vaccine Has 'Modest' Results Critics say the trial's results may have been accidental and whatever benefits the vaccine might produce may have limited effect. ‘Voice of America’ Nature, 2009

12. Why do HIV treatments fail? What about a vaccine? • Recent efforts concentrate on ‘conserved’ epitopes • Important to HIV function = mutations in these rare • Dozens of such sites have been identified October 18, 2012, Nature. Increased HIV-1 vaccine efficacy against viruses with genetic signatures in Env V2 Morgane Rolland, Paul T. Edlefsen, Brendan B. Larsen, SodsaiTovanabutra, Eric Sanders-Buell, Tomer Hertz, Allan C. deCamp, Chris Carrico, Sergey Menis, Craig A. Magaret, Hasan Ahmed, Michal Juraska, Lennie Chen, Philip Konopa, SnehalNariya, Julia N. Stoddard, Kim Wong, Hong Zhao, Wenjie Deng, Brandon S. Maust, Meera Bose, Shana Howell, Adam Bates, Michelle Lazzaro, Annemarie O’Sullivan, Esther Lei, Andrea Bradfield, Grace Ibitamuno, VatcharainAssawadarachai, Robert J. O’Connell, Mark S. deSouza, SorachaiNitayaphan, SupachaiRerks-Ngarm, Merlin L. Robb, Jason S. McLellan,IvelinGeorgiev, Peter D. Kwong, Jonathan M. Carlson, Nelson L. Michael, William R. Schief, Peter B. Gilbert, James I. Mullins & Jerome H. Kim

13. Why do HIV treatments fail? Can we use our understanding of evolution to help infected individuals?

14. What happens if these people stop taking AZT? Resistance after 6 months Why do HIV treatments fail? Fig 1.6

15. shift in favoured form of HIV & short-term decrease in virus load Why do HIV treatments fail? How to help infected individuals? 1. periodic shifts in the selective environment • switch to drugs with different activity • periodic elimination of treatment drugs • (controversial)

16. Why do HIV treatments fail? How to help infected individuals? See Fig 1.15a 2. Simultaneously treat with multiple anti-retroviral drugs • mixture or ‘cocktail’ of drugs • each target different stage of HIV cycle • Virion must carry multiple beneficial mutations to be resistant

17. Why do HIV treatments fail? Fig 1.15, Box 1.1 e.g., HAART Highly Active Ant-Retroviral Therapy 2 reverse transcriptase inhibitors + one protease inhibitor

18. Significant decrease in mortality rates & secondary infections. HIV replication often ceases during treatment. But virus eventually adapts in most cases…(~3 yrs) Why do HIV treatments fail? How to help infected individuals? See Fig 1.15a 2. Simultaneously treat with multiple anti-retroviral drugs • mixture or ‘cocktail’ of drugs • each target different stage of HIV cycle • Virion must carry multiple beneficial mutations to be resistant

19. Why do HIV treatments fail? HIV can quickly evolve resistance to drugs within the body of a single host Why is HIV fatal? (Evolutionary causes) • A. Natural selection within a host (rapid replication) • B. Natural selection for viral transmission between hosts • C. Humans have not evolved resistance to HIV

20. High virulence = rapid growth rate of virus Low virulence = slow growth rate of virus leads to slow development of illness or little effect on host leads to severe host illness and/or death Within hosts = ‘short sighted evolution’ B. Transmission rate hypothesis Virulence = tendency to cause disease in host Why has HIV evolved a high degree of virulence?

21. B. Transmission rate hypothesis Within the body of one host, HIV evolves to more virulent over time

22. Why has HIV evolved a high degree of virulence? By definition: the most common strains of HIV in a human populationwill be those that infect the largest number of hosts Does high virulence increase the number of hosts infected?

23. Why has HIV evolved a high degree of virulence? The Transmission rate hypothesis Natural selection favours increased virulence of sexually transmitted diseases when transmission to new hosts is frequent (and favours decreased virulence when transmission to new hosts is infrequent)

24. High virulence • many virions/ml blood • rapid illness and death of host decreased # copulations before death of host increased chance of transmission at each copulation There is a reproductive trade-off for HIV Cost to virus Benefit to virus

25. Frequent partner changes Infrequent partner changes Does high virulence increase the numberof hosts infected? Depends on how quickly people change sex partners... Largest # hosts infected with HIGH virulence strain Largest # hosts infected with LOW virulence strain

26. Each new shape = new sex partner Transmission rate hypothesis HIV infected host High virulence strain HIV infected host Low virulence strain virion virion Infected individual

27. Transmission rate hypothesis RARE partner changes, LOW virulence 2 new hosts

28. Transmission rate hypothesis RARE partner changes, HIGH virulence 1 new host

29. Transmission rate hypothesis FREQUENT partner changes, LOW virulence 2 new hosts

30. Transmission rate hypothesis FREQUENT partner changes, High virulence 3 new hosts

31. Transmission rate hypothesis So # of new hosts infected is greatest for: • HIGH virulence strains when partner change is FREQUENT • LOW virulence strains when partner change is RARE