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Lecture 2 Evolution in action: the HIV virus The HIV/AIDS pandemic Life expectancy in Botswana What is HIV? What is HIV? • HIV is a retrovirus (i.e., RNA-based) with 9 genes What is HIV? • HIV is a retrovirus (i.e., RNA-based) with 9 genes • is diploid (i.e., has 2 copies of each RNA strand) The life cycle of HIV Q: How does HIV cause AIDS? Q: How does HIV cause AIDS? A: By attacking a key player in our immune system – CD4 helper T cells. The role of helper T cells in the immune response The progression of an HIV infection Changes in CD4 T-cell count during HIV infection The life cycle of HIV Natural selection, AZT, and the HIV virus • What is AZT? Natural selection, AZT, and the HIV virus • What is AZT? • AZT (azidothymidine) is a base analogue. Structure of azidothymidine Natural selection, AZT, and the HIV virus • What is AZT? • AZT (azidothymidine) is a base analogue. • Incorporation of AZT (instead of T) by reverse transcriptase halts replication. How AZT blocks reverse transcriptase Evolution of AZT resistance Resistance evolves in the polymerase’s active site Evolution of the HIV virus Resistance to AZT has evolved in all patients taking the drug (usually in ~6 months)! • This is an example of parallel evolution. How does HIV evolve so rapidly? How does HIV evolve so rapidly? 1. High mutation rate • HIV’s mutation rate is 106 higher than ours! How does HIV evolve so rapidly? 1. High mutation rate • HIV’s mutation rate is 106 higher than ours! 2. Short generation time • 1 year ≅ 300 viral generations. How does HIV evolve so rapidly? 1. High mutation rate • HIV’s mutation rate is 106 higher than ours! 2. Short generation time • 1 year ≅ 300 viral generations. 10 years of viral ≅ evolution 2-3 x 106 years of human evolution! Evolution of HIV within an individual patient Where did HIV come from? Phylogeny of HIV-1 and related viruses Where did HIV come from? • HIV “jumped” to humans multiple times from different primate hosts. Where did HIV come from? • HIV “jumped” to humans multiple times from different primate hosts. • Inter-species transfers of infectious diseases are called zoonoses. Other examples of zoonoses… Malaria (P. falciparum) Cholera Plague Dengue fever H1N1 swine flu Ebola SARS West Nile virus Creutzfeldt-Jakob disease Marburg fever Leishmaniasis Hantavirus Toxoplasmosis Rabies Ringworms Cowpox Lyme disease Yellow fever Human Plasmodium falciparum Chimpanzee Plasmodium spp. see Rich et al. Proc. Natl. Acad. Sci. U.S.A. 106: 14902 Dating the origin of HIV-1 in humans Dating the origin of HIV-1 in humans Dating the origin of HIV-1 in humans Q: Why is HIV infection usually fatal? Q: How do viruses achieve reproductive success? Q: How do viruses achieve reproductive success? 1. Infect host Q: How do viruses achieve reproductive success? 1. Infect host 2. Reproduce within host Q: How do viruses achieve reproductive success? 1. Infect host 2. Reproduce within host 3. Infect new host Q: How do viruses achieve reproductive success? 1. Infect host 2. Reproduce within host 3. Infect new host Strategy 1: Reproduce rapidly within host Strategy 1: Reproduce rapidly within host ↓ ↑ Chance of infecting new host ↓ Host viability Strategy 1: Reproduce rapidly within host ↓ ↑ Chance of infecting new host ↓ Host viability Strategy 2: Reproduce slowly within host Strategy 1: Reproduce rapidly within host ↓ ↑ Chance of infecting new host ↓ Host viability Strategy 2: Reproduce slowly within host ↓ ↓ Chance of infecting new host ↑ Host viability Q: Why is HIV infection usually fatal? Q: Why is HIV infection usually fatal? A: Because the virus is “shortsighted” Q: Why is HIV infection usually fatal? A: Because the virus is “shortsighted” - lethal strains predominate because of a shortterm advantage in survival and reproduction. Q: Why has a vaccine for HIV-1 not been successfully developed? Q: Why has a vaccine for HIV-1 not been successfully developed? A1: Because the virus evolves very rapidly. Q: Why has a vaccine for HIV-1 not been successfully developed? A1: Because the virus evolves very rapidly. A2: Because of HIV-1 strain diversity. Distribution of HIV-1 major clades The CCR5-Δ32 allele confers resistance to HIV infection