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Why are Rhesus Macaques Resistant to HIV-1?

Why are Rhesus Macaques Resistant to HIV-1?. What About the Rest of Us?. Presentation By: Melanie Smith. Endogenous PtERV. Extinct Virus: PtERV. P an t roglodytes E ndogenous V irus 4 million years old 100+ copies of PtERV in gorilla and chimpanzee genomes Absent in humans

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Why are Rhesus Macaques Resistant to HIV-1?

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  1. Why are Rhesus Macaques Resistant to HIV-1? What About the Rest of Us? Presentation By: Melanie Smith

  2. Endogenous PtERV

  3. Extinct Virus: PtERV • Pan troglodytesEndogenous Virus • 4 million years old • 100+ copies of PtERV in gorilla and chimpanzee genomes • Absent in humans • Studies Suggest Viral Activity 3 to 4 Million Years Ago

  4. Immunity Protein: TRIM5alpha • Intrinsic Immune Protein • General Immune Response Against Retroviruses • Attaches to Capsid • Labels Capsid for Destruction • Makes Rhesus Macaques Resistant to HIV-1 • What Does it Do for Others?

  5. Immunity Evolution • Positive Selection Suggests TRIM5alpha Evolved via Viral Infections • Suggests at Least One Virus Challenged Human Lineage • Occurred in the Past 4 to 5 Million Years • Can we Figure Out What Virus?

  6. Hypothesis • Human TRIM5alpha has poor antiviral activity • Compared to other Primates • However, Strongly blocks γ-retrovirus N-MLV • N-MLV related to PtERV • Hypothesis: TRIM5alpha may have protected early humans against PtERV

  7. The Test • Inactive PtERV in Chimpanzee Genome • Acquired many Mutations • Chimpanzee Genome only had pieces of PtERV • Reconstructed PtERV in silico • 50% Similar to MLV

  8. PtERV Resurrection • TRIM5alpha Targets Fully Formed Virus • Combined PtERV genes with MLV genes to make a Complete Virus • Capsid and p12 helper gene from PtERV • Structural Proteins and enzymes from MLV • Can you bring back an extinct virus?

  9. Testing TRIM5alpha • Expression of TRIM5alpha restricts virulence of MLV/PtERV • Reduced Infectivity by a Factor of 100+ • How did TRIM5alpha become a PtERV killer?

  10. TRIM5alpha Specificity • Patch is under positive selection • Determines gene specificity • Can TRIM5alpha Restrict Both HIV-1 and PtERV?

  11. Is Restriction of HIV-1 and PtERV Mutually Exclusive?

  12. Conclusions? • Study Suggests TRIM5alpha was fixed in Population because of PtERV • Other possibilities exist for why PtERV did not infect Humans • What are the Arguments against TRIM5alpha Restricting PtERV?

  13. The Chimpanzee Exception • Chimpanzees have R332, but have PtERV in their Genome • How do Chimpanzees have Endogenous PtERV?

  14. The Parsimonious Explanation • R332 was fixed in Chimpanzee and Human ancestor • Paradox: Chimpanzee TRIM5alpha did not Prevent PtERV Infection • Defense: Maybe TRIM5alpha does not work alone

  15. The Less Parsimonious Explanation • Human and Chimpanzees Independently Fixed R332 after the Species Diverged • In other lineages, 332 fixed independently • Strong Positive Selection may allow separate fixation events • Chimpanzees could have fixed R332 after PtERV infection

  16. The Interesting Conjecture • Evolutionary Selection for Resistance to one retrovirus could abolish resistance to another retrovirus • Protection against PtERV may be responsible for poor resistance to HIV-1

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