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The biology of HIV

The biology of HIV. x14,555. Lecture outline. HIV structure and life cycle Characteristics of human immune response How HIV interacts with immune response Overview of anti-HIV drugs. Envelope glycoproteins

lesley-zimmerman
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The biology of HIV

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  1. The biology of HIV x14,555

  2. Lecture outline • HIV structure and life cycle • Characteristics of human immune response • How HIV interacts with immune response • Overview of anti-HIV drugs

  3. Envelope glycoproteins • gp120 binds to 2 receptors on T cells & phagocytes: CD4 molecule and chemokine receptor • gp41 facilitates fusion of viral and cell membranes

  4. Flexible lipid bilayer • composed of host cell • surface membrane

  5. Capsid: provides structure to virus and protects the genome • p17 is associated with viral membrane • p24 condenses to form shell • Multiple functions during entire life cycle.

  6. Protease assembles new viral proteins • Integrase incorporates viral DNA into host DNA and integrase

  7. RNA genome present in 2 copies • Reverse transcriptase • Dual enzyme composed of DNA polymerase and ribonuclease • Synthesizes DNA copy of viral genome

  8. LTR gag pol env vif tat vpu nef vpr rev LTR HIV genome • RNA, 9 genes, 9.7 kilobases • LTR: long terminal repeats-initiate transcription • gag-capsid proteins pol-reverse transcriptase, others env-gp120, gp41 vif, tat, vpu, nef, vpr, rev-regulatory genes

  9. General viral life cycle • 1. Virus envelope recognizes host cell • 2. Virus binds to host cell, releases contents • Capsid is removed by host enzymes • Viral genome is replicated by host • Viral genes transcribed into mRNA by host • Viral mRNA translated by host • Viral proteins processed/packaged • 8. Capsids assembled around copy of viral genome • 9. Virus is assembled and buds from host cell

  10. HIV life cycle: adsorption Union between virus and host cell

  11. 1. gp120 binds to CD4 molecule • gp120 changes shape, peels back and binds to chemokine receptor • 3. gp41 darts out and pierces cell membrane and anchors virus • 4. Fusion of membranes begins

  12. Fusion of viral and host membranes Viral core (capsid and genome) enter host cytoplasm HIV life cycle: penetration

  13. Reverse transcription

  14. 1. Viral RTase-DNA polymerase makes ssDNA copy of RNA genome 2. Viral ribonuclease degrades RNA 3. Viral DNA polymerase replicates ssDNA -> dsDNA 4. dsDNA migrates to nucleus using host cytoskeleton (up to 20 μM, several minutes) 5. Viral integrase incorporates dsDNA into host DNA at random site Now termed a provirus-latent or productive

  15. HIV life cycle: replication 1. Transcription of provirus by host RNA polymerase 2. Host translation of viral mRNA and production of viral RNA copies 3. Virus proteins and RNA are assembled by protease (viral) 4. Mature viruses released by budding, may kill host cell. T cells die easily, macrophages live months

  16. The human immune response

  17. Four characteristics • Diversity • Specificity • Memory • Self/Non-self discrimination

  18. Macrophages Phagocytose foreign particles, make cytokines, activate lymphocytes Lymphocyte: 2 subclasses B lymphs: make antibodies T lymphs: regulate response, effector cells Helper: make cytokines, activate T and B cells, CD4 Cytolytic: lyse infected cells, CD8

  19. How do we fight viruses? 1. Recognize the virus-recognize a portion of the virus, the ‘antigen’ 2. Effector stage-elimination of virus 3. Proliferation of T cells specific for viral antigen

  20. Cell Recognition Major histocompatibility complex (MHC) protein complex on surface of cells, presents antigens

  21. CD8 T cell Class I MHC Expressed on nearly all nucleated cells in body Present intracellular antigens to CD8 (cytolytic) T cell

  22. CD4 T cell Class II MHC Expressed on antigen-presenting cells Present extracellular antigens to CD4 (helper) T cell

  23. Cell Class I MHC Class II MHC Antigen from inside of the cell Antigen from outside of the cell Presenting cell destroyed Presenting cell lives Nearly all cells in body Only on specialized cells

  24. Effector stage • CD8 T cell attaches to presenting cell • T cell releases enzymes that form pores in presenting cell’s membrane-water enters presenting cell-swells and bursts • T cells kill only presenting cell • T cells are not injured

  25. T cell Infected cell

  26. Proliferation Activated T cell with receptor specific for antigen stimulates clonal proliferation. All new T cells have exactly same receptor

  27. Four characteristics • Diversity—Tcells recognize 109 antigens • Specificity—Only T cell with receptor specific for the presented antigen will be activated (random chance) • Memory—Cloned T cells differentiate into memory cells, may last up to 20 years • Self/Non-self discrimination—T cells with receptors recognizing ‘self’ antigens do not mature

  28. HIV and the human immune response

  29. Diversity and Specificity • HIV reverse transcriptase extremely error-prone: 24 h after infection with 1 virion, EVERY genetic variant could be present-new strains elude the immune system • HIV can increase by 100 billion virions/day T cells can increase at 1-2 billion cells/day • Lysed T cells represent losses of diversity/specificity opportunistic infections

  30. Memory • After initial burst of virus production in cells throughout the body, most HIV production occurs in lymph nodes (plasma viral load very low), where circulating memory T cells are not present • Selective impairment of memory T cells, mechanism unknown

  31. Self/non-self discrimination • HIV envelope composed of host membrane

  32. What aspects of HIV life cycle can be safely targeted by drugs?

  33. Nucleoside analog • AZT: when abundant in cytoplasm, replaces thymidine, lacks the OH group-halts reverse transcription • RTase irreversibly binds to AZT • Viral RTase prefers AZT, host polymerases prefer thymidine • Other examples: 3TC, ddC, ddI

  34. Nonnucleoside analogs • React directly with RTase, termed NNRTIs. Most are structurally similar to nucleotides • Problem – patients treated with NNRTIs tend to accumulate resistant mutants. 1 study: 29 patients on NNRTI-containing regimen, 83% had more than two NNRTI-resistant forms. Mutants persisted 12 months after therapy stopped.Antimicro. Agents Chemother. 2004

  35. Protease inhibitors • Protease is involved in final assembly of viral proteins • Drugs block protease active site • Saquinavir, lopinavir, ritonavir • Generally studied/administered in combinations and +/- NNRTIs

  36. HAART –Highly Active Antiretroviral Therapy • Introduced in 1996, formalized by FDA in 2001. • Combination of two nucleoside analogs with either a protease inhibitor or an NNRTI. • First treatment given to patients, should keep viral load at < 50 copies/ml, which can prevent emergence of drug-resistant mutants. • If first HAART fails, subsequent treatment much less likely to succeed (mutants accumulate). Netherlands J. Med. 2004 62:424-440.

  37. Fusion inhibitors • Enfuvirtide (T20) targets conserved sequence in gp41, inhibits assembly by targeting only known conserved sequence on gp41. PNAS in press 2005 Entry inhibitors • Antibody fragment F105 may block CD4 binding site of gp120 J. Virol. 2005

  38. Questions?

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