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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 gp120 binds to CD4 molecule and portion of chemokine receptor

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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 CD4 molecule • and portion of chemokine receptor • on T cells/phagocytes • gp41 facilitates fusion of viral • and cell membranes

  4. Flexible lipid bilayer composed of host cell surface membrane

  5. Capsid proteins: provide structure to virus and protect the genome

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

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

  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. HIV life cycle: penetration • Viral core (capsid and genome) enter host cytoplasm

  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. Proliferation of T cells specific for viral antigen 3. Effector stage-elimination of virus

  20. Recognition Major histocompatibility complex (MHC) protein complex on surface of cells, presents antigens 2 classes: MHC1-expressed on nearly all nucleated cells—CD8 MHC2 -expressed on antigen-presenting cells—CD4

  21. Class II MHC Present extracellular antigens to CD4 (helper) T cell CD4 T cell

  22. CD8 T cell Class I MHC Present intracellular antigens to CD8 (cytolytic) T cell

  23. Effector stage & proliferation: • 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-will also make cytokines, stimulate production of antibodies against HIV envelope proteins, and trigger proliferation of T cell clones-cytotoxic and memory

  24. 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

  25. HIV and the human immune response

  26. Diversity and Specificity • HIV reverse transcriptase extremely error-prone: 24 h after infection with 1 virion, EVERY genetic variant is 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

  27. 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

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

  29. Therapeutic drugs Drug either eliminate the pathogen or prevent it from multiplying without damaging the host HIV exists as a provirus, therefore cannot kill all infected cells-probably kill the host HIV replication: • Steps utilize host enzymes and cellular machinery • HIV infects a variety of cells • High mutation rate

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

  31. Reverse transcriptase inhibitors • 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

  32. Nonnucleoside analogs Protease inhibitors • React directly with RTase • Protease is involved in final assembly of viral proteins • Drugs block protease active site

  33. Fusion inhibitors • T-20 binds to gp41, blocking fusion of viral and cell membranes Entry inhibitors • Interfere with chemokine coreceptors on host cell membranes

  34. Trojan horse virus • Manufactured stomach virus from cattle with capsid protein genes replaced with genes for CD4 and chemokine receptors • Stomach virus replicates in cells, is released • HIV gp120 and gp41 bind to stomach virus • Stomach virus eliminates HIV

  35. mRNA antisense molecules • Synthetic RNA molecules combine with and destroy viral mRNA as it leaves host cell nucleus, preventing synthesis of viral proteins or incorporation of mRNA into new virions

  36. Questions?

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