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HIV Infectivity in Relation to gp120 Knobs: Variables and Parameters to Consider

This article discusses the relationship between HIV infectivity and the number of gp120 knobs on virions, exploring the variables and parameters that should be taken into account. It also covers the implications for humoral immunity, vaccine efficacy trials, and the effects of pre- and post-attachment blocking drugs.

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HIV Infectivity in Relation to gp120 Knobs: Variables and Parameters to Consider

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  1. EPIDEMIOLOGY 200BMethods II – Prediction and ValidityScott P. Layne, MD

  2. PART 4Human Immunodeficiency virusEpidemic Within Hosts March 2010

  3. TWO EPIDEMICS Between people HIV is a risk-based disease Not all individuals are at equal risk Within people HIV-1 & HIV-2 disable the immune system Predisposes to opportunistic infections & cancer

  4. HIV-1 / HIV-2 Overall Features 100 nm diameter Two copies of single-stranded RNA (diploid) Genome contains approximately 10,000 RNA bases Many viral particles are non-infectious or defective Viral particles labile (spontaneously lose infectivity) Reverse transcriptase error rate 1 - 3 per 104 bases Each newly infected cell has 1 - 3 point mutations

  5. Life Cycle

  6. ProteinSizeFunction Gag p25 Capsid structural protein p17 Matrix protein p9 RNA binding protein p6 RNA binding protein, helps in budding Protease p10 Post-translational processing of proteins Polymerase p66, p51 Reverse transcriptase, RNAse-H activity Integrase p32 Integration of cDNA Vif p23 Promotes viral maturation Envelope gp120 Attachment via cellular CD4 gp41 Fusion with cellular membrane Tat p14 Increases rate of viral mRNA synthesis Rev p19 Promotes transport of mRNA to cytoplasm Nef p27 Suppression, latency Vpr p15 Replication, transactivation Vpu p16 Release, disrupts gp120-CD4 complexes Vpx p15 Helps with infectivity Tev p26 Tat and Rev activities

  7. Genome Organization Simple Combinatoric Argument

  8. REGULATION Viral genome can exist for prolonged periods without expressing viral proteins HIV has an array of regulatory proteins that are responsible for latent periods Leads to pool of cells that hide from immune system

  9. TROPISM Targets of HIV infection are CD4+ cell T lymphocytes Monocytes Macrophages Other cells express CD4 molecules Enterocytes Brain astrocytes Renal epithelium Co-receptors: CCR-5, RANTES T Lymphocytes Monocytes Macrophages

  10. Humoral Time X Cellular

  11. Physical-Chemical Model

  12. Electron Microscopy Loss of gp120 knobs

  13. QUESTION How does HIV infectivity relate to number of gp120 knobs? What variables and parameters should be considered?

  14. Shedding Non-Specific Killing Infection Complex Formation

  15. EQUATIONS Infection Non-specific killing Complex formation Complex disassociation Loss of free Infection Loss of complexed

  16. OBSERVATIONS HIV infectivity is proportional to gp120 knobs on virions For drugs that block viral attachment, blocking activities are inversely related to cell concentrations For drugs that block post-attachment (fusion inhibitors), blocking activities are independent of cell concentrations

  17. IMPLICATIONS HUMORAL IMMUNITY Decreased blocking activity Genital ulcer disease Inflammation Lymph nodes Vaccine efficacy trials Outcomes may vary with population Pre-attachment blocking Post-attachment blocking

  18. READING Scott P. Layne, et al. 1898. Quantifying the infectivity of human immunodeficiency virus. Proc. Natl. Acad. Sci. USA 86, 4644 – 4648.

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