1 EPIDEMIOLOGY 200B Methods II – Prediction and Validity Scott P. Layne, MD

2 PART 4 Human Immunodeficiency virus Epidemic 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 per 10 4 bases Each newly infected cell has point mutations

5 Life Cycle

6 ProteinSizeFunction Gagp25Capsid structural protein p17Matrix protein p9RNA binding protein p6RNA binding protein, helps in budding Proteasep10Post-translational processing of proteins Polymerasep66, p51Reverse transcriptase, RNAse-H activity Integrasep32Integration of cDNA Vifp23Promotes viral maturation Envelopegp120Attachment via cellular CD4 gp41Fusion with cellular membrane Tatp14Increases rate of viral mRNA synthesis Revp19Promotes transport of mRNA to cytoplasm Nefp27Suppression, latency Vprp15Replication, transactivation Vpup16Release, disrupts gp120-CD4 complexes Vpxp15Helps with infectivity Tevp26Tat 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 Time Humoral 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

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

17 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

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19 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

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