HIV, CD4, and More

1. HIV, CD4, and More Karen Hutcherson Jenn Mann Elizabeth McCauley Michael Powers Courtney Wilson

2. CD4 Receptor… • ...is a member of the IgG superfamily • …is a cell surface receptor expressed on helper T lymphocytes, monocytes, and B-lymphocytes, among others • Free HIV virus binds to CD4 receptors in order to penetrate the cell • in addition to being a receptor for HIV, CD4 participates in the recognition of foreign peptides bound to class II MHC complexes

3. Acute Phase (Phase 1) 0-9 weeks from start of infection hefty viral replication and killing of CD4 T cells Symptoms: fever, rash, muscle and headaches, enlarged nymph nodes symptoms eventually lessen as body gains some control over the virus Chronic Phase (Phase 2) prolonged stage where the replication rate drops good health and few, if any, symptoms due to high enough CD4 levels for normal defensive responses maintain viral levels at “set point” 8-10 years before major HIV complications occur “Full Blown AIDS” (Phase 3) once CD4 T cell count drops below 200 cells/mm3 => AIDS once under 100 cells/mm3, microbes proliferate giving rise to deadly opportunistic diseases once these diseases appear, AIDS becomes lethal in about 1-2 years Time Course of HIV

4. HIV Life Cycle 1. Free virus binds to cell at CD4 receptor sites 2. Virus penetrates the cell and the contents are emptied into the cell 3. Single strands of viral RNA are converted into double-stranded DNA by the reverse transcriptase enzyme 4. Viral DNA is combined with the cell’s own DNA by the integrase enzyme 5. When the infected cell divides, the viral DNA is “read” and long chains of proteins are made 6. Sets of viral protein chains come together

5. Life Cycle Continued 7. Immature virus pushes out of the cell, taking some cell membrane with it 8. Immature virus breaks free of the infected cell 9. The protein chains in the new viral particle are cut by the protease enzyme into individual proteins that combine to make a working virus • Therapy Targets (suppression) • Reverse Transcription • Protease Enzyme Cutting

6. HIV Life Cycle

7. HAART (highly active antiretroviral therapy) • Based on triple therapy • 2 nucleoside analogues • 1 protease inhibitor • Cost: $10,000 - $12,000/year • In clinical trials, patients who had CD4 T-cell counts between 200-500 cell per m3 achieved viral loads below 500 RNA copies per mL within 24-100 weeks in 75-85% of cases • 50% of patients given triple drug therapy achieved the goal of viral loads below 500 copies per milliliter 6-52 weeks after the start of treatment

8. HARRT Downside • Patients must swallow 8-16 pills/day - each with different directions • many patients are incapable of following the treatment schedule • HAART is unforgiving of non-adherence • Side effects: rashes, nausea, possible diabetes, etc • Downside overview: • side effects • complicated regimens • possibility of resistance to therapy • If HAART fully stops replication, it seems to prevent the development of resistance and thus should work indefinitely

9. Viral Loads • Viral-load assays have gained information on HIV’s behavior and have developed new way to provide therapy • Assays measure the viral RNA per milliliter of blood plasma • Low viral RNA concentrations generally lead to prolonged life due to suppression • During the early stages of infection, viral assays have shown concentrations as high as 20 - 30 thousand copies per milliliter

10. References • http://www.niaid.nih.gov/daids/dtpdb/virpage1.htm • http://www.nmia.com/~hivcc/415-life-cycle.html • IMPROVING HIV THERAPY. John G. Bartlett and Richard D. Moore in Scientific American; July, 1998.