HIV and AIDS

1. HIV and AIDS Human Immunodeficiency Virus (HIV) is the virus that causes Acquired Immunodeficiency Syndrome (AIDS).

2. Human Immunodeficiency Virus (HIV) • enters the human body through direct contact of bodily fluids (blood, saliva, semen) • infects and replicates in immune cells, macrophages and helper T cells • Loss of helper T cells prevents B cell activation • Activated B cells - needed for antibody production Secondary infections can be fatal in people with HIV because their immune systems cannot respond

3. AIDS • AIDS = Acquired Immune Deficiency Syndrome or Acquired Immunodeficiency Syndrome - disease resulting from HIV infection • When a person has AIDS,their HIV infection is severely impairing immune system function

4. General facts: • Between 30.6-36.1 million people infected with HIV in 2007; infection killed ~2.1 million in 2007 ~1-1.2 million infected in USA • Sub-Saharan Africa,>15% infected with HIV • 90% of HIV transmission from heterosexual contact • Male circumcision 50-65% effective at preventing HIV infection (2005-NIH)

5. Structure of the HIV virion HIV has an RNA genome Viral RNA is enclosed within a capsid inside of the viral envelope Glycoproteins on viral envelope bind to cell surface molecules on human cells The RNA genome encodes a reverse transcriptase enzyme, a DNA polymerase that uses RNA as a template HIV RT synthesizes a DNA copy of the viral RNA

6. HIV Virion (Outside cell) CCR5 CD4 (Inside cell) HIV envelope glycoproteins bind to the CD4 and CCR5 receptors on helper T cells

7. HIV infection cycle 1. Virus binds receptors on host cell membrane and enters cell. Envelope and capsid are degraded. 2. HIV reverse transcriptase (RT) catalyzes formation of DNA that is complementary to the viral RNA 3. Double-stranded DNA is made 4. Integration of viral dsDNA into host chromosome catalyzed by HIV integrase 5. Viral genes are transcribed into a long messenger RNA 6. Viral mRNA is translated into a polyprotein that is processed (cut up into functional proteins) by HIV protease 7. New HIV virus particles are assembled in the cytoplasm of the infected cell 8. New viruses bud from the host cell and can infect another susceptible cell

8. http://www.cellsalive.com/hiv0.htm

9. Late in HIV infection HIV mutates rapidly due to mistakes made by reverse transcriptase (~ 1 in 5,000 bases). HIV variants occur that can bind receptors on other immune cells and this induces apoptosis. Lack of immune cells severely impairs response to secondary infections and cancer.

10. Resistance to AIDS? • Some individuals are less susceptible to AIDS than others • Called Long-term non-progressors • Usually have a mutated CCR5 receptor gene (with a 32-base pair deletion). The deletion truncates the CCR5 receptor protein and prevents it from going to the cell surface. • Long-term non-progressors are infected but remain healthy

11. Infection HIV Virion CCR5 CD4 Resistance to AIDS The people who are “immune” to HIV often have a truncated CCR5 receptor. Therefore, HIV can’t make the correct contacts to enter cell.

12. Some anti-HIV Drugs Drug TypeMechanism Reverse Transcriptase blocks copying of viral RNA Inhibitor into DNA Protease Inhibitor blocks processing of viral proteins Entry Inhibitor blocks ability of HIV to bind, fuse with and enter a cell

13. deoxythymidine 3-azidothymidine Reverse transcriptase inhibitors - Nucleoside analogs • Faulty DNA building blocks • Incorporated into HIV DNA during reverse transcription - prevent further elongation of DNA chain • First anti-HIV drug: 3-azidothymidine (AZT) - the 3'-azido group prevents further 5' to 3' phosphodiester linkages

14. 1A30 HIV-1 Protease Complexed With A Tripeptide Protease Inhibitor HIV Protease Inhibitors HIV protease processes viral proteins inside of the cell HIV Protease Inhibitors prevent the processing of HIV proteins and assembly of new infectious viruses

15. HIV Virion CCR5 CD4 HIV Entry Inhibitors First entry-suppressive factors identified were small proteins called chemokines. Chemokines are the normal ligands for the CCR5 receptor

16. MIP-1b CD4 Steric Hindrance CCR5 CD4 Internalization Chemokine MIP-1bblocks HIV infection Normal Infection HIV Virion CCR5

17. HIV Virion X CCR5 CD4 Anti-HIV Entry Inhibitor Drugs FDA approved T20 in 2003 and MVC in 2007 T20 interacts with glycoproteins on HIV envelope - blocks HIV from entering CCR5+ cells MVC interacts with the CCR5 receptor - blocks HIV from entering CCR5+ cells

18. Treatment of HIV infection • Drug therapies have cut the mortality rate from AIDS in half since 1996. • Patients take a combination of antiretroviral drugs known as highly active antiretroviral therapy, or HAART • Cocktails containing two reverse transcriptase inhibitors and a protease inhibitor are commonly used Side effects and cost (>$12,000/year) make staying on treatments difficult for most people.

19. FDA approved HIV/AIDS drugs * * * *

20. Mysteries remain Multidrug resistance: • After several years on ANY anti-HIV therapy, the drugs become less effective • Due to mutations in the target proteins A 2003 study showed that mutations in HIV protease decrease the affinity for drugs by 100-1000 fold. But the affinity for the natural HIV substrate was only slightly reduced. (Biochemistry, web release 10/30/03)

21. Mysteries remain: • HIV virus levels can be dropped below detectable levels, yet come back in huge amounts => reservoirs of HIV “hide” from drugs. • SIV does not cause disease in African monkeys. HIV can infect some monkeys, does not replicate after entering cell. What do African monkeys have that we need??

22. TRIM5a protein in monkeys stops HIV and SIV from replicating soon after it enters the cell This is why monkeys don’t get HIV Human TRIM5 doesn’t work as well, so we get infected Nature 427 848-853 (2004)

23. The end

24. HIV virus particle (virion) Envelope gp41 RNA Capsid gp120 Matrix Reverse Transcriptase

25. MIP-1b The CCR5 receptor is normally bound by MIP-1b, a chemokine that stimulates immune cells NH2 Extracellular Surface CCR5

26. HIV virus gp41 gp120 CD4 CCR5 or CXCR4 Human cell The HIV fusion process and inhibition by T-20 Trimer of Hairpins, Fusion gp41 C Receptor Binding N T-20 Inhibits fusion T-20 binds gp41, stops trimer of hairpin formation