1. Basics of Human Immunodeficiency Virus (HIV) Brian Rybarczyk, PhD University of North Carolina- Chapel Hill

2. Nature of HIV Infection HIV is a retrovirus having RNA as its genome (humans have a DNA genome) HIV is a retrovirus having RNA as its genome (humans have a DNA genome) HIV infects immune cells ultimately destroying a person’s defense against foreign invaders HIV infects immune cells ultimately destroying a person’s defense against foreign invaders Uses CD4 receptor on immune cells to infect (enter) cells Uses CD4 receptor on immune cells to infect (enter) cells

3. How Does HIV cause AIDS? Ultimately, HIV destroys a person’s immune cells to a level that the body cannot protect from foreign invaders Ultimately, HIV destroys a person’s immune cells to a level that the body cannot protect from foreign invaders This opens up the host for a multitude of other diseases including Pneumocystis carinii, Tuberculosis, Kaposi sarcoma This opens up the host for a multitude of other diseases including Pneumocystis carinii, Tuberculosis, Kaposi sarcoma

4. Three Important HIV Enzymes Reverse Transcriptase (RT) – converts HIV RNA genome into a DNA copy Reverse Transcriptase (RT) – converts HIV RNA genome into a DNA copy Integrase (IN) – inserts the HIV DNA copy into host genome Integrase (IN) – inserts the HIV DNA copy into host genome Protease (PR) – cuts and processes immature HIV proteins into mature, functioning proteins Protease (PR) – cuts and processes immature HIV proteins into mature, functioning proteins

5. HIV lifecycle CD4 coreceptor 1. HIV binds to immune cells using CD4 and a coreceptor 2. HIV fuses with cell membrane and injects core with RNA genome 4. Integrase incorporates HIV genome copy into host genome 3. RT copies HIV RNA into DNA 5. Protease processes immature proteins into mature HIV proteins 6. Virus buds from cell producing many viral progeny

6. CD4 coreceptor Strategies of HIV Therapy Protease Blockers indinavir, ritonavir Reverse transcriptase blockers nucleoside analogs: AZT, 3TC, d4T non-nucleoside: nevirapine Entry Inhibitors T-20

7. Development of Drug Resistant HIV Mutants Anti-HIV drug HIV variants susceptible to drug HIV variant resistant to drug

8. How do mutations arise in HIV? HIV’s reverse transcriptase does not copy the HIV RNA genome into DNA accurately HIV’s reverse transcriptase does not copy the HIV RNA genome into DNA accurately This leads to mutations that can be beneficial or harmful to HIV This leads to mutations that can be beneficial or harmful to HIV Mutations that allow viruses to survive will produce progeny that will also be resistant Mutations that allow viruses to survive will produce progeny that will also be resistant Anti-HIV drugs provide a selective pressure that allows HIV to develop drug resistant mutants Anti-HIV drugs provide a selective pressure that allows HIV to develop drug resistant mutants

9. Why is there no cure for HIV? High mutation rate caused by RT High mutation rate caused by RT The outer protein envelope (gp120) mutates, therefore the host’s immune system cannot recognize and destroy all HIV present The outer protein envelope (gp120) mutates, therefore the host’s immune system cannot recognize and destroy all HIV present HIV permanently incorporates into host DNA HIV permanently incorporates into host DNA Development of drug resistant mutants Development of drug resistant mutants