HIV

Question 1

Natural History HIV

Answer 1

1. Primary HIV infection - Transient condition. In this phase we see an initial rise of the virus in the blood, a decrease in blood and tissue CD4⁺ cells, and a large increase in blood CD8⁺. This is a period of rapid replication and infection of CD4. Often signs and symptoms of primary infection appear 2-4 weeks after virus exposure and generally lasts less than 14 days (fever, lymphadenopathy, sore throat, rash, myalgia, diarrhea, weight loss, headache).
2. Chronic asymptomatic phase - A long period of latency (2-12 years). During this period there are no signs and symptoms of illness (may have lymphadenopathy). Characterized by stable levels of virus replications and CD4⁺ count in the blood (See accumulation of the virus in the lymph impairing immune response over time - will eventually result in rapid increase in blood levels of virus and drop in CD4⁺ levels).
3. Overt AIDs - End stage of HIV infection. In absence of antiretrovirals results in death in 2-3 years. AIDs is characterized by CD4 cell count < 200 cells/microL or the presence of any AIDS- defining condition (ex. multiple or recurrent bacterial infections, candidasis of esophagus, invasive cerival cancer, etc).

Question 2

Labs HIV

Answer 2

• CD4 count - CD4 cells are a target of the HIV virus. Thus, as HIV infection progresses the number of CD4 decline. A normal range is 500-1500. When levels drop below 200 a person is said to have AIDs.
• CD8 count - These cells try to fight off the virus, and thus levels are increased in those with HIV.
• CD4/CD8 ratio - a normal ratio is ~2.0 with CD4 levels greater than CD8 levels. In people with HIV this ratio may be below 1, indicating that the CD8 levels are greater than CD4 levels.
• HIV viral load/ HIV RNA - measures amount of HIV in the blood. HIV viral load is typically indetectable below levels of 40-75 copies/mL. An undetectable viral load levels slows of stops disease progression and prevents HIV transmission to sex partners.

Question 3

HIV replication

Answer 3

1. Entry - binding of HIV to surface receptors on the CD4 cell. Further binding of HIV with a chemokine co-receptor promotes membrane fusion and internalization of viral genetic material and enzymes needed for replication into the cell.
2. Reverse transcription - Genetic material of HIV is RNA. Virus uses reverse transcriptase to convert RNA into DNA. Next, double - strained DNA product goes into the cell nucleus.
3. Integration - Virus uses enzyme integrase to integret its DNA into the host CD4 cell (cell is now infected for life)
4. Replication - HIV preferentially replicates in activated cells. Proviral DNA is formed by transcription using the machinery of the host CD4 cell to create new viral RNA.
5. Assembly - New vial proteins and enzymes move to cells outer membrane where they assemble into an immature noninfectious HIV particle.
6. Budding and maturation - Virus bud is released from host CD4 cell. Viral protease cuts long HIV polyprotein chains into smaller functional HIV proteins, making mature, infectious viral particles.

Question 4

Antiretroviral Therapy

Answer 4

• Combined antiretroviral therapy - Treatment that used a combination of 3 or more drugs to treat HIV infection. Stops the virus from making copies of itself in the body. Often involved the following drug classes:
  
  • 2 NRITs/Nukes (inhibits reverse transcriptase) + a third drug from a different class. Either:
  • Integrate inhibitors (inhibits virus from integrating into DNA)
  • Protease inhibitor (prevents mature HIV virons from budding out of the cell). Tends to involve more pills than other combinations and may have to be taken with food. Also have to add “boosting” agent to increase levels of protease inhibitor in the blood
  • Non-nukes - Block revease transcription (different mechanism than Nuke). Tends to develop resistance faster than other classes of drugs
  • Fusion inhibitors - bind to envelope glycoprotein to prevent viral fusion to CD4 cell
  • CCRS inhibitor - blockers CCRS receptor (co-receptor the promotes membrane fusion and internalization of viral genetic material).