Unit 18 - Immunopathogenesis of HIV-1

Question 1

What qualifies as HIV seropositive?

Answer 1

Patient has the Ab to HIV.

Question 2

What qualifies as AIDS?

Answer 2

Patient has Th CD4+ cells < 200/micoliter blood.

Patient may also have symptoms of opportunistic infections and/or Kaposi’s Sarcoma

(Note: normal Th CD4+ cells are 500 - 1000/microliter blood).

Question 3

What are the world numbers for HIV/AIDS?

Answer 3

Total HIV = 35 million
New infections = 2.1 million/year
AIDS deaths = 1.5 million/year

Question 4

What are the USA numbers for HIV/AIDS?

Answer 4

Total HIV = 1.1 million

New Infections = 50,000/year

Question 5

What are the total world wide deaths from AIDS since the start of the pandemic?

Answer 5

About 36 million

Question 6

Describe the basics of the HIV-1 virus:

Key characteristics, classification, origin

Answer 6

1. Non-transforming retrovirus (aka a RNA virus with NO oncogenes)
2. Brings reverse transcriptase with it to create DNA from its RNA to integrate into the host cell
3. Is a lentivirus (also in sheep, horses, cats)
4. Originated from the Simian Immunodeficiency Virus (SIV) in the 1940s in Zaire (Repub of Congo). Came to USA in 1978 from Haiti.

Question 7

What causes antigenic variability in HIV?

Answer 7

The viral reverse transcriptase is super error prone and creates LOTS of variation.

Question 8

How might a person be resistant to HIV?

Answer 8

Two ways:
1. 32 base pair deletion for chemokine receptor CCR5
CCR5 is an HIV co-receptor
Person that is homozygous for this deletion has good resistance (“long term survivor”)

2. Have the HLA-B57 allele
   Produces Cytotoxic T Lymphocytes that are effective against HIV peptides presented on HLA-B57
   (“Elite controllers”)

Question 9

Pathogenesis of HIV:

What is taking place post exposure during days 0 - 2?

Answer 9

Virus adheres to lectin on dendritic cells –> DC-SIGN.
The dendritic cells then carry the HIV to Th CD4+ cells in the lymph nodes.
HIV enters the Th CD4+ Cells.

Question 10

Pathogenesis of HIV:

What takes place at approximately 4 - 11 days post infection?

Answer 10

HIV replicates in the CD4+ cells inside the lymph nodes.

HIV is released into the blood

Question 11

Pathogenesis of HIV:

At about day 11 post infection:

Answer 11

Virus spreads to other organs.

Question 12

What are the stages of HIV replication once it reaches the lymph nodes?

Answer 12

1. HIV binds its envelope glycoprotein gp120 to the Th CD4+ cells.
2. A conformational change in HIV’s gp120 takes place.
3. HIV is able to bind to the host cell’s CCR5.
4. HIV is injected into Th CD4+ cell.
5. Viral dsDNA from the viral RNA is made using viral reverse transcriptase.
6. Viral dsDNA is inserted via viral integrase into the host cell’s DNA.
7. The cell does the work and creates HIV proteins: gag-pol-env
8. Viral protease cleaves the viral proteins
9. New viral particles bud off host cell & enter blood.

Question 13

What must HIV bring with it into the host cell to be successful?

Answer 13

Viral RNA
Viral reverse transcriptase
Viral integrase
Viral protease

Question 14

When do high blood virus levels peak?

Answer 14

6 weeks

Question 15

What signs are there in the gut mucosa of early HIV infection?

Answer 15

Loss of CD4+ Cells, an increase in gut permeability

Question 16

What is the viral “set point” referring to?

Answer 16

The virus level the patient’s immune system is able to maintain.

Question 17

When does Ab to HIV peak?

Answer 17

At about 9 weeks Ab peaks, and consequently the virus blood levels fall sharply.

Question 18

Without treatment, how long might a patient live with HIV until they have AIDS?

Answer 18

About 9.5 years

Question 19

What is CCR5?

Answer 19

CCR5 is located on Th CD4+ cells and is the main chemokine receptor used by HIV to bind to.

Cells also have CxCR4.

Question 20

What is gp41?

Answer 20

The glycoprotein associated with the HIV envelope glycoprotein gp120.

Question 21

What might become of the Th host cell?

Answer 21

1. May die rapidly - too many virus buds tear holes.
2. May become a persistent virus producer - become memory T-cells in the secondary lymph tissue.
3. May become latent - viral DNA is integrated into host DNA but is not replicated.

Question 22

What is secondary lymph tissue?

Answer 22

Spleen, lymph nodes, lymph tissue in lungs and GI tract.

Question 23

Why is HIV Variation important, and what are the important subtypes to know?

Answer 23

Mutations are advantageous to the virus and can lead to longer survival. Must treat with 3 drugs at a time to even make a strong impact.

Subtype C dominates the epidemic.
Subtype M was the major subtype to transmit from chimp to human.

Question 24

How do CTLs interact with HIV infected T-cells?

Answer 24

CTLs do see infected cells: recognize peptide presented on MHC class I molecules on the infected cells.

CTLs are responsible for the initial drop in plasma virions by week 9.

BUT CTLs can not enter the B-cell follicles where the virus is replicating…so they can’t get ahead of the infection.

Question 25

How do B cells interact with HIV infected T-cells?

Answer 25

Usually Th CD4+ cells activate B-cells to produce Ab. But, disruption of Th cells leads to dysregulation of B cells. B-cells eventually become "exhausted"

Question 26

What are the main outcomes of immune impairment?

Answer 26

1. Impaired cellular immunity (Ag-specific lymphocyte proliferation, IL-2 production, IFN-gamma production, etc) 2. Impaired Ab response

Question 27

Why is TB incidence increasing in areas of high HIV rates?

Answer 27

Not only is there less immune protection from an initial infection, but TB can be reactivated from latent form in those with HIV.

Question 28

Describe the interaction of CMV (cytomegalovirus) and HIV patients:

Answer 28

2/3 of population has CMV - latent, no big deal. | Immunosuppressed patients can reactivate CMV and it can cause blindness.

Question 29

What is the increase in risk for pneumococcal pneumonia for those with HIV?

Answer 29

A 50 - 100 fold increase risk!

Question 30

What co-infections are significant for HIV patients?

Answer 30

1. HSV-2 (herpes) increases risk of transmission of HIV | 2. HIV progression can accelerate in those infected with TB or pneumonia

Question 31

Review: what is Kaposi's Sarcoma?

Answer 31

Herpes virus HHV8 that causes tumor of endothelial cells lining lymphatics.

Question 32

How is HIV diagnosed?

Answer 32

Use an Ab to HIV - -> Test with ELISA - -> Confirm with the Western-blot Test (use gp120 and gp41 and see if patient has the Ab)

Question 33

What are the 5 main mechanisms of treatment used today?

Answer 33

1. Reverse transcriptase inhibitors - can't make viral DNA 2. Protease inhibitors - can't cleave viral protein 3. Fusion inhibitors - binds to gp41 so that viral membrane can't fuse with Th CD4+ 4. CCR5 antagonists - blocks CCR5 from engaging gp120 5. Integrase Inhibitors - viral DNA can't integrate into host DNA

Question 34

Which drugs are generally chosen?

Answer 34

Always use a combination of 3: Use 2 different reverse transcriptase inhibitors (to account for the mutations) Use 1 of the other types of drugs

Question 35

What are the main barriers to a vaccine?

Answer 35

1. virus variability 2. poor immunogenicity of HIV envelope 3. Lack of a good animal model 4. Human trials aren't ethical 5. Masking of neutralizing epitopes (i.e. the key epitope is concealed on the gp120/gp41 complex so that it is invisible to B-cells).

Question 36

Can the future treatment of AIDS rely on Ab?

Answer 36

No - Ab doesn't protect well agains HIV --> B-cells can't see it. Need an increase in Th1 cells and CTLs.

Question 37

What are the barriers to an HIV cure?

Answer 37

1. HIV can go latent - hard to attack. 2. Host immune impairment is difficult to boost 3. Cell reservoirs are difficult to attack

Question 38

What might be the mechanisms of a cure?

Answer 38

1. Flush out the virus from latent cells | 2. Create resistant cells --> use the Zn finger to modify CCR5 gene?