Immunology of AIDS & Drugs

Question 1

What does it mean to be HIV-seropositive?

Answer 1

People are ‘seropositive’ if they have antibody to HIV, which is the most common way in which infection is first detected

Question 2

When is someone considered to have AIDS?

Answer 2

HIV-seropositive individuals once they get symptoms of opportunistic infections or Kaposi’s sarcoma, or their Th (CD4+) cells fall below 200/uL of blood. (normal range: 500-1000/

Question 3

What virus causes AIDS?

Answer 3

HIV-1, for Human Immunodeficiency Virus. HIV is a nontransforming retrovirus (carries no oncogene), and reproduces by its RNA into DNA by means of reverse transcriptase.

Question 4

T or F: HIV evolved from SIV (simian immunodeficiency virus)

Answer 4

True

Question 5

Where/when did HIV originate from?

Answer 5

as recently as the 1940s and possibly in Zaire

Question 6

What is the approximate number of cases in the U.S. and in the world?

Answer 6

• US: 1,144,500 people (16% don’t know it)

- World: 35.3 Million

Question 7

How many new cases of HIV infection per year in the US?

Answer 7

50,000

Question 8

When do blood virus level peak?

Answer 8

6 weeks

Question 9

When do blood anti-HIV Abs peak?

Answer 9

9 weeks

Question 10

What is the mean incubation period of HIV without treatment?

Answer 10

9.5 years

Question 11

T or F: HIV is taken up by dendritic cells but not harmed

Answer 11

True. They bind to DC-SIGN on DC and use it as a mean to get to T cells.

Question 12

Where does HIV bind on the CD4 T cell?

Answer 12

on the CD4 molecule……

Question 13

What on HIV surface binds to CD4? What does that lead to?

Answer 13

gp120 binds to CD4, changes conformation and is now allowed to bind to CCR5 (gp120 co-receptor, known chemokine receptor)

Question 14

How is gp41 activated?

Answer 14

by the binding of gp120 to CCR5

Question 15

How does gp41 allow entry of virus into cell?

Answer 15

By exposing a very hydrophobic region that literally melts away the T cell’s membrane, so the cell and virus fuse.

Question 16

How does HIV show diversity in proteins with a small genome?

Answer 16

• Uses 3 different reading frames to encode 9 genes: pol, env, and gag which are common to all RT viruses. Additionally, has 6 more genes regulating latency and virulence
• alternative RNA splicing, and
• protease-mediated cleavage of 3 large precursor proteins making a total of 16 polypeptides.

Question 17

How is latency regulated?

Answer 17

It may be that HIV goes latent in resting cells and replicates productively in activated ones (that’s the proposed idea, no evidence).

Question 18

T or F: the response to HIV is tilted towards Tfh and Th2 rather than Th1

Answer 18

True. the helping of CTL activation via IL-2 from Th1 is diminished

Question 19

What change in the immune system promote a better response against HIV?

Answer 19

If patients made more Th1 they might stimulate more CTL, and do better.

Question 20

What kind of immunity is affected in AIDS?

Answer 20

Cell-mediated immunity

Question 21

What types of infections seen in AIDS patients?

Answer 21

primarily of types that require T cell-mediated immunity.

• viral infection, including cytomegalovirus, hepatitis and especially herpes simplex and zoster
• fungi, especially Candida albicans and Pneumocystis jirovecii
• opportunistic intracellular bacteria usually Mycobacterium avium complex or MAC and M. tuberculosis (leading cause of death in AIDS pts)

Question 22

Why does the total number of CD4 cells decline?

Answer 22

looks like simple exhaustion of the ability to make more of them. it has been estimated that the entire population of virus is replaced daily, and CD4 cells every 3 days

Question 23

How does HIV infect near by cells without an extracellular phase?

Answer 23

Early expression of gp120 & 41, relocation to plasma membrane, binding to near by cells resulting in fusion of the two cells and formation of a syncytium.

Question 24

Are Abs effective against HIV?

Answer 24

No, Though they bind to the virus, they do not block infection of Th cells. There are neutralizing epitopes on the virus, but they are shielded by carbohydrate (gp120/41) and not readily available to B cells.

Question 25

What are elite controllers?

Answer 25

They make more, and more diverse, CTL against HIV peptides. They are HLA-B57. harbor HIV but retain normal immune function for many years

Question 26

What is the laboratory diagnosis process of AIDS?

Answer 26

Most common: Anti-HIV antibody via ELISA, HOWEVER, must be confirmed with a western blot due to false positives.
Virus RNA PCR, available in wealthy areas.

Question 27

Discuss the prospects and problems of AIDS vaccine development

Answer 27

we need a vaccine that can preferentially stimulate Th1 cells and CTL; the current vaccines seem to be best at inducing antibody responses, and antibody doesn’t protect very well. The key epitope on HIV seems to be well-concealed within the gp120/gp41 complex and almost invisible to B cells
-some people make is broadly neutralizing (bnAb)

Question 28

What is the standard Antiretroviral Therapy (ART)?

Answer 28

combines a protease inhibitor and two reverse transcriptase inhibitors

Question 29

What HIV drugs are targeted at RT?

Answer 29

RT inhibitors:

• nucleosides, which are competitive inhibitors and chain-terminator
• non-nucleoside inhibitors, bind a hydrophobic pocket on enzyme, changes the conformation and activity of the catalytic site.

Question 30

What kind of drugs inhibit cleavages of the pol-gag-env polyprotein?

Answer 30

protease inhibitors.

Question 31

What is Enfuvirtide (Fuzeon®)?

Answer 31

binds to part of gp41, prevents fusion b/t virus and cell. Fusion inhibitor.

Question 32

Maraviroc (Selzentry®)?

Answer 32

CCR5 antagonist that blocks viral entry into CD4+ cells. Binds transmembrane portion of CCR5

Question 33

Raltegravir, what it do?

Answer 33

integrase inhibitor, inhibits insertion of virus genome in host DNA.