HIV

Question 1

First cases of HIV

Answer 1

~1950

Zaire, Cameroon

Question 2

Is HIV enveloped?

Answer 2

yes

Question 3

Estimated number of people living with HIV/AIDS in 2012

Answer 3

35.3 million

Question 4

Estimated number of AIDS deaths in 2012

Answer 4

1.6 million

Question 5

Proteins making up membrane spike

Answer 5

gp41 (membrane spike), gp120 (trimer)

Question 6

HIV matrix protein

Answer 6

p17

Question 7

HIV capsid protein

Answer 7

p24

Question 8

HIV nucleocapsid protein

Answer 8

p7

Question 9

HIV reverse transcriptase protein

Answer 9

p66/51

Question 10

HIV integrase protein

Answer 10

p32

Question 11

HIV protease protein

Answer 11

p11

Question 12

HIV structural proteins of the matrix, capsid, core, nucleocapsid

Answer 12

gag

Question 13

HIV viral enzymes

Answer 13

pol

Question 14

HIV viral envelope proteins

Answer 14

env

Question 15

Contents of gag

Answer 15

HIV structural proteins

Capsid, nucleocapsid, core, matrix

Question 16

Contents of pol

Answer 16

Viral enzymes

Question 17

Contents of env

Answer 17

HIV viral envelope proteins

Question 18

How are gag and pol expressed?

Answer 18

As a polyprotein, before autocleavage

Question 19

HIV genome

Answer 19

2 identical copies of + sense RNA

Question 20

Mistake rate of HIV reverse transcriptase

Answer 20

~1 mistake per 10,000 bases

Roughly one mistake per copy of genome

Question 21

HIV replication cycle
1)
2)
3)
4)
5)
6)
7)
8)

Answer 21

1) gp120 binds CD4
2) Fusion of envelope with host cell membrane
3) Reverse transcriptase makes DNA copy of genome
4) DNA separated into two linear strands
5) Integrase integrates viral genome into host genome
6) mRNA of viral genes produced
7) Assembly
8) Budding

Question 22

Phases of HIV infection
1)
2)
3)

Answer 22

1) Primary infection - massive loss of CD4+ cells, high viral load
2) Clinical latency - Viral replication, slightly contained by immune system. Gradual decline in immune system function
3) AIDS

Question 23

CCR5

Answer 23

Coreceptor of CD4 for HIV gp120

Question 24

[CD4+] threshold for opportunistic infection

Answer 24

200 CD4+/mL

Question 25

Extent of HIV killing of immune cells in gut

Answer 25

Kills ~60% of GALT within days of infection

Question 26

Effect of HIV infection on gut

Answer 26

Loss of tight junctions Enterocyte apoptosis This leads to microbial invasion (LPS) Intestinal fatty acid binding protein (I-FABP)

Question 27

Undetectable viral load

Answer 27

<50 viral copies/mL

Question 28

How does HIV evade the immune system?

Answer 28

1) Extremely high mutation rate 2) Deletion of HIV-specific CD4 clones 3) Faliure of HIV-specific Ab, CTL

Question 29

Effects of HIV infection on immune function

Answer 29

Decrease in Th function Decrease in neutrophil killing Decrease in NK killing Th can't activate B cells, macrophages Macrophages decrease chemotaxis, phagocytosis, killing B cells produce more antibodies, autoantibodies, respond poorly to vaccines, reduce killing of encapsulated bacteria

Question 30

``` Targets for anti-HIV therapy 1) 2) 3) 4) ```

Answer 30

1) Fusion, entry inhibitors 2) Reverse transcriptase inhibitors 3) Integrase inhibitors 4) Protease inhibitors

Question 31

HAART

Answer 31

Highly active antiretroviral therapy | Use a combination of antiretroviral drugs

Question 32

Advantages of HAART

Answer 32

Minimise chance of resistance development

Question 33

Shortened life expectancy of HAART patients

Answer 33

About 10 years less than healthy controls

Question 34

``` Difficulties in making an HIV vaccine 1) 2) 3) 4) 5) ```

Answer 34

1) Natural immune response fails to control the virus 2) Mechanisms of immune control of HIV incompletely understood 3) Very high HIV sequence diversity 4) HIV can evade antibodies, CTL, NK 5) HIV latency and genome integration

Question 35

Immune responses desired for an HIV vaccine 1) 2)

Answer 35

1) CD8+ - Kill HIV infected cells Could silence HIV for a functional cure 2) Antibodies - Prevent transmission Evaded by sequence variation in the viral envelope

Question 36

Difference in binding location between neutralising and non-neutralising antibodies against HIV

Answer 36

Neutralising antibodies bind to structured p120 trimers Non-neutralising antibodies bind highly immunogenic inner face of gp120 monomers

Question 37

Qualities of broad-neutralising antibodies

Answer 37

Long CDRH domain | Highly mutated

Question 38

Issues with dead protein HIV vaccines

Answer 38

Efficacy

Question 39

Issues with live attenuated HIV vaccines

Answer 39

Safety

Question 40

Issues with genetically engineered live vector HIV vacciens

Answer 40

Require new technology

Question 41

Phase I clinical trials

Answer 41

10-30 volunteers | 8-12 months

Question 42

Phase II clinical trials

Answer 42

50-500 volunteers | 18-24 months

Question 43

Phase III clinical trials

Answer 43

Thousands of volunteers | 3 years or more

Question 44

Outsome of B-clade vaccine in Sydney, 2003-2005

Answer 44

Poor CD8, CD4 response

Question 45

Merck STEP trial

Answer 45

rAd5 expressing HIV B clade gag, Pol, Nef. Strong CD4, CD8 response Expected to reduce viral load, have no effect on transmission

Question 46

rAd5

Answer 46

Recombinant adenovirus type 5 | Expressing HIV gag, pol, nef

Question 47

Outcome of STEP trial

Answer 47

Vaccine enhanced rate of HIV infection

Question 48

RV-144 vaccine efficacy

Answer 48

~31%

Question 49

RV-144 vaccine effects

Answer 49

No obvious impact on viral load No obvious correlates with immunity Limited CD8 immunity Limited primary neutralising antibodies

Question 50

Vaccine trials against HIV

Answer 50

1) STEP 2) B-clade in Sydney 3) RV-144

Question 51

Animal that naturally produces broad neutralising antibodies

Answer 51

Macaques | Against chimeric simian-human immunodeficiency viruses

Question 52

Reason for few broad-neutralising antibodies being produced naturally in body

Answer 52

Most are autoreactive, or have many mutations - eliminated by tolerance mechanisms HIV envelope is similar to host antigens