Jakub vaccines and HIV

Question 1

what kind of virus is HIV?

Answer 1

lentivirus

Question 2

Two main types of HIV and 4 groups associated with the former?

Answer 2

HIV-1 and HIV-2 (restricted to west Africa)

HIV-1 includes MNOP (M and N from chimpanzees and O and P from gorillas).

Question 3

5 routes of HIV transmission?

Answer 3

sexual,
vertical (exposure to blood and fluids in the birth canal)
IV drug use, blood transfusions and work-related exposure

Question 4

What integrin does on target cells do V1/V2 loop of env proteins bind to for entry?

Answer 4

a4b7 (integrin on host cell), binding causes a conformational change that allows co receptor proximity.

Question 5

What co-receptors does HIV bind to?

Answer 5

CCR5 and CXCR4

Question 6

Why is there high levels of mutations and variation within HIV populations (quasispecies)?

Answer 6

Due to the high rate of reverse transcriptase error, and diploid RNA recombination.

Question 7

What are the main clades of HIV-1 M group in Europe and Sa?

Answer 7

Europe and America is clade B. In SA and India, it is clade C

Question 8

Three general phases of HIV patient Ab responses?

Answer 8

1) non-neutralising igM response to acute infection.
2) Non-neutralising IgG response (2- 3 weeks after exposure)
3) Neutralising Ab against V1/2/3 regions of gp120 after 3-12 month?

Question 9

Problem with Ab response against V1/2/3 regions of gp120?

Answer 9

These are highly variable sites that are susceptible to HIV escape.

Question 10

3 ways Ab could fight against HIV?

Answer 10

neutralisation, FC dependent antiviral activities, and inhibition of viral transcytosis and intracellular neutralisation .

Question 11

Does CD4+ T cell destruction affect Ab response?

Answer 11

Yes there will be poor T cell help for B cell responses and somatic hypemutation.

Question 12

how does aspects of glycoproteins impair the B cell responses?

Answer 12

Extensive glycan shields are poorly immunogenic.
Conserved/ functionally important epitopes shielded by this.
V2 loops block CD4+ T cell binding site, and V1 nad V” loops cover the C3 loops associated with the cro receptor.

Question 13

3 Characteristics of BnAbs

Answer 13

1) lots of exposure to HIV variants and somatic hypermutation.
2) Lots of indels in light and heavy chains
3) elongated HCDR3 to access underneath glycan shield/

Question 14

3 targets of BnAbs?

Answer 14

1) CD4 T cell binding site
2) N glycans of gp120 and gp141 bridging region,
3) membrane proximal region.

Question 15

The phenotype of Tfh cells for extensive SHM?

Answer 15

CD4+ CVCR3- PD1+ CXCR5 CCR7- (located in lympho nodes)

Question 16

Three kinds of costimulatory molecules important for B and Tell interactions.

Answer 16

CD40-CD40L
ICOS:ICOSL
SLAM

Question 17

How could autoreactive preursor B cells be activated for HIV?

Answer 17

Because they may haev some autoreactivity but also cross-reactivity with gp120 that might make them good for SHM to generate BnAbs.

Question 18

Why might using adenovirus vectors be seen as risky?

Answer 18

Because people have existing repsonse against them and activated T cells may increase HIV susceptibility.

Question 19

Which vaccine has demonstrated the most efficacy so far?

Answer 19

RV144- ALVAX and AIDSVAX heterologous prime boost.

Question 20

correlates of protection with RV144

Answer 20

1) non neutralisting Ab against V1/2 (via ADCC?)
2) however this was negated by IgA specific responses
3) CD4+ T cells with specific cytokine profiles.

Question 21

Two strategies for generatign betteer BnAbs?

Answer 21

1) trimers of gp120 should be used (or use BCR sequencing to help design trimer immunogens)
2) identify B cell precursors with long HCDR3 regions./