Lecture 15 - HIV Biomedical Prevention, Possible Cures

Question 1

Behavioural ways to prevent HIV
1)
2)
3)

Answer 1

1) Education
2) Testing
3) Condoms

Question 2

Biological ways to prevent HIV
1)
2)
3)
4)

Answer 2

1) Vaccine
2) Microbicides
3) Antiretroviral therapy
4) Treat sexually-transmitted infections (increase risk of transmission)

Question 3

PREP

Answer 3

Pre-exposure phrophylaxis

Treat with cART before exposure to HIV

Question 4

Possible vaccine approaches
1)
2)
3)
4)
5)
6)
7)

Answer 4

1) Recombinant proteins
2) DNA vaccines
3) Live vector vaccines
4) Live attenuated
5) Prime boost
6) Broadly-neutralising antibodies
7) CMV vectors

Question 5

HIV recombinant protein vaccine

Answer 5

Good antibody response, no T cell response

Provides no protection

Question 6

HIV DNA vaccines

Answer 6

Good T cell response, poor antibody response

Question 7

HIV live-vector vaccines

Answer 7

1) Non-replicating poxvirus vector provides good T cell activation
2) Ad5 vector used in STEP trial. Might have increased risk of disease

Question 8

Problems with live attenuated HIV vaccine

Answer 8

Potentially unsafe

Could revert to virulence

Question 9

What is a prime boost vaccine?

Answer 9

DNA vaccine + protein or vector

Question 10

Possible pro of CMV vaccine

Answer 10

Constant antigen presentation

Question 11

Example of a prime boost vaccine

Answer 11

ALVAC + gp120

Provided 30% protection

Question 12

Example of a DNA prime + recombinant Ad5 boost vaccine

Answer 12

1) DNA vaccine for gag, env, nef, pol at weeks 0, 4, 8
2) rAd5 boost of gag, pol, env at week 24

Not effective

Question 13

When do broadly neutralising antibodies normally appear?

Answer 13

1-2 years into infection

At this point in infection, don’t help patient

Question 14

Leukophoresis

Answer 14

Isolates T cells

Question 15

Immune response elicited by CMV vectors
1)
2)
3)

Answer 15

1) Unconventional MHCII-restricted CD8+ response
2) Breadth of epitope recognition
3) Promiscuity

Question 16

How much does male circumcision protect against HIV infection?

Answer 16

70%

Question 17

How does male circumcision decrease HIV infection rate?

Answer 17

Langerhans cells in foreskin are absent

Langerhans cells are what bring HIV into lymph nodes

Question 18

Microbicide that can protect against HIV infection

Answer 18

Tenofovir

Question 19

Tenofovir

Answer 19

Nucleoside reverse transcriptase inhibitor

Question 20

BAT24 gel

Answer 20

Contains tenofovir

Applied 24 hours before sex, 24 hours after sex

Question 21

Efficacy of tenofovir

Answer 21

30% reduction in female transmission

Question 22

Antivirals given as PREP

Answer 22

Tenofovir

Truvada

Question 23

PREP

Answer 23

Give tenofovir, truvada daily to uninfected, but at risk of infection

Question 24

PREP efficacy

Answer 24

Oral truvada decreased transmission among gay men by 40%, up to 70% if compliance was high

Question 25

Does treatment with HAART decrease chance of transmission?

Answer 25

Yes | 97% reduction in discordant couples

Question 26

Discordant couple

Answer 26

One partner HIV+, one partner HIV-

Question 27

Most effective means of preventing transmission

Answer 27

ART treatment

Question 28

Two different models of HIV cure

Answer 28

1) Cure - Complete absence of HIV-infected cells | 2) Remission - Undetectable level of HIV with cessation of ART

Question 29

Sterilising HIV cure

Answer 29

A complete cure <1 HIV RNA copy/mL

Question 30

Functional HIV cure

Answer 30

Remission of HIV <50 HIV RNA copy/mL

Question 31

Proof of possibility of cure 1) 2)

Answer 31

1) Berlin patient - Cured after receiving bone marrow transplant from a naturally-resistant donor 2) Mississippi baby - Born to HIV+ mother, given ART within 30 hours of birth. Cleared infection

Question 32

Reasons for viral resurgence after ART stopped 1) 2) 3)

Answer 32

1) Latently-infected T cells 2) Residual viral replication 3) Anatomical reservoirs

Question 33

HIV latency

Answer 33

In resting T cells, HIV proteins not expressed When T cell is activated, HIV replication begins, other cells infected Latent cells are very long-lived (EG: macrophages, memory T cells) and always infectious

Question 34

Estimated number of latently-infected T cells in a patient controlling HIV with ART

Answer 34

~60/million T cells infected

Question 35

Latent reservoir of cells

Answer 35

Naive, transitional memory, central memory T cells

Question 36

Residual replication

Answer 36

ART can't prevent all HIV replication | Replication continues at a low level

Question 37

Anatomical reservoirs

Answer 37

Brain, testes, gut, lymph nodes

Question 38

Cells in anatomical reservoirs in which HIV resides

Answer 38

Macrophages Astrocytes Dendritic cells

Question 39

Possible way to eliminate infected cells 1) 2)

Answer 39

1) Activate latently-infected cells | 2) This makes cells display virus-infection markers, will be destroyed by immune system

Question 40

Candidate for activating latently-infected cells

Answer 40

Histone deacetylase inhibitors Promote transcription of all genes, including HIV genes --> Turn HIV genes on

Question 41

``` Possible anti-HIV gene therapies 1) 2) 3) 4) ```

Answer 41

1) RNA interference --> block action of HIV genome 2) Express an anti-viral factor --> Mutant APOBEC3G 3) Remove an essential host factor --> CCR5 4) Block LTR of integrated HIV

Question 42

Way to eliminate CCR5 expression

Answer 42

Zinc-finger nuclease heterodimer Cuts part of CCR5, inactivates it

Question 43

``` Possible application of gene therapy 1) 2) 3) 4) ```

Answer 43

1) Take blood, isolate T cells with leukophoresis 2) Remove CCR5 from T cells with zinc-finger nucelase 3) Reinfuse T cells 4) HIV will kill off CCR5+ cells, not CCR5- cells