HIV Part 1 Wk 3

Question 1

Overview + classification Baltimore class VI

Answer 1

ICTV classification = family retrovididae

Question 2

Structure

Answer 2

Small linear ssRNA genome of positive (+) sense
Virions contain 2 copies of genome (diploid)
Small enveloped capsid (deformed icosahedron = cone-shaped

Question 3

Retroviruses known to infect humans
Class VI Baltimore system

Answer 3

HIV-1, HIV-2 AIDS

HTLV-1, HTLV-2 adult T-cell lymphomas

HTLV-3, HTLV-4 no symptoms identified

Question 4

Family retroviridae has several sub-families

Question 5

Origins of HIV-1

Answer 5

From simian immunodeficiency virus (SIV) infections in primate species 4 times
Continued genetic variation in humans has given rise to 4 HIV-1 types (groups/genogroups)
M,N,O - simian immunodeficiency virus in chimps SIVcmp
P - simian immunodeficiency virus in gorilla SIVgor

Question 6

M group is dominant globally

Answer 6

Circulating recombinant form genomes seen in few individuals

Question 7

C = Southern/eastern Africa,
A= eastern Africa, Asia
B = North/south America, Australia, Europe

Answer 7

F = Eastern Europe, South America
E,G,H,J,K = central/west Africa

Question 8

Origins of HIV-2

Answer 8

Evolved from simian immunodeficiency virus in sooty mangabey SIVsmm
A+B groups widespread - west Africa!
C-H unique genomes found only in 1 or 2 individuals

Question 9

Structural detail

Answer 9

Protease
Lipid membrane
Gagp17 matrix protein
P7 nucleocapsid protein
if,Vpr,Nef
Reverse transcriptase
Integrase
P24 capsid protein
Gp41 virus fusion protein
Gp120 virus attachment protein

Question 10

Retrovirus genome – core coding regions

Question 11

Retrovirus genome – regulatory regions

Question 12

Complex retrovirus genomes (e.g. HIV) code for additional proteins

Answer 12

Tat
Rev
Vif
Nef
Vpr
Vpu HIV-1
Vpx HIV-2

Question 13

HIV is transmitted to new hosts via blood transfer …..

Answer 13

Direct sexual contact
Vertical transmission (mother baby)
Injection processes or injuries
Latrogenic transmission (contaminated blood)

Question 14

HIV replication cycle - attachment & penetration

Answer 14

Receptors = CD4 - plasma membrane protein (similar to immunoglobulins)
- T-helper lymphocytes and macrophages (monocytes)
Co-receptor = 1 of 2 B-chemokine receptors
CCR-5 on macrophages/monocytes
CXCR-4 on T-helper lymphocytes

Question 15

Virus attachment protein = gp120 envelope glycoproteins (trimer)

Question 16

Coreceptor CCR5

Answer 16

Found on macrophages
M-tropic (R5) strains
Majority of circulating HIV subtypes

Question 17

Coreceptor CXCR4

Answer 17

Found on T-helper lymphocytes
T-tropic (X4) strains
Some circulating subtypes, often develop in host over lifetime (mutation events)

Question 18

Antiviral drug target - gp120 and CCR5 coreceptor binding

Answer 18

Maraviroc CCR5 coreceptor antagonist
Binds to CCR5 and competes with gp120
Inhibits binding of gp120 with coreceptor CCR5
Blocks infection of macrophages by M-tropic HIV types

Question 19

Antiviral drug target - gp120 and attachment

Answer 19

Ibalizumab humanised monoclonal antibody
Binds to CD4 extracellular domain 2, with some attachment across domain 1
Steric hindrance blocks conformation change in gp120 bound to the CD4 molecule - V1 and V2 cannot rotate out of position
Prevents exposure of V3 loop = gp120 cannot bind to a co-receptor protein

Question 20

Virus fusion protein = gp41 envelope glycoproteins (trimer)

Answer 20

Binding of gp120 to co-receptor (via V3 loop) causes conformational change
GP41 anchoring/fusion protein regions of the trimer are exposed

Question 21

Antiviral drug target - gp41 and the fusion process

Answer 21

Enfuvirtide fusion peptide mimic
Same amino acid sequence as gp41 fusion peptide domain (heptagon repeat region)
Enfuvirtide bonds to the heptane regions, stabilising this conformation
Heptads unable to change conformation - no fusion between virus envelope and plasma membrane

Question 22

HIV resistance - mutation in CCR5 coreceptor gene

Answer 22

CCR5 = transmembrane protein on macrophages cells
7 membrane-spanning domains
3 external loops
Co-receptor for attachment/penetration of M-trophic (R5) HIV subtypes

Question 23

HIV resistance - mutation in CCR5 coreceptor gene

Answer 23

CCR5 - a32 mutation
= deletion of 32-bp (nucleotides 794 to 825)
Truncated protein (frame shift)
-4 membrane-spanning domains
-1 external loop
Individuals carrying mutation are partially (heterozygous) of fully (homozygous) resistant to M-trophic (R5) HIV subtypes

Question 24

CCR5-a32 - basis for treatment

Answer 24

2007 charite hospital, Berlin
Bone marrow transplant for leukaemia in HIV-positive patient Timothy Ray Brown
2016 Chelsea + Westminster hospital, london
Bone marrow transplants for Hodgkin’s lymphoma in HIV-positive patient Adam Castillejo