1. HIV/AIDS

2. HIV
World view
Virus lifecycle
Suface receptors
Tropism
Escape from CTL killing
Drug resistance
Role of APOBEC3G
HIV vaccine strategies
Reading: Parham Chapter 9

3. Global distribution of HIV infection

4. HIV structure

6. HIV is a simple virus with only 9 genes encoding 15 proteins.
HIV is a retrovirus, with a 9.2 kilobase RNA genome that is copied into DNA by reverse transcriptase.
The dsDNA copy is then inserted into the host genome.

7. Nothing is known about how HIV avoids NK mediated lysis
Downregulation of MHC class I
transcription
ER retention
Internalization
from surface
Downregulation of APOBEC G3
Binds uracil-DNA glycosylase (UNG)

8. Figure 9-15 part 1 of 4

9. Protease dependent maturation of HIV envelope

10. HIV infects cells that coexpress CD4 and either CCR5 or CXCR4 chemokine receptors.
This leads to infection of either macrophages, which express low levels of CD4 and CCR5, or helper T cells, which express high levels of CD4 and CXCR4.

11. HIV evolves in the host from primary infections with M-tropic virus, to the AIDS inducing L-tropic form.
L-tropic
M-tropic

12. Some HIV infected people who are long term non-progressors to AIDS carry a recessive mutation in CCR5
10% frequency in some populations = ~1% mutant homozygotes

13. Figure 9-15 part 2 of 4

14. Red=RNA
Blue=DNA
Reverse transcriptase conversion of HIV RNA genome to double stranded DNA
Reverse transcriptase has a high error rate, contributing to virus variability and escape mutants
See next slide

15. dsDNA of HIV
HIV integrase inserts reverse transcribed HIV DNA into host cell chromosome

16. Figure 9-15 part 3 of 4

17. Late gene expression generates structural proteins and the viral genome (unspliced)
Early gene expression generates regulatory proteins

18. Figure 9-15 part 4 of 4

19. Figure 9-18

20. Figure 9-16

21. Figure 9-17

22. Figure 9-21

23. Figure 9-22

27. Mutated TCR contact residues
HIV escape mutants that avoid cytotoxic T cell killing
Mutations that affect processing of peptide to a size that can be held by MHC class I
Mutated anchor residues
Mutated TCR contact residues

28. Evidence for intense selection for mutational variants in patients1 2 3 4 5
Sequence difference 6 7 8 9
time

31. Figure 9-19

32. Figure 9-20

33. Viral recombination can lead to fears about rapid acquisition of multidrug resistance

34. Sequence evidence that HIV may have jumped from chimpanzees to humans (and vice versa)

35. HIV-1 group M is believed to have arisen very recently

36. APOBEC3G
is an AID related cytidine deaminase that suppresses viral disease by mutating single stranded DNA intermediates.
HIV vif protein binds APOBECG3 and targets it for proteasomal degradation.

37. Ways that antibodies can suppress HIV

38. gp41
gp120

39. Evidence for intense selection for mutational variants in patients1 2 3 4 5
Sequence difference 6 7 8 9
time

40. Vaccine generation
Current vaccines issues include the problem of generating immunogens that include the trimeric form of gp120 to elicit neutralizing antibodies and strategies to get cytoplasmic expression to promote CTL priming.
Because of the ability of HIV to undergo recombination, the use of attenuated HIV virus as vaccine has been abandoned for now.
One promising approach is DNA vaccination, in which expression plasmids that drive expression of HIV protein subunits are introduced into host cells.
So far, all attempts of generating HIV vaccines have failed.

41. Concepts
HIV is a major public health problem
Its high mutation rate combined with the ability to kill CD4 T cells accounts for its deadliness.
CTL and antibodies probably keep the disease at bay and direct viral evolution.
Virus countermeasures against the immune system include suppression of MHC class I, class II and CD4. Suppression of APOBEC3G, and probably other mechanisms.
Development of a vaccine represents a major challenge.