1. HIV susceptibility and CCR5
Anna-Lisa Doebley
Final Presentation
May 6th 2014

2. The HIV/AIDS epidemic
35.3 Million Total

4. The only person who has been cured of HIV:
Timothy Brown was infected with HIV in Controlled the disease with antiretroviral therapy. Developed Leukemia many years later. Treated with a bone marrow transplant from an HIV resistant donor. He no longer has any detectable HIV in his immune system. The success of this treatment has inspired research which may someday cure AIDS.
How?

5. What is the HIV virus? Blood Borne Pathogen Infects Immune cells
Causes AIDS if not treated

6. CCR5 is a gene associated with AIDS resistance
Human
7 tm_1
352aa
352aa
Cellular component: Biological process: Molecular function:
Plasma membrane Cell communication Chemokine binding
Chemokine

7. CCR5 is well conserved across vertebrates
Human
7 tm_1
352aa
Chimpanzee
7 tm_1
352aa 99%
Orangutan
7 tm_1
352aa 99%
Gorilla
7 tm_1
352aa 99%
Mouse
7 tm_1
354aa 82%
Chemokine receptor
Natural function not well known
Chicken
7 tm_1
355aa 62%
Zebrafish
7 tm_1
358aa 42%

8. What is the function of CCR5 in HIV infection?
HIV Virus
CCR5
Host Cell

9. HIV binds CCR5
HIV Virus
CCR5
Host Cell

10. HIV enters the cell
Host Cell

11. CCR5 alleles can block HIV infection
7 tm_1
Human Wild Type
352aa
CCR5 Δ32 allele: 32 bp deletion results in a frame shift and stop codon
7 tm_1
Human Δ32
215aa (31 after frame shift)

12. CCR5 alleles can block HIV infection
WT CCR5
HIV
CCR5 Δ32aaa a
HIV

13. SIVs do not cause AIDS… Why?
Where did HIV come from?
SIV
HIV
HIV evolved from the family of Simian Immunodeficiency Viruses which infect non-human primates
Transmitted from Chimpanzees to humans on several separate occasions
SIVs do not cause AIDS… Why?

14. HIV does not cause AIDS in chimpanzees
WT CCR5
SIV
WT CCR5
HIV

15. Why don’t SIVs cause AIDS?
Goal: understand how non-human primates are able to combat SIV/HIV infection
Hypothesis: sequence similarities between human AIDS-resistant CCR5 alleles and primate CCR5 alleles may help explain AIDS resistance

16. Aim 1: Determine which regions of CCR5 are conserved in non-human primates
7 tm_1
352aa
Chimpanzee
7 tm_1
352aa 99%
Orangutan
7 tm_1
352aa 99%
Chemokine receptor
Natural function not well known
Gorilla
7 tm_1
352aa 99%

17. Approach: Determine which regions of CCR5 are conserved in non-human primates
VandeWoude and Apetrei, 2006
34 species of primates infected
with SIVs (3 progress to AIDS)
22 sequences available
Chemokine receptor
Natural function not well known

18. CCR5 amino acid substitutions in AIDS resistant Primates
7 tm_1
Each blue bar represents an amino acid that is different between different species of primates

19. Aim 2: determine if primate CCR5 alleles are similar to AIDS-resistant human CCR5 alleles.
Carrington et al. 1999
9 CCR5 sequences (3 believed to be AIDS resistant)
**deletion alleles not included
Combine data with
Primate sequences

20. AIDS susceptible allele
AIDS resistant allele

21. CCR5 amino acid substitutions
7 tm_1
Resistant
Susceptible
What is in these regions?

22. Aim 3: Determine if particular protein domains are found in the non-conserved regions of CCR5

23. CCR5 amino acid substitutions affect areas outside of transmembrane domains
7 tm_1
Transmembrane domains

24. Future directions
Sequence the 5’ and 3’ UTRs of primate CCR5 genes Study the sequences of CCR5 genes in other species that are affected by immunodeficiency viruses

25. Sources Images: Info: Human: http://genetics.wisc.edu/Ikeda.htm
Slide 2: Map:
Total statistic:
Slide 3:
Slide 4:
Slide 5:
Slide 6:
Slide 7: Plasma membrane:
Communication:
Chemokine: Modified image from Akihiro Ikeda
Slides 9 to 11: Modified image from: Image:
Slide 13: Sick Person: person-300x286.jpg
Healthy Person: jogging_cartoon_03.jpg
Slide 15: Chimpanzee: chimp_763_600x450.jpg
Human:
“SIV” virus:
Slide 16: Monkey:
Info:
Naif HM Pathogenesis of HIV Infection. Infect Dis Rep 5:e6.
de Groot NG, Bontrop RE The HIV-1 pandemic: does the selective sweep in chimpanzees mirror humankind's future? Retrovirology 10:53.
Wooding S, Stone AC, Dunn DM, Mummidi S, Jorde LB, Weiss RK, Ahuja S, Bamshad MJ Contrasting effects of natural selection on human and chimpanzee CC chemokine receptor 5. Am J Hum Genet 76:
Carrington M, Dean M, Martin MP, O'Brien SJ Genetics of HIV-1 infection: chemokine receptor CCR5 polymorphism and its consequences. Hum Mol Genet 8:
VandeWoude S, Apetrei C Going wild: lessons from naturally occurring T-lymphotropic lentiviruses. Clin Microbiol Rev 19:

26. Questions??