HIV susceptibility and CCR5
Anna-Lisa Doebley Final Presentation
May 6th 2014
The HIV/AIDS epidemic
35.3 Million Total
The only person who has been cured of HIV:
How?
Blood Borne Pathogen
Infects Immune cells
Causes AIDS if not treated
What is the HIV virus?
CCR5 is a gene associated with AIDS resistance
352aa7 tm_1Human 352aa
Cellular component: Biological process:Molecular function:Plasma membrane Cell communicationChemokine binding
Chemokine
CCR5 is well conserved across vertebrates
352aa7 tm_1
7 tm_1 352aa 99%
7 tm_1
7 tm_1
Human
Chimpanzee
7 tm_1
7 tm_1
7 tm_1
352aa 99%Orangutan
Gorilla
Mouse
Chicken
Zebrafish
352aa 99%
354aa 82%
355aa 62%
358aa 42%
What is the function of CCR5 in HIV infection?HIV Virus
Host Cell
CCR5
HIV binds CCR5
Host CellCCR5
HIV Virus
HIV enters the cell
Host Cell
CCR5 alleles can block HIV infection
7 tm_1Human Wild Type 352aa
215aa (31 after frame shift) 7 tm_1
Human Δ32
CCR5 Δ32 allele: 32 bp deletion results in a frame shift and stop codon
CCR5 Δ32aaa a
CCR5 alleles can block HIV infection
WT CCR5
HIV
HIV
Where did HIV come from?
SIV HIV
SIVs do not cause AIDS… Why?
HIV does not cause AIDS in chimpanzees
SIV
HIV
WT CCR5
WT CCR5
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
Aim 1: Determine which regions of CCR5 are conserved in non-human primates
352aa7 tm_1
7 tm_1 352aa 99%
7 tm_1
7 tm_1
Human
Chimpanzee
352aa 99%Orangutan
Gorilla 352aa 99%
Approach: Determine which regions of CCR5 are conserved in non-human primates
VandeWoude and Apetrei, 200634 species of primates infected with SIVs (3 progress to AIDS)
22 sequences available
CCR5 amino acid substitutions in AIDS resistant Primates
0 50 100 150 200 250 300 350 400
CCR5 Protein Sequence
Each blue bar represents an amino acid that is different between different species of primates
7 tm_1
Aim 2: determine if primate CCR5 alleles are similar to AIDS-resistant human CCR5 alleles.
Carrington et al. 19999 CCR5 sequences (3 believed to be AIDS resistant)**deletion alleles not included
Combine data with Primate sequences
AIDS susceptible allele
AIDS resistant allele
0 50 100 150 200 250 300 350 400
CCR5 Protein Sequence
ResistantSusceptible
CCR5 amino acid substitutions
What is in these regions?
7 tm_1
Aim 3: Determine if particular protein domains are found in the non-conserved
regions of CCR5
0 50 100 150 200 250 300 350 400
CCR5 Protein Sequence
CCR5 amino acid substitutions affect areas outside of transmembrane domains
7 tm_1
Transmembrane domains
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
SourcesImages: Slide 2: Map: http://www.who.int/hiv/data/global_data/en/
Total statistic: http://www.who.int/gho/hiv/epidemic/hiv_001.jpgSlide 3: http://www.redpepper.co.ug/hivaids-patients-hit-hard-by-health-workers-strike/Slide 4: http://en.wikipedia.org/wiki/Signs_and_symptoms_of_HIV/AIDSSlide 5: http://a.abcnews.com/images/Health/wabc_berlin_patient_120724_wg.jpgSlide 6: http://siklusair.com/what-does-hiv-virus-look-likeSlide 7: Plasma membrane: http://www.scs.illinois.edu/~mlkraft/images/cell%20membrane%20smaller.jpg
Communication: http://openclipart.org/image/800px/svg_to_png/183631/communication.pngChemokine: Modified image from Akihiro Ikeda
Slides 9 to 11: Modified image from: Image: http://www.niaid.nih.gov/SiteCollectionImages/topics/hivaids/hivReplicationCycle.gifSlide 13: Sick Person: http://1.bp.blogspot.com/-aZDdz8HAmWU/TlWCfOxg3kI/AAAAAAAAAD0/Pr3HpiZ5yV4/s1600/sick- person-300x286.jpg
Healthy Person: http://classroomclipart.com/images/gallery/Clipart/Sports/Jogging_Clipart/ jogging_cartoon_03.jpgSlide 15: Chimpanzee: http://images.nationalgeographic.com/wpf/media-live/photos/000/007/cache/young-chimp_763_600x450.jpg
Human: http://genetics.wisc.edu/Ikeda.htm“SIV” virus: http://aidsthekiller.files.wordpress.com/2010/04/hiv-virus-picture.png
Slide 16: Monkey: http://bestclipartblog.com/clipart-pics/monkey-clipart-6.jpg
Info:• Naif HM. 2013. Pathogenesis of HIV Infection. Infect Dis Rep 5:e6.• de Groot NG, Bontrop RE. 2013. 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. 2005. Contrasting effects of natural selection
on human and chimpanzee CC chemokine receptor 5. Am J Hum Genet 76:291-301.• Carrington M, Dean M, Martin MP, O'Brien SJ. 1999. Genetics of HIV-1 infection: chemokine receptor CCR5 polymorphism and its
consequences. Hum Mol Genet 8:1939-1945.• VandeWoude S, Apetrei C. 2006. Going wild: lessons from naturally occurring T-lymphotropic lentiviruses. Clin Microbiol Rev 19:728-
762
Questions??