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??