The Influence of CCL3L1 Gene-The Influence of CCL3L1 Gene-Containing Segmental Duplications Containing Segmental Duplications

on HIV-1/AIDS Susceptibilityon HIV-1/AIDS Susceptibility

Gonzalez et al. Mar 4, 2005 :Gonzalez et al. Mar 4, 2005 :307307 Science Science

Presenter: Braydon BurgessPresenter: Braydon Burgess

Dept. Of Pathology and Laboratory Medicine, Dept. Of Pathology and Laboratory Medicine, Masters ProgramMasters Program

Estimated number of adults and Estimated number of adults and children children

living with HIV by region, 1985living with HIV by region, 1985——20042004

0

10

20

30

40

50

1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004

Caribbean

North Africa & Middle East

Eastern Europe & Central Asia

Western and Central Europe & North America

Latin America

Asia

Sub-Saharan Africa

Number of people living with HIV

Million

s

Source: UNAIDS/WHO AIDS Epidemic Update, Dec 2004

HIV EpidemiologyHIV Epidemiology

People newly infected with HIV in 2004 Total 4.9 million (4.3 – 6.4 million)

AIDS deaths in 2004Total 3.1 million (2.8 – 3.5 million)

Institutional spending for HIV and AIDS Institutional spending for HIV and AIDS 1996−20021996−2002 (US$ disbursements in millions)(US$ disbursements in millions)

0

500

1,000

1,500

2,000

2,500

3,000

1996 1997 1998 1999 2000 2001 2002

Domestic

Private

UN System

Bilateral

US

$ m

illion

s

Source: UNAIDS Resource Tracking Consortium

2004 Report on the Global AIDS Epidemic (Fig 37)

Human Immunodeficiency Virus-1 Human Immunodeficiency Virus-1

Transmission:Transmission:Horizontal: Adult Horizontal: Adult Adult AdultVertical: Mother Vertical: Mother Child Child

Cell Binding:Cell Binding:Host Receptor: Host Receptor: CD4CD4Co-receptor:Co-receptor: CCR5 CCR5

Membrane fusionMembrane fusion

Viral replication & cell deathViral replication & cell death

BackgroundBackground

CD4CD4 Cell signalling moleculeCell signalling molecule A defining feature of T-helper cellsA defining feature of T-helper cells The REQUIRED receptor for HIV entryThe REQUIRED receptor for HIV entry

Chemokine Receptor 5 (CCR5)Chemokine Receptor 5 (CCR5) Highly expressed on memory T-cellsHighly expressed on memory T-cells Major co-receptor for HIV entryMajor co-receptor for HIV entry

Chemokine Ligand 3-like-1 (CCL3L1)Chemokine Ligand 3-like-1 (CCL3L1) Released following immunological challengeReleased following immunological challenge CCL3L1 strongest ligand for CCR5CCL3L1 strongest ligand for CCR5 Known to be a dominant suppressor of HIVKnown to be a dominant suppressor of HIV

BackgroundBackground

CCL3L1 gene contained on a CCL3L1 gene contained on a hotspot for segmental hotspot for segmental duplicationduplication

Copy # was known to be Copy # was known to be variable in human populationsvariable in human populations

Gene dose is proportionate to Gene dose is proportionate to chemokine levelschemokine levels

Research QuestionResearch Question

Can segmental duplications causing Can segmental duplications causing dosage effects of host defence genes dosage effects of host defence genes be associated with phenotypic effects be associated with phenotypic effects

in vivo?in vivo?

Do extra gene copies of CCL3L1 Do extra gene copies of CCL3L1 decrease HIV susceptibility?decrease HIV susceptibility?

Study PopulationsStudy Populations

Human Diversity Cell Line PanelHuman Diversity Cell Line Panel Tissue samples from ancestral populations Tissue samples from ancestral populations

Wilford Hall Medical Centre (WHMC)Wilford Hall Medical Centre (WHMC) Cohort of 1330 HIVCohort of 1330 HIV++ USAF Military Personnel & USAF Military Personnel &

matched controlsmatched controls

Non-WHMCNon-WHMC HIVHIV-- civilian cohort, 1300 individuals matched to the civilian cohort, 1300 individuals matched to the

WHMC cohortWHMC cohort

Argentinean ChildrenArgentinean Children Composed of 450 HIVComposed of 450 HIV++ children and controls children and controls allall

exposed perinatally to HIVexposed perinatally to HIV

Q: What is the Global Variation in Q: What is the Global Variation in CCL3L1 Copy # CCL3L1 Copy #

Conclusion: CCL3L1 gene copy # is variable between populations but similarly dispersed within populations.

ANOVA indicates that geography accounts for 35% of copy# variance.

Q: Is CCL3L1 Copy # Associated Q: Is CCL3L1 Copy # Associated with HIV Acquisitionwith HIV Acquisition

Conclusion: There is a significant correlation between copy # and HIV prevalence in all populations

Each CCL3L1 copy decreases risk of HIV infection by 4.5%-10.5%

Clinical AnswerBiochemical Answer

Q: Does CCL3L1 Copy # Affect Q: Does CCL3L1 Copy # Affect Progression to AIDSProgression to AIDS

Conclusion:

1: Progression to AIDS is accelerated in low copy # individuals.

2: Low CCL3L1 copy # elevates CCR5 exposure, increasing accessibility to HIV

3: Low copy # is associated with a poorer clinical prognosis

Epidemiology Answer

Q: Is Copy # an Absolute Q: Is Copy # an Absolute Determinant of HIV ProgressionDeterminant of HIV Progression

Conclusion: Copy # in the context of genetic background determines which copy #s are beneficial

Q: Are Copy # Phenotypes Affected Q: Are Copy # Phenotypes Affected by Genetic Interactions by Genetic Interactions

Conclusion: CCL3L1 copy # effect is stronger than CCR5 genotype and copy # enhances CCR5 defects

CCR5 and CCL3L1 Are Major CCR5 and CCL3L1 Are Major Contributors to HIV SusceptibilityContributors to HIV Susceptibility

SummarySummary

CCL3L1 copy number shows inter- and intra-CCL3L1 copy number shows inter- and intra-population variation (0-10+ copies)population variation (0-10+ copies)

CCL3L1 copy # is positively associated with a CCL3L1 copy # is positively associated with a dose-dependant protection from HIV acquisition dose-dependant protection from HIV acquisition and progression to AIDS.and progression to AIDS.

Low CCL3L1 copy # and detrimental CCR5 Low CCL3L1 copy # and detrimental CCR5 mutations have harmful interactions and account mutations have harmful interactions and account for variability in disease progression (~30%) and for variability in disease progression (~30%) and in transmission (~20-40%) in transmission (~20-40%)