Transcript Gonzalez, 2005

The Influence of CCL3L1 GeneContaining Segmental Duplications
on HIV-1/AIDS Susceptibility
Gonzalez et al. Mar 4, 2005 :307 Science
Presenter: Braydon Burgess
Dept. Of Pathology and Laboratory Medicine,
Masters Program
Estimated number of adults and children
living with HIV by region, 1985—2004
Caribbean
50
Number
of people
living
with HIV
40
North Africa
& Middle East
Eastern Europe
& Central Asia
Millions
Western and Central Europe
& North America
30
Latin America
Asia
20
Sub-Saharan Africa
10
0
1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004
Source: UNAIDS/WHO AIDS Epidemic Update, Dec 2004
HIV Epidemiology
People newly infected with HIV in 2004
Total
4.9 million (4.3 – 6.4 million)
AIDS deaths in 2004
Total
3.1 million (2.8 – 3.5 million)
US$ millions
Institutional spending for HIV and AIDS
1996−2002 (US$ disbursements in millions)
3,000
2,500
Domestic
2,000
Private
1,500
UN System
1,000
Bilateral
500
0
1996
1997
Source: UNAIDS Resource Tracking Consortium
2004 Report on the Global AIDS Epidemic (Fig 37)
1998
1999
2000
2001
2002
Human Immunodeficiency Virus-1
Transmission:
Horizontal: Adult  Adult
Vertical: Mother  Child
Cell Binding:
Host Receptor: CD4
Co-receptor: CCR5
Membrane fusion
Viral replication & cell death
Background
CD4



Cell signalling molecule
A defining feature of T-helper cells
The REQUIRED receptor for HIV entry
Chemokine Receptor 5 (CCR5)


Highly expressed on memory T-cells
Major co-receptor for HIV entry
Chemokine Ligand 3-like-1 (CCL3L1)



Released following immunological challenge
CCL3L1 strongest ligand for CCR5
Known to be a dominant suppressor of HIV
Background
CCL3L1 gene contained on a
hotspot for segmental
duplication
Copy # was known to be
variable in human populations
Gene dose is proportionate to
chemokine levels
Research Question
Can segmental duplications causing
dosage effects of host defence genes
be associated with phenotypic effects
in vivo?
Do extra gene copies of CCL3L1
decrease HIV susceptibility?
Study Populations
Human Diversity Cell Line Panel

Tissue samples from ancestral populations
Wilford Hall Medical Centre (WHMC)

Cohort of 1330 HIV+ USAF Military Personnel &
matched controls
Non-WHMC

HIV- civilian cohort, 1300 individuals matched to the
WHMC cohort
Argentinean Children

Composed of 450 HIV+ children and controls all
exposed perinatally to HIV
Q: What is the Global Variation in
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
with 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%
Q: Does CCL3L1 Copy # Affect
Progression to AIDS
Biochemical
Answer
Epidemiology
Clinical Answer
Answer
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
Q: Is Copy # an Absolute
Determinant of HIV Progression
Conclusion: Copy # in the
context of genetic background
determines which copy #s are
beneficial
Q: Are Copy # Phenotypes Affected
by Genetic Interactions
Conclusion: CCL3L1 copy # effect is stronger than CCR5 genotype
and copy # enhances CCR5 defects
CCR5 and CCL3L1 Are Major
Contributors to HIV Susceptibility
Summary
CCL3L1 copy number shows inter- and intrapopulation variation (0-10+ copies)
CCL3L1 copy # is positively associated with a
dose-dependant protection from HIV acquisition
and progression to AIDS.
Low CCL3L1 copy # and detrimental CCR5
mutations have harmful interactions and account
for variability in disease progression (~30%) and
in transmission (~20-40%)