The Influence of CCL3L1 Gene-Containing Segmental Duplications on HIV-1/AIDS Susceptibility

1. The Influence of CCL3L1 Gene-Containing 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

2. Estimated number of adults and children living with HIV by region, 1985—2004 Caribbean 50 North Africa & Middle East Number of people living with HIV Eastern Europe & Central Asia 40 Western and Central Europe & North America 30 Latin America Millions 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

3. 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)

4. 3,000 US$ millions 2,500 Domestic 2,000 Private 1,500 UN System 1,000 Bilateral 500 0 1996 1997 1998 1999 2000 2001 2002 Source: UNAIDS Resource Tracking Consortium 2004 Report on the Global AIDS Epidemic (Fig 37) Institutional spending for HIV and AIDS 1996−2002(US$ disbursements in millions)

5. 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

6. 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

7. 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

8. 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?

9. 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

10. 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.

11. 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%

12. Epidemiology Answer Biochemical Answer Clinical Answer Q: Does CCL3L1 Copy # Affect Progression 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

13. Q: Is Copy # an Absolute Determinant of HIV Progression Conclusion: Copy # in the context of genetic background determines which copy #s are beneficial

14. Q: Are Copy # Phenotypes Affected by Genetic Interactions Conclusion: CCL3L1 copy # effect is stronger than CCR5 genotype and copy # enhances CCR5 defects

15. CCR5 and CCL3L1 Are Major Contributors to HIV Susceptibility

16. Summary • CCL3L1 copy number shows inter- and intra-population 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%)