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Maternal HLA-A*2301 is Associated with Increased Vertical HIV-1 Transmission

Maternal HLA-A*2301 is Associated with Increased Vertical HIV-1 Transmission. Romel D. Mackelprang University of Washington International AIDS Conference August 6, 2008. HLA Class I Molecules. Encoded by the HLA-A, B and C genes Most polymorphic genes found in humans

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Maternal HLA-A*2301 is Associated with Increased Vertical HIV-1 Transmission

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  1. Maternal HLA-A*2301 is Associated with Increased Vertical HIV-1 Transmission Romel D. Mackelprang University of Washington International AIDS Conference August 6, 2008

  2. HLA Class I Molecules • Encoded by the HLA-A, B and C genes • Most polymorphic genes found in humans • Found on all leukocytes • Critical component of cellular immune responses • Present peptides to CD8+ T cells

  3. HLA Class I Function

  4. HLA Class I Function

  5. HLA Class I Function

  6. Maternal HLA and HIV-1 • HLA alleles influence susceptibility to HIV-1 infection and progression • Maternal HLA might also be associated with transmission risk • Via influence on maternal HIV-1 progression • Selection of virulent/infectious viral isolates • Proxy for infant alleles

  7. Specific Aims • Examine associations between maternal HLA class I alleles and vertical HIV-1 transmission • Early (in utero, peripartum, and via early breastfeeding) • Late (via breastfeeding)

  8. Recruitment and Follow-up

  9. Recruitment and Follow-up

  10. Recruitment and Follow-up

  11. Statistical Methods Logistic regression for early transmission Cox regression for late transmission Adjusted for maternal plasma HIV-1 viral load at 32-weeks gestation Alleles with => 10% allele frequency Bonferroni correction for each locus

  12. Description of the Cohort

  13. HLA Alleles 88 unique alleles (33 A, 44 B, 11 C alleles) 20 alleles expressed by >10%

  14. Early Transmission

  15. Early Transmission

  16. Early Transmission • A*2301 • Unadjusted OR=3.21 (1.42, 7.27), p=0.005 • Significant after Bonferroni correction (p<0.006) • Carriers had higher plasma VL • 5.03 versus 4.65 log10 copies/ml, p=0.03 • Similar trend for VL in other compartments • Viral load adjusted OR= 3.07 (1.26, 7.51), p=0.014 • Possible effect beyond influence on VL

  17. Late transmission • A*0201 = increased late transmission risk • 6 (12%) mothers with allele transmitted • 5 (3%) mothers without allele transmitted • HR=4.41 (1.37, 14.18), p=0.01 • Evidence that HLA-Bw4 motif = decreased transmission risk • aHR=0.5 (0.3, 0.9), p=0.02 • Small numbers, interpret with caution

  18. Maternal A*2301 is associated with increased transmission • OR≈3 before and after adjusting for VL • Possible effect beyond influence on VL • Infant A*23 not associated with susceptibility • Consistent with non-MTCT studies • ≈3-fold risk of seroconversion among Kenyan CSWs (MacDonald, 1998) • Faster disease progression among children in the US (Chen, 1997) • A*23 = faster disease progression, ↑ risk of Kaposi’s Sarcoma (Kaslow, 1996; Mann, 1990; Prince, 1984)

  19. Conclusion Data emphasize complex roles immunogenetic factors play in HIV-1 transmission Strengthen evidence that HLA should be considered when developing vaccines and other interventions

  20. Acknowledgements • Oxford • Sarah Rowland-Jones • Fred Hutchinson • Julie Overbaugh • Sandy Emery • Dana Panteleeff • University of Nairobi • Dorothy Mbori-Ngacha • • Rose Bosire • • Elizabeth Obimbo • • Phelgona Otieno • • Dalton Wamalwa • • Christine Gichuhi • • Jennifer Mabuka • • Grace Wariua Special thanks to the women and infants who participated. • University of Washington • Carey Farquhar • Grace John-Stewart • Barbra Richardson • Barbara Lohman-Payne • Jenn Slyker • NCI-Frederick • Mary Carrington • Xiaojiang Gao Funding sources NICHD, NCI, FIC

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