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

TransmissionRomel D. Mackelprang

University of Washington

International AIDS ConferenceAugust 6, 2008

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

HLA Class I Function

HLA Class I Function

HLA Class I Function

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

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)

Recruitment and Follow-up

Recruitment and Follow-up

Recruitment and Follow-up

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

Description of the Cohort

N=277

Mean (sd) or number (%)

CD4+ T cell count (cells/µl) 469 (253)

Maternal HIV-1 viral load (log10 copies/ml) 4.7 (0.9)

Number of HIV-1 infected infants 58 (21%)

Early (<=1 month) 47 (81%)

Late (>age 1 month) 11 (19%)

HLA Alleles

• 88 unique alleles (33 A, 44 B, 11 C alleles)• 20 alleles expressed by >10%

Early Transmission

Early Transmission

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

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

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)

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

Acknowledgements

University of WashingtonCarey FarquharGrace John-Stewart•Barbra Richardson•Barbara Lohman-Payne•Jenn Slyker

NCI-FrederickMary Carrington•Xiaojiang Gao

Special thanks to the women and infants who participated.

Oxford•Sarah Rowland-Jones

Fred HutchinsonJulie Overbaugh•Sandy Emery•Dana Panteleeff

University of NairobiDorothy Mbori-Ngacha• Rose Bosire• Elizabeth Obimbo• Phelgona Otieno• Dalton Wamalwa• Christine Gichuhi• Jennifer Mabuka• Grace Wariua

Funding sourcesNICHD, NCI, FIC