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ART Exposure at Delivery Alters but Does Not Eliminate Effects of Host Genetic Variants on MTCT in Sub-Saharan Africa
Kumud Singh*1, M Hughes2, J Chen2, C Rousseau3, L Kuhn4, A Coutsoudis5, J Jackson6, L Guay6, R Semba6, and S Spector1
1Univ of California, San Diego, US; 2Harvard Sch of Publ Hlth, Boston, MA, US; 3Univ of Washington, Seattle, US; 4Columbia Univ Mailman Sch of Publ Hlth, New York, NY, US; 5Univ of Natal, Durban, South Africa; and 6Johns Hopkins Univ, Baltimore, MD, US
Background: Genetic
variants of chemokines and chemokine
receptors have been shown to affect HIV-1 infection and disease progression. However,
the role of genetic variants in mother-to-child transmission (MTCT) and how the
effect of these genetic factors is altered by ART given at delivery is unknown.
Methods: CX3CR1 V/I249, -T/M280, CCR5-59029-G/A,
CCR5-59353-T/C, and CCR5-59356-C/T polymorphisms were
detected by real-time polymerase chain reaction (RT-PCR) in 980 children born
to ART-naïve HIV-1-infected mothers from Malawi (n = 322) and South Africa (n
= 300); both cohorts involved in vitamin A intervention trials to reduce MTCT
of HIV-1; and from Uganda (HIVNET-012, n
= 358) where intra-partum and neonatal single-dose nevirapine
(NVP) was compared with intra-partum zidovudine (ZDV)
7 days after birth for preventing MTCT. Data were assessed by Cochran-Mantel-Haenszel test and logistic regression analyses.
Results: Overall 210 (21%) of 980 infants were HIV-1 infected. Genetic
variants associated with significantly higher risk for early infection of ART-naïve
infants included CCR5 59029-A allele vs G/G (OR 1.51), 59353-C allele vs
T/T (in linkage disequlibirium with 59029) (OR 1.81),
and CCR2-A/A vs G allele (OR 3.44). Presence of
59356-C/C vs T allele decreased MTCT (OR 0.63). Of
note, exposure to NVP or ZDV altered genetic susceptibility. For CCR5-59029 (G/G vs
A/A or G/A) and CCR5-59353 (T/T vs C/C or T/C), in
the NVP-exposed mother-infant pairs, there was a markedly decreased risk for
MTCT. For both polymorphisms, there was an opposite trend for infection for
those mother-infant pairs treated with ZDV. These differences in effects
observed for CCR5-59029 and 59353 were highly significant (p = 0.004). For CX3CR1-745-G/A, infants with the A
allele were at greater risk for infection compared with those with the G/G
genotype for both NVP (OR 5.64, p = 0.015)
and ZDV (OR 5.02, p = 0.003) exposed mother-infant
pairs.
Conclusions: These findings indicate that polymorphisms in CCR5 alter MTCT, likely through its role
as co-receptor for HIV-1 infection, whereas genetic alterations of CX3CR1
expression likely affect MTCT by modulating the initial immune response. Additionally,
the use at delivery of ART that is partially effective in reducing HIV MTCT may
significantly alter, but not eliminate, the effect of host genetics on
transmission.
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