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MBL2-O Allele Is Associated with CNS Impairment of HIV-1-infected Children
Kumud Singh*1, A Lieser2, P Ruan3, T Fenton3, M Hughes3, C Alvero3, and S Spector1
1Univ of California, San Diego, US; 2Univ of California, Irvine, US; and 3Harvard Sch of Publ Hlth, Boston, MA, US
Background: The MBL2 gene
encodes mannose-binding lectin, a protein associated
with the innate immune response. Genetic variants of MBL2 may affect HIV-1 disease progression; however, their effects
on HIV-1 neuropathogenesis are unknown.
Methods: HIV-1-infected children (n = 1058) aged 42 days to 18 years from the Pediatric AIDS Clinical
Trials Group (PACTG) protocols 152 and 300 who received either zidovudine (ZDV), didanosine (ddI), ZDV/ddI, or ZDV/lamivudine (3TC) therapy were evaluated for MBL2 alleles using real-time polymerase
chain reaction (RT-PCR). MBL2 exon 1 wild
type allele (A
allele), 230G/A (B allele), 239G/A (C allele), 223C/T (D allele), variants at –550nt (H/L), –221 (X/Y) or at +4nt (P/Q)
were studied. MBL2 genotypes were
defined as AA (wild type), AO (heterozygote including A/B, A/C, A/D genotypes), and OO (homozygous variant including B/B, B/C, B/D, C/C, C/D, D/D genotypes).
The progression of central nervous system (CNS) disease was defined as
deterioration in brain growth, psychological function or neurological status. Log-rank
tests/Kaplan-Meir analyses were used to evaluate the effects of MBL2 alleles on HIV-1 related CNS
impairment.
Results: MBL2-O
allele frequency was 0.27 in non-Hispanic blacks, 0.25 in Hispanics, and 0.21
in non-Hispanic whites. Children with homozygous variant OO genotype underwent more rapid CNS impairment than those with
wild type AA genotype (RHOO vs
AA =1.46, 95%CI 0.98, 2.16, p = 0.054) and those with heterozygous AO genotype (RHOO vs AO = 2.24, 95%CI 1.00, 5.01, p = 0.045). Additionally, children with OO genotype showed more rapid disease
progression than those with either AA
or AO genotypes (RHOO vs (AO+AA)
= 2.15, 95%CI 1.00, 4.64, p = 0.045).
These associations followed the same trends in multivariate analyses
controlling for baseline CD4+ lymphocytes and log10 HIV-1
RNA; treatments, race, sex, or other genotypes (CCR5-wt/D32,
CCR5-59029, CX3CR1-249-V/I, -280-T/M, or SDF-1). We found no evidence of an association
between MBL2-H/L, P/Q, X/Y
genotypes/haplotypes and HIV-1 disease progression in
children.
Conclusions: Our findings suggest that the presence of the
MBL2-O allele, which results in lower
expression of MBL protein and impaired innate immunity
is associated with more rapid development of HIV-1-related CNS impairment in
children. Thus, the MBL2-O allele may
be an important factor in HIV-1 neuropathogenesis and
CNS disease in children.
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