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Toll-Like Receptor 9 Genetic Variation Increases Risk of Mother-to-Child HIV Transmission

SUMMARY: Mothers with 2 specific variations in the gene for toll-like receptor 9 (TLR9) were more likely to transmit HIV to their babies during pregnancy or delivery, according to an Italian study published in the May 25 online edition of the Journal of Translational Medicine.

By Liz Highleyman

Elisabetta Ricci from the University of Padova and colleagues investigated the influence of TLR9 genetic variants on mother-to-child HIV transmission.

Toll-like receptors help recognize disease-causing pathogens and play a crucial role in innate immune response by triggering maturation of immune cells and cytokine production, the study authors noted as background. TLR9 "plays a pivotal role in the induction of first-line defense mechanisms of the innate immune system and triggers effective adaptive immune responses to different bacterial and viral pathogens," they wrote. Therefore, variations in TLR genes may influence host-virus interactions in a way that affects HIV transmission.

The study included 118 HIV-infected and 182 uninfected children in Italy born to HIV positive women between 1984 and 1996 to mothers who did not take antiretroviral drugs. In 1996, findings from the ACTG 076 trial showed that use of zidovudine (AZT, Retrovir) by pregnant women and infants soon after birth could dramatically reduce perinatal HIV transmission, and that protocol was thereafter widely adopted worldwide. All were white, most (94%) were born via vaginal delivery, and none were breast-fed.

The researchers analyzed single nucleotide polymorphisms (SNPs), or variations in a single nucleotide at a specific location in the genome. They focused on 2 SNPs in the TLR9 gene that were previously were linked to viral load and disease progression in HIV positive adults: NM_017442.2: c.4-44G > A (rs352139) and c.1635A > G (rs352140).

Results

As in the general Caucasian population, the c.4-44GA genotype was most common in both HIV-infected and uninfected children, and c.1635AG was the most common in uninfected children.
The GG and AA haplotypes (genetic patterns) were uncommon, but were seen more often in children with HIV than in uninfected children.
When considered separately, neither of the 2 SNPs was significantly associated with risk of perinatal HIV transmission.
However, the AA and GG haplotypes were associated with a higher risk of HIV infection compared to the more common GA and AG pattern:
 
AA: odds ratio 3.16 (P = 0.016);
GG: odds ratio 5.54 (P = 0.004).
In a follow-up analysis of pregnant women who received ART, the GG haplotype remained associated with a higher risk of HIV transmission after adjusting for maternal viral load.

These findings led the researchers to conclude, "Overall, results demonstrate a significant correlation between specific genetic variants of the TLR9 gene and risk of mother-to-child transmission of HIV-1, thus confirming a critical role of innate immunity in perinatal HIV-1 infection."

This knowledge may be valuable in the development of new therapeutic strategies including the use the specific adjuvants," they suggested in their discussion. "More studies are needed to evaluate if strategies aimed at modulating innate immunity might be useful for future treatment of pediatric HIV-1 infection and AIDS."

Investigator affiliation: Department of Oncology and Surgical Sciences, Oncology Section, AIDS Reference Center, University of Padova, Padova, Italy; Department of Neurosciences, University of Padova, Padova, Italy; Istituto Oncologico Veneto-IRCCS, Padova, Italy; Department of Pediatrics, University of Padova, Padova, Italy.

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Reference
E Ricci. S Malacrida, M Zanchetta, and others. Toll-like receptor 9 polymorphisms influence mother-to-child transmission of human immunodeficiency virus type 1. Journal of Translational Medicine 8:49 (Free full text). May 25, 2010.



 

 

 

 

 

 

 

 

 

 

 

 

 


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