Toll-Like
Receptor 9 Genetic Variation Increases Risk of Mother-to-Child HIV
Transmission
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.
7/910
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.
