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Mitochondrial DNA Content of Peripheral Blood Mononuclear Cells in Uninfected Infants Born to HIV-infected Women with or without ART Exposure in the Women and Infants Transmission Study
Grace Aldrovandi*1, J Moye2, C Chu3, W Meyer4, B Ha5, E Handelsman6, W Shearer7, M Foca8, K Rich9, K McIntosh10, and the Women and Infants Transmission Study Group
1Children's Hosp of Los Angeles, CA, US; 2Natl Inst Child Hlth and Devt, NIH, DHHS, Bethesda, MD, US; 3Clinical Trials & Surveys, Baltimore, MD, US; 4Quest Diagnostics, Baltimore, MD, US; 5GlaxoSmithKline, Research Triangle Park, NC, US; 6State Univ of New York Downstate, Brooklyn, NY, US; 7Baylor Coll of Med, Houston, TX, US; 8Columbia Univ Mailman Sch of Publ Hlth, New York, NY, US; 9Univ of Illinois Coll of Med, Chicago, US; and 10Children's Hosp of Boston, MA, US
Background: Nucleoside reverse transcriptase inhibitor (ART)
agents can inhibit DNA polymerase gamma, which can inhibit mitochondrial DNA (mtDNA) synthesis, resulting in depletion or dysfunction. Concern
for potential adverse effects of fetal and neonatal ART chemotherapy has led
the U.S. Public Health Service to recommend long-term follow-up of ART-exposed
children. The Women and Infants Transmission Study (WITS) cohort spans the
period before (pre-1994) and after (1994 and later) introduction of antiretroviral
chemoprophylaxis of mother-to-child HIV transmission. We compared mtDNA content of stored peripheral blood mononuclear cells
(PBMC) in WITS from 142 nontransmitting mother/infant
pairs in whom there was in utero ART exposure with 71 nontransmitting
mother/infant pairs in whom there was not.
Methods: The mtDNA from cryopreserved PBMC was quantified using the Primagen Retina Mitox DNA assay
in specimens from birth and 2 years in infants and from delivery in women. Data
were log transformed and compared by analysis of variance.
Results: Results are shown in the table below. Mean
freezer storage time for birth and 2-year specimens was 12.7 and 10.8 years in
unexposed, 8.8 and 7.3 years in ZDV alone, and 6.3 and 5.0 years in ZDV plus
other ART group. Significant differences persist when adjusted for maternal
delivery HIV RNA and absolute CD4 values. Higher HIV RNA was associated with
lower mtDNA in infants and in women. Maternal CD4 was
not associated with infant or maternal mtDNA content.
Mean (n: 95%CI) mtDNA copy number per cell by
ART exposure category
|
Timepoint
|
Unexposed
|
ZDV alone
|
ZDV + other ART
|
|
Birth
|
192 (68: 161-230)
|
263 (65: 219-315)*
|
324 (71: 270-383)**
|
|
2 years
|
220 (61: 186-259)
|
263 (71: 226-307)
|
348 (71: 295-400)**
|
|
Delivery
|
215 (67: 184-252
|
289 (64: 246-340)*
|
316 (71: 272-369)**
|
*p <0.05, **p <0.001 compared with unexposed
Conclusions: Contrary to expectation, mtDNA
levels in PBMC are significantly higher in ART-exposed infants at birth and 2 years
and in women at delivery than in unexposed infants and women. Further
experiments are underway to establish appropriate reference ranges and to
determine the effect of freezer storage on mtDNA
recovery since ART exposure is confounded by changing treatment practices over
time.
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