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* Partners AIDS Research Center and Infectious Disease Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02115;
Kingston Perinatal AIDS Program and Department of Obstetrics, Gynecology, and Pediatrics, University of the West Indies, Kingston, Jamaica;
Children’s Hospital, Boston, MA 02115;
Massachusetts General Hospital Biostatistics Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;
¶ Clinical Investigator Training Program: Harvard/Massachusetts Institute of Technology Health Sciences and Technology-Beth Israel Deaconess Medical Center, in collaboration with Pfizer and Merck, Boston, MA 02215; and
|| Howard Hughes Medical Institute, Chevy Chase, MD 20815
Perinatal HIV infection is characterized by a sustained high-level viremia and a high risk of rapid progression to AIDS, indicating a failure of immunologic containment of the virus. We hypothesized that age-related differences in the specificity or function of HIV-specific T cells may influence HIV RNA levels and clinical outcome following perinatal infection. In this study, we defined the HIV epitopes targeted by 76 pediatric subjects (47 HIV infected and 29 HIV exposed, but uninfected), and assessed the ability of HIV-specific CD8 and CD4 T cells to degranulate and produce IFN-
, TNF-
, and IL-2. No responses were detected among HIV-uninfected infants, whereas responses among infected subjects increased in magnitude and breadth with age. Gag-specific responses were uncommon during early infancy, and their frequency was significantly lower among children younger than 24 mo old (p = 0.014). Importantly, Gag responders exhibited significantly lower HIV RNA levels than nonresponders (log viral load 5.8 vs 5.0; p = 0.005). Both the total and Gag-specific T cell frequency correlated inversely with viral load after correction for age, whereas no relationship with targeting of other viral proteins was observed. Functional assessment of HIV-specific T cells by multiparameter flow cytometry revealed that polyfunctional CD8 cells were less prevalent in children before 24 mo of age, and that HIV-specific CD4 cell responses were of universally low frequency among antiretroviral-naive children and absent in young infants. These cross-sectional data suggest that qualitative differences in the CD8 response, combined with a deficiency of HIV-specific CD4 cells, may contribute to the inability of young infants to limit replication of HIV.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the Elizabeth Glaser Pediatric AIDS Foundation (to M.E.F. and C.D.C.C.), Jewelers for Children, Charles H. Hood Foundation (to M.E.F.), and National Institutes of Health (R01-AI068497, to M.E.F.). S.H. is supported by the Clinical Investigator Training Program. B.D.W. is a Doris Duke Distinguished Clinical Scientist and a Howard Hughes Investigator. C.D.C.C. is a recipient of the International Leadership Award from the Elizabeth Glaser Pediatric AIDS Foundation. M.E.F. is a recipient of the 2006 Jewelers for Children Elizabeth Glaser Scientist Award.
2 Address correspondence and reprint requests to Dr. Margaret E. Feeney, Massachusetts General Hospital-East, 5th Floor, 149 13th Street, Charlestown, MA 02129. E-mail address: mfeeney{at}partners.org
3 Abbreviations, used in this paper: SFC, spot-forming cell; VL, viral load.
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