title: Deficiency of HIV-Gag-specific T cells in early childhood correlates with poor viral containment.
abstract: 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-gamma, TNF-alpha, 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.
authors.affiliation: Partners AIDS Research Center and Infectious Disease Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sihong
authors.initials: S
authors.lastname: Huang
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Dunkley-Thompson
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Tang
authors.forename: Eric A
authors.initials: EA
authors.lastname: Macklin
authors.forename: Julianne
authors.initials: J
authors.lastname: Steel-Duncan
authors.forename: Indira
authors.initials: I
authors.lastname: Singh-Minott
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Ryland
authors.forename: Monica
authors.initials: M
authors.lastname: Smikle
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.forename: Celia D C
authors.initials: CD
authors.lastname: Christie
authors.forename: Margaret E
authors.initials: ME
authors.lastname: Feeney
mesh_terms: D000293:Adolescent; D000367:Age Factors; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D015550:Cell Degranulation; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007223:Infant; D007371:Interferon-gamma / Q000097:blood / Q000276:immunology; D007376:Interleukin-2 / Q000097:blood / Q000276:immunology; D008297:Male; D012367:RNA, Viral / Q000097:blood / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000276:immunology; D019562:Viral Load; D014779:Virus Replication / Q000276:immunology; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000276:immunology*
chemical_list: C508594:IL2 protein, human; D007376:Interleukin-2; D012367:RNA, Viral; D014409:Tumor Necrosis Factor-alpha; D054301:gag Gene Products, Human Immunodeficiency Virus; D007371:Interferon-gamma