917
Increases in HIV-specific Interferon-gamma and Proliferative Responses in Children Undergoing Structured Treatment Interruption
E J McFarland*1, W Borkowsky2, P Muresan 3, T Fenton3, P Harding 1, L M Frenkel4, B Heckman5, E Capparelli6, S Jankelevich7, J Moye8, R Yogev9, and Pediatric AIDS Clinical Trials Group P1015 Team
1Univ. of Colorado Hlth. Sci. Ctr., Denver, USA; 2New York Univ. Sch. of Med., NY, USA; 3Frontier Sci. and Technology Res. Fndn.-Harvard Sch. of Publ. Hlth., Boston, MA, USA; 4Univ. of Washington, Seattle, USA; 5Frontier Sci. and Technology Res. Fndn.-Data Management Ctr., Amherst, NY, USA; 6Univ. of California, San Diego, USA; 7NIAID, NIH, DHHS, Bethesda, MD, USA; 8NICHD, NIH, DHHS, Bethesda, MD, USA; and 9Chicago Children's Mem. Hosp., Chicago, IL
Background: Structured treatment interruption in adults
acutely infected with HIV induces HIV-specific responses that may enhance
control of viremia. The effect of structured
treatment interruption in children is not known.
Methods: In this ongoing, prospective,
non-randomized study, 11 children with chronic HIV on HAART with plasma virus
<50 copies/mL have undergone sequentially lengthening periods of structured
treatment interruption, followed by 28 to 84 days of HAART if virus exceeds 50
copies/mL (GrpS); 21 children have received continuous HAART (GrpC). Ten and 20
subjects have evaluable immunology data. Interferon-g responses
in PBMC to inactivated whole HIV and recombinant HIV/vaccinia
vectors (HIV/vv) expressing gag, env, pol, or nef are assessed by ELISpot
expressed as spot-forming-cells (SFC)/106
PBMC. ELISpot with depleted PBMC show whole HIV and HIV/vv responses are mediated
primarily by CD4 and CD8 cells, respectively. Proliferative responses to whole HIV
and Candida are determined by
standard lymphoproliferation assay expressed as a stimulation index (SI >3
defined as positive).
Results: Baseline median SFC
was 26, 0, 2, 17, and 0 (GrpS n = 10)
and 52, 10, 0, 68, and 10 (GrpC n = 20,
19, 19, 19, 15) for whole HIV, gag, env, pol, and nef, respectively. Responses >50 SFC for one or more HIV antigen were detected in 7/10
and 13/20 of GrpS and GrpC, respectively. The fraction of subjects with an SI >3
was 5/10 and 12/20 for GrpS and GrpC, respectively. Median change from baseline
in whole HIV SFC and SI for GrpS after
the fourth structured treatment interruption during which plasma virus was
>50 copies/mL (median time on study = 48 week) was 135 and 8 (n = 8) and for GrpC at 36 week (the
closest comparable study visit) was 38 and -1 (n = 16, 18). At those times, large increases in HIV/vv ELISpot (>4-fold
increase and SFC >200),
occurred for one or more HIV/vv for 4/8 (GrpS) and 1/15 (GrpC). Whole HIV lymphoproliferation
assay in PBMC samples at the end of an structured treatment interruption, when
virus was circulating, were positive in only 4/17 assays from 7 subjects but
became positive in 14/17 at 28 days after reinitiating HAART. By contrast, Candida lymphoproliferation assay were
positive for 13/15 and 14/15 assays at the end of an structured treatment
interruption and after 28 days of HAART, respectively. ELISpot responses >50
were detected in 10/14 and 12/14 assays at these times.
Conclusions: The majority of these children on HAART had detectable HIV-specific lymphoproliferation
assay and IFN-g responses at
baseline. CD4 and CD8-mediated IFN- g responses increased substantially after
structured treatment interruption. HIV-specific lymphoproliferation
assay, but not Candida-specific lymphoproliferation assay nor IFN- g
responses, were suppressed in the presence of viremia.
Keywords: structured treatment interruption; lymphoproliferation; interferon-gamma
