title: Planned multiple exposures to autologous virus in HIV type 1-infected pediatric populations increases HIV-specific immunity and reduces HIV viremia.
abstract: We tested to determine if planned multiple exposures to autologous HIV in pediatric patients with HIV-1 infection will induce cellular immunity that controls viremia. A prospective multicenter study of aviremic pediatric patients on highly active antiretroviral therapy who underwent progressively longer antiretroviral treatment interruptions in cycles starting with 3 days, increasing by 2 days in length each consecutive cycle, was conducted. Eight individuals became viremic and reached Cycle 13 or greater with an "off-therapy" interval of >or=27 days. HIV-specific interferon-gamma (IFN-gamma) production to inactivated HIV and vaccinia vectors expressing gag, env, nef, and pol increased (>10-fold) from baseline in six of eight subjects. The HIV-specific lymphoproliferative response as measured by the median stimulation index (SI) increased in the treatment group from 1 at baseline to 16, 12, 4, and 3 at Cycles 7, 10, 13, and 17, respectively. Median plasma RNA levels peaked at Cycle 7 (4.45 log) and declined to levels <10(4) cp/ml after Cycle 10 (4.1, 3.5, and 3.4 at Cycles 10, 13, and 17). In a subset of five patients who reached Cycle 17, HIV-specific IFN-gamma frequencies were 4- to 30-fold higher and median RNA levels were 0.32-2.10 (median 1.3) log lower than at comparable days off treatment at Cycle 8 (17 days off therapy). A second group of children, not undergoing drug interruption, did not develop significant increases in either HIV-specific IFN-gamma production or SI. Increased HIV-specific immune responses and decreased HIV RNA were seen in those children who have had >10 cycles of antiretroviral discontinuations of increasing durations acting as autologous virus vaccinations. Other studies may have failed due to an insufficient number of exposures to HIV; most of the studies had fewer than six drug interruptions.
authors.affiliation: NYU School of Medicine, New York, New York 10016, USA. borkow01@gcrc.med.nyu.edu
authors.forename: William
authors.initials: W
authors.lastname: Borkowsky
authors.forename: Ram
authors.initials: R
authors.lastname: Yogev
authors.forename: Petronella
authors.initials: P
authors.lastname: Muresan
authors.forename: Elizabeth
authors.initials: E
authors.lastname: McFarland
authors.forename: Lisa
authors.initials: L
authors.lastname: Frenkel
authors.forename: Terry
authors.initials: T
authors.lastname: Fenton
authors.forename: Edmund
authors.initials: E
authors.lastname: Capparelli
authors.forename: Jack
authors.initials: J
authors.lastname: Moye
authors.forename: Paul
authors.initials: P
authors.lastname: Harding
authors.forename: Nina
authors.initials: N
authors.lastname: Ellis
authors.forename: Barbara
authors.initials: B
authors.lastname: Heckman
authors.forename: Joyce
authors.initials: J
authors.lastname: Kraimer
mesh_terms: D000293:Adolescent; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active; D049109:Cell Proliferation; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000276:immunology; D011446:Prospective Studies; D012367:RNA, Viral / Q000097:blood; D019562:Viral Load; D014766:Viremia / Q000517:prevention & control*; D028761:Withholding Treatment
chemical_list: D019380:Anti-HIV Agents; D012367:RNA, Viral; D007371:Interferon-gamma