title: A phase II randomized study of HIV-specific T-cell gene therapy in subjects with undetectable plasma viremia on combination antiretroviral therapy.
abstract: Highly active antiretroviral therapy (HAART) can suppress HIV replication to undetectable levels in plasma, but it is unlikely to eradicate cellular reservoirs of virus. Immunotherapies that are cytolytic may be useful adjuncts to drug therapies that target HIV replication. We have generated HIV-specific CD4(+) and CD8(+) T cells bearing a chimeric T-cell receptor (CD4zeta) composed of the extracellular and transmembrane domain of human CD4 (which binds HIVgp120) linked to the intracellular-zeta signaling chain of the CD3 T-cell receptor. CD4zeta-modified T cells can inhibit viral replication, kill HIV-infected cells in vitro, and survive for prolonged periods in vivo. We report the results of a phase II randomized trial of CD4zeta gene-modified versus unmodified T cells in 40 HIV-infected subjects on HAART with plasma viral loads <50 copies/ml. Serial analyses of residual blood and tissue HIV reservoirs were done for 6 months postinfusion. No significant between-group differences were noted in viral reservoirs following therapy. However, infusion of gene-modified, but not unmodified, T cells was associated with a decrease from baseline in HIV burden in two of four reservoir assays and a trend toward fewer patients with recurrent viremia. Both groups experienced a treatment-related increase in CD4(+) T-cell counts.
authors.affiliation: University of California, San Francisco, California 94110, USA.
authors.forename: Steven G
authors.initials: SG
authors.lastname: Deeks
authors.forename: Bridget
authors.initials: B
authors.lastname: Wagner
authors.forename: Peter A
authors.initials: PA
authors.lastname: Anton
authors.forename: Ronald T
authors.initials: RT
authors.lastname: Mitsuyasu
authors.forename: David T
authors.initials: DT
authors.lastname: Scadden
authors.forename: Christine
authors.initials: C
authors.lastname: Huang
authors.forename: Catherine
authors.initials: C
authors.lastname: Macken
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Richman
authors.forename: Cindy
authors.initials: C
authors.lastname: Christopherson
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
authors.forename: Richard
authors.initials: R
authors.lastname: Lazar
authors.forename: David F
authors.initials: DF
authors.lastname: Broad
authors.forename: Sayeh
authors.initials: S
authors.lastname: Jalali
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Hege
mesh_terms: D019264:Adoptive Transfer; D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D001706:Biopsy; D015704:CD4 Antigens / Q000235:genetics*; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D015331:Cohort Studies; D004279:DNA, Viral / Q000097:blood; D005240:Feasibility Studies; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects; D015658:HIV Infections / Q000276:immunology / Q000473:pathology / Q000628:therapy* / Q000821:virology; D015497:HIV-1 / Q000302:isolation & purification; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D012367:RNA, Viral / Q000097:blood; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D012007:Rectum / Q000473:pathology / Q000821:virology; D013601:T-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D019562:Viral Load; D014766:Viremia / Q000628:therapy
chemical_list: D015704:CD4 Antigens; D004279:DNA, Viral; D008565:Membrane Proteins; D012367:RNA, Viral; D011948:Receptors, Antigen, T-Cell; C054979:antigen T cell receptor, zeta chain