title: Anti-human immunodeficiency virus type 1 (HIV-1) CD8(+) T-lymphocyte reactivity during combination antiretroviral therapy in HIV-1-infected patients with advanced immunodeficiency.
abstract: The long-term efficacy of combination antiretroviral therapy may relate to augmentation of anti-human immunodeficiency virus type 1 (HIV-1) CD8(+) T-cell responses. We found that prolonged treatment of late-stage HIV-1-infected patients with a protease inhibitor and two nucleoside reverse transcriptase inhibitors failed to restore sustained, high levels of HIV-1-specific, HLA class I-restricted, cytotoxic-T-lymphocyte precursors and gamma interferon (IFN-gamma) production by CD8(+) T cells. In some patients, particularly those initiating three-drug combination therapy simultaneously rather than sequentially, there were early, transient increases in the frequency of anti-HIV-1 CD8(+) T cells that correlated with decreases in HIV-1 RNA and increases in T-cell counts. In the other patients, HIV-1-specific T-cell functions either failed to increase or declined from baseline during triple-drug therapy, even though some of these patients showed suppression of plasma HIV-1 RNA. These effects of combination therapy were not unique to HIV-1 specific T-cell responses, since similar effects were noted for CD8(+) T cells specific for the cytomegalovirus pp65 matrix protein. The level and breadth of CD8(+) cell reactivity to HLA A*02 HIV-1 epitopes, as determined by IFN-gamma production and HLA tetramer staining after combination therapy, were related to the corresponding responses prior to treatment. There was, however, a stable, residual population of potentially immunocompetent HIV-1-specific T cells remaining after therapy, as shown by tetramer staining of CD8(+) CD45RO(+) cells. These results indicate that new strategies will be needed to target residual, immunocompetent HIV-1-specific CD8(+) T cells to enhance the effectiveness of antiretroviral therapy in patients with advanced immunodeficiency.
authors.affiliation: Graduate School of Public Health, Pittsburgh, Pennsylvania 15261, USA. rinaldo+@pitt.edu
authors.forename: C R
authors.initials: CR
authors.lastname: Rinaldo
authors.forename: X L
authors.initials: XL
authors.lastname: Huang
authors.forename: Z
authors.initials: Z
authors.lastname: Fan
authors.forename: J B
authors.initials: JB
authors.lastname: Margolick
authors.forename: L
authors.initials: L
authors.lastname: Borowski
authors.forename: A
authors.initials: A
authors.lastname: Hoji
authors.forename: C
authors.initials: C
authors.lastname: Kalinyak
authors.forename: D K
authors.initials: DK
authors.lastname: McMahon
authors.forename: S A
authors.initials: SA
authors.lastname: Riddler
authors.forename: W H
authors.initials: WH
authors.lastname: Hildebrand
authors.forename: R B
authors.initials: RB
authors.lastname: Day
authors.forename: J W
authors.initials: JW
authors.lastname: Mellors
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D018791:CD4 Lymphocyte Count; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019070:Cell Lineage; D004359:Drug Therapy, Combination; D015683:Gene Products, gag / Q000276:immunology; D015684:Gene Products, pol / Q000276:immunology; D015658:HIV Infections / Q000188:drug therapy* / Q000276:immunology* / Q000503:physiopathology / Q000821:virology; D017320:HIV Protease Inhibitors / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D019469:Indinavir / Q000627:therapeutic use; D007371:Interferon-gamma / Q000096:biosynthesis; D019259:Lamivudine / Q000627:therapeutic use; D008137:Longitudinal Studies; D008213:Lymphocyte Activation; D010455:Peptides / Q000276:immunology; D010641:Phenotype; D010750:Phosphoproteins / Q000276:immunology; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D019562:Viral Load; D014763:Viral Matrix Proteins / Q000276:immunology; D015215:Zidovudine / Q000627:therapeutic use
chemical_list: D019380:Anti-HIV Agents; D015683:Gene Products, gag; D015684:Gene Products, pol; D017320:HIV Protease Inhibitors; D010455:Peptides; D010750:Phosphoproteins; D018894:Reverse Transcriptase Inhibitors; D014763:Viral Matrix Proteins; C065418:cytomegalovirus matrix protein 65kDa; D019259:Lamivudine; D015215:Zidovudine; D019469:Indinavir; D007371:Interferon-gamma