title: Functional discrepancies in HIV-specific CD8+ T-lymphocyte populations are related to plasma virus load.
abstract: The potent ability of current antiretroviral drug regimens to control human immunodeficiency Virus-1 (HIV-1) replication, in conjunction with the clinical practice of structured therapeutic interruptions, provides a system in which virus levels are manipulated during a persistent infection in humans. Here, we exploit this system to examine the impact of variable plasma virus load (pVL) on the functionality of HIV-specific CD8+ T-lymphocyte populations. Using both ELISpot methodology and intracellular cytokine staining for interferon (IFN)-gamma to assess functional status, together with fluorochrome-labeled peptide-major histocompatibility complex (pMHC) class I tetramer analysis to detect the physical presence of CD8+ T lymphocytes expressing cognate T-cell receptors (TCRs), we observed that the proportion of HIV-specific CD8+ T lymphocytes capable of mounting an effector response to antigen challenge directly ex vivo is related to the kinetics of virus exposure. Specifically, (a) after prolonged suppression of pVL with antiretroviral therapy (ART), physical and functional measures of HIV-specific CD8+ T-lymphocyte frequencies approximated; and (b) the percentage of functionally responsive cells in the HIV-specific CD8+ T lymphocyte populations declined substantially when therapy was discontinued and pVL recrudesced in the same patients. These results corroborate and extend observations in animal models that describe nonresponsive CD8+ T lymphocytes in the presence of high levels of antigen load and have implications for the interpretation of quantitative data generated by methods that rely on functional readouts.
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, England. aoxenius@micro.biol.ethz.ch
authors.forename: Annetie
authors.initials: A
authors.lastname: Oxenius
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Sewell
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Dawson
authors.forename: Huldrych F
authors.initials: HF
authors.lastname: Günthard
authors.forename: Marek
authors.initials: M
authors.lastname: Fischer
authors.forename: Geraldine M
authors.initials: GM
authors.lastname: Gillespie
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Rowland-Jones
authors.forename: Catherine
authors.initials: C
authors.lastname: Fagard
authors.forename: Bernard
authors.initials: B
authors.lastname: Hirschel
authors.forename: Rodney E
authors.initials: RE
authors.lastname: Phillips
authors.forename: David A
authors.initials: DA
authors.lastname: Price
mesh_terms: D019380:Anti-HIV Agents / Q000627:therapeutic use; D018791:CD4 Lymphocyte Count; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D005434:Flow Cytometry; D005805:Genes, MHC Class I / Q000276:immunology; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007118:Immunoassay / Q000379:methods; D007371:Interferon-gamma / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D019562:Viral Load
chemical_list: D019380:Anti-HIV Agents; D011948:Receptors, Antigen, T-Cell; D007371:Interferon-gamma