title: Human immunodeficiency virus type 1 escapes from interleukin-2-producing CD4+ T-cell responses without high-frequency fixation of mutations.
abstract: The presence of interleukin-2 (IL-2)-producing human immunodeficiency virus type 1 (HIV-1)-specific CD4(+) T-cell responses has been associated with the immunological control of HIV-1 replication; however, the causal relationship between these factors remains unclear. Here we show that IL-2-producing HIV-1-specific CD4(+) T cells can be cloned from acutely HIV-1-infected individuals. Despite the early presence of these cells, each of the individuals in the present study exhibited progressive disease, with one individual showing rapid progression. In this rapid progressor, three IL-2-producing HIV-1 Gag-specific CD4(+) T-cell responses were identified and mapped to the following optimal epitopes: HIVWASRELER, REPRGSDIAGT, and FRDYVDRFYKT. Responses to these epitopes in peripheral blood mononuclear cells were monitored longitudinally to >1 year postinfection, and contemporaneous circulating plasma viruses were sequenced. A variant of the FRDYVDRFYKT epitope sequence, FRDYVDQFYKT, was observed in 1/21 plasma viruses sequenced at 5 months postinfection and 1/10 viruses at 7 months postinfection. This variant failed to stimulate the corresponding CD4(+) T-cell clone and thus constitutes an escape mutant. Responses to each of the three Gag epitopes were rapidly lost, and this loss was accompanied by a loss of antigen-specific cells in the periphery as measured by using an FRDYVDRFYKT-presenting major histocompatibility complex class II tetramer. Highly active antiretroviral therapy was associated with the reemergence of FRDYVDRFYKT-specific cells by tetramer. Thus, our data support that IL-2-producing HIV-1-specific CD4(+) T-cell responses can exert immune pressure during early HIV-1 infection but that the inability of these responses to enforce enduring control of viral replication is related to the deletion and/or dysfunction of HIV-1-specific CD4(+) T cells rather than to the fixation of escape mutations at high frequencies.
authors: Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada. brad.jones@utoronto.ca
authors: R Brad
authors: RB
authors: Jones
authors: Feng-Yun
authors: FY
authors: Yue
authors: Xiao Xiao Jenny
authors: XX
authors: Gu
authors: Diana V
authors: DV
authors: Hunter
authors: Shariq
authors: S
authors: Mujib
authors: Gabor
authors: G
authors: Gyenes
authors: Rosemarie D
authors: RD
authors: Mason
authors: Ruqaya
authors: R
authors: Mohamed
authors: Kelly S
authors: KS
authors: MacDonald
authors: Colin
authors: C
authors: Kovacs
authors: Mario A
authors: MA
authors: Ostrowski
mesh_terms: D000328:Adult; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018604:Epitope Mapping; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D015658:HIV Infections / Q000276:immunology* / Q000821:virology*; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology* / Q000302:isolation & purification; D006801:Humans; D007108:Immune Tolerance; D007376:Interleukin-2 / Q000378:metabolism*; D008137:Longitudinal Studies; D008297:Male; D020125:Mutation, Missense / Q000276:immunology*; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology
chemical_list: D018984:Epitopes, T-Lymphocyte; C508594:IL2 protein, human; D007376:Interleukin-2; D054301:gag Gene Products, Human Immunodeficiency Virus