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Journal of Virology, September 2009, p. 8722-8732, Vol. 83, No. 17
0022-538X/09/$08.00+0     doi:10.1128/JVI.00433-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Human Immunodeficiency Virus Type 1 Escapes from Interleukin-2-Producing CD4⁺ T-Cell Responses without High-Frequency Fixation of Mutations

R. Brad Jones,^1*, Feng-Yun Yue,^1, Xiao Xiao Jenny Gu,¹ Diana V. Hunter,¹ Shariq Mujib,¹ Gabor Gyenes,¹ Rosemarie D. Mason,¹ Ruqaya Mohamed,^1,2 Kelly S. MacDonald,^1,2,4 Colin Kovacs,^2,3 and Mario A. Ostrowski^1,2,5

Department of Immunology,¹ Department of Medicine, University of Toronto, Toronto, Ontario M5S 1A8, Canada,² Maple Leaf Medical Clinic, Toronto, Ontario M5B 1L6, Canada,³ Department of Microbiology, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada,⁴ Li Ka Shing Institute, St. Michael's Hospital, Toronto, Ontario M5B 1W8, Canada⁵

Received 28 February 2009/ Accepted 13 June 2009

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.

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* Corresponding author. Mailing address: Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada. Phone: (416) 946-0277. Fax: (416) 978-8765. E-mail: brad.jones{at}utoronto.ca

Published ahead of print on 24 June 2009.

R.B.J. and F.-Y.Y. contributed equally to this work.

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Journal of Virology, September 2009, p. 8722-8732, Vol. 83, No. 17
0022-538X/09/$08.00+0     doi:10.1128/JVI.00433-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.