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Journal of Virology, April 2009, p. 3719-3733, Vol. 83, No. 8
0022-538X/09/$08.00+0     doi:10.1128/JVI.01844-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Induction of a Striking Systemic Cytokine Cascade prior to Peak Viremia in Acute Human Immunodeficiency Virus Type 1 Infection, in Contrast to More Modest and Delayed Responses in Acute Hepatitis B and C Virus Infections {triangledown}

Andrea R. Stacey,1,{dagger} Philip J. Norris,2,3,{dagger} Li Qin,4,5 Elizabeth A. Haygreen,1 Elizabeth Taylor,1 John Heitman,2 Mila Lebedeva,2 Allan DeCamp,4 Dongfeng Li,4,6 Douglas Grove,4 Steven G. Self,4,5 and Persephone Borrow1*

The Jenner Institute, University of Oxford, Compton, Berkshire RG20 7NN, United Kingdom,1 Blood Systems Research Institute, 270 Masonic Avenue, San Francisco, California 94118,2 University of California, San Francisco, California 94143,3 Statistical Center for HIV/AIDS Research and Prevention, Vaccine and Infectious Disease Institute, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N., LE-400, Seattle, Washington 98109,4 Department of Biostatistics, University of Washington, Seattle, Washington 98105,5 Department of Probability and Statistics, Peking University, Beijing, China6

Received 2 September 2008/ Accepted 7 January 2009

Characterization of the immune responses induced in the initial stages of human immunodeficiency virus type 1 (HIV-1) infection is of critical importance for an understanding of early viral pathogenesis and prophylactic vaccine design. Here, we used sequential plasma samples collected during the eclipse and exponential viral expansion phases from subjects acquiring HIV-1 (or, for comparison, hepatitis B virus [HBV]or hepatitis C virus [HCV]) to determine the nature and kinetics of the earliest systemic elevations in cytokine and chemokine levels in each infection. Plasma viremia was quantitated over time, and levels of 30 cytokines and chemokines were measured using Luminex-based multiplex assays and enzyme-linked immunosorbent assays. The increase in plasma viremia in acute HIV-1 infection was found to be associated with elevations in plasma levels of multiple cytokines and chemokines, including rapid and transient elevations in alpha interferon (IFN-{alpha}) and interleukin-15 (IL-15) levels; a large increase in inducible protein 10 (IP-10) levels; rapid and more-sustained increases in tumor necrosis factor alpha and monocyte chemotactic protein 1 levels; more slowly initiated elevations in levels of additional proinflammatory factors including IL-6, IL-8, IL-18, and IFN-{gamma}; and a late-peaking increase in levels of the immunoregulatory cytokine IL-10. Notably, there was comparatively little perturbation in plasma cytokine levels during the same phase of HBV infection and a delayed response of more intermediate magnitude in acute HCV infection, indicating that the rapid activation of a striking systemic cytokine cascade is not a prerequisite for viral clearance (which occurs in a majority of HBV-infected individuals). The intense early cytokine storm in acute HIV-1 infection may have immunopathological consequences, promoting immune activation, viral replication, and CD4+ T-cell loss.

* Corresponding author. Mailing address: The Jenner Institute, University of Oxford, Compton, Berkshire RG20 7NN, United Kingdom. Phone: 44 1635 577913. Fax: 44 1635 577901. E-mail: persephone.borrow{at}jenner.ac.uk

{triangledown} Published ahead of print on 28 January 2009.

{dagger} A.R.S. and P.J.N. contributed equally to this study.

Journal of Virology, April 2009, p. 3719-3733, Vol. 83, No. 8
0022-538X/09/$08.00+0     doi:10.1128/JVI.01844-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



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