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Journal of Virology, August 2008, p. 7700-7710, Vol. 82, No. 15
0022-538X/08/$08.00+0     doi:10.1128/JVI.00605-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Induction of Plasma (TRAIL), TNFR-2, Fas Ligand, and Plasma Microparticles after Human Immunodeficiency Virus Type 1 (HIV-1) Transmission: Implications for HIV-1 Vaccine Design ^,

Duke Human Vaccine Institute, Departments of Medicine,¹ Surgery, Immunology,² Pathology, Duke University School of Medicine, Durham, North Carolina 27710,³ Durham VA Hospital, Durham, North Carolina 27710,⁴ Fred Hutchinson Cancer Research Center, Seattle, Washington 98109,⁵ Statistical Center for HIV/AIDS Research and Prevention (SCHARP), Seattle, Washington 98109,⁶ University of Alabama-Birmingham, Birmingham, Alabama 35223,⁷ Department of Ecology and Evolutional Biology, Cornell University, Ithaca, New York 14853⁸

Received 18 March 2008/ Accepted 19 May 2008

The death of CD4⁺ CCR5⁺ T cells is a hallmark of human immunodeficiency virus (HIV) infection. We studied the plasma levels of cell death mediators and products—tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), Fas ligand, TNF receptor type 2 (TNFR-2), and plasma microparticles—during the earliest stages of infection following HIV type 1 (HIV-1) transmission in plasma samples from U.S. plasma donors. Significant plasma TRAIL level elevations occurred a mean of 7.2 days before the peak of plasma viral load (VL), while TNFR-2, Fas ligand, and microparticle level elevations occurred concurrently with maximum VL. Microparticles had been previously shown to mediate immunosuppressive effects on T cells and macrophages. We found that T-cell apoptotic microparticles also potently suppressed in vitro immunoglobulin G (IgG) and IgA antibody production by memory B cells. Thus, release of TRAIL during the onset of plasma viremia (i.e., the eclipse phase) in HIV-1 transmission may initiate or amplify early HIV-1-induced cell death. The window of opportunity for a HIV-1 vaccine is from the time of HIV-1 transmission until establishment of the latently infected CD4⁺ T cells. Release of products of cell death and subsequent immunosuppression following HIV-1 transmission could potentially narrow the window of opportunity during which a vaccine is able to extinguish HIV-1 infection and could place severe constraints on the amount of time available for the immune system to respond to the transmitted virus.

Published ahead of print on 28 May 2008.

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