The Journal of Experimental Medicine
Torrey Pines Biolabs
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Published 15 November 2004. doi:10.1084/jem.20041049
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 10, 1299-1314
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Insufficient Production and Tissue Delivery of CD4+ Memory T Cells in Rapidly Progressive Simian Immunodeficiency Virus Infection

Louis J. Picker1, Shoko I. Hagen1, Richard Lum1, Edward F. Reed-Inderbitzin1, Lyn M. Daly1, Andrew W. Sylwester1, Joshua M. Walker1, Don C. Siess1, Michael Piatak, Jr.4, Chenxi Wang2, David B. Allison2, Vernon C. Maino3, Jeffrey D. Lifson4, Toshiaki Kodama5, and Michael K. Axthelm1

1 Vaccine and Gene Therapy Institute, Department of Pathology and Department of Molecular Microbiology and Immunology, and the Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006
2 Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL 35294
3 Becton Dickinson Biosciences, San Jose, CA 95131
4 AIDS Vaccine Program, Science Applications International Corporation Frederick, Inc., National Cancer Institute (NCI), Frederick, MD 21702
5 Department of Molecular Genetics and Biochemistry, University of Pittsburgh, Pittsburgh, PA 15260

Address correspondence to Louis J. Picker, Vaccine and Gene Therapy Institute, Oregon Health & Science University, West Campus, 505 NW 185th Ave., Beaverton, OR 97006. Phone: (503) 418-2720; Fax: (503) 418-2719; email: pickerl{at}ohsu.edu

The mechanisms linking human immunodeficiency virus replication to the progressive immunodeficiency of acquired immune deficiency syndrome are controversial, particularly the relative contribution of CD4+ T cell destruction. Here, we used the simian immunodeficiency virus (SIV) model to investigate the relationship between systemic CD4+ T cell dynamics and rapid disease progression. Of 18 rhesus macaques (RMs) infected with CCR5-tropic SIVmac239 (n = 14) or CXCR4-tropic SIVmac155T3 (n = 4), 4 of the former group manifested end-stage SIV disease by 200 d after infection. In SIVmac155T3 infections, naive CD4+ T cells were dramatically depleted, but this population was spared by SIVmac239, even in rapid progressors. In contrast, all SIVmac239-infected RMs demonstrated substantial systemic depletion of CD4+ memory T cells by day 28 after infection. Surprisingly, the extent of CD4+ memory T cell depletion was not, by itself, a strong predictor of rapid progression. However, in all RMs destined for stable infection, this depletion was countered by a striking increase in production of short-lived CD4+ memory T cells, many of which rapidly migrated to tissue. In all rapid progressors (P < 0.0001), production of these cells initiated but failed by day 42 of infection, and tissue delivery of new CD4+ memory T cells ceased. Thus, although profound depletion of tissue CD4+ memory T cells appeared to be a prerequisite for early pathogenesis, it was the inability to respond to this depletion with sustained production of tissue-homing CD4+ memory T cells that best distinguished rapid progressors, suggesting that mechanisms of the CD4+ memory T cell generation play a crucial role in maintaining immune homeostasis in stable SIV infection.

Key Words: AIDS • CD4+ T lymphocytes • lymphocyte depletion • immunologic memory • rhesus macaque

Abbreviations used in this paper: APC, allophycocyanin; BAL, bronchoalveolar lymphocyte; BrdU, 5-bromo-2'-deoxyuridine; RhCMV, rhesus CMV; RM, rhesus macaque; SIV, simian immunodeficiency virus.


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