Insufficient production and tissue delivery of CD4+ memory T cells in rapidly progressive simian immunodeficiency virus infection

Louis J. Picker, Shoko I. Hagen, Richard Lum, Edward F. Reed-Inderbitzin, Lyn M. Daly, Andrew W. Sylwester, Joshua M. Walker, Don C. Siess, Michael Piatak, Chenxi Wang, David B. Allison, Vernon C. Maino, Jeffrey D. Lifson, Toshiaki Kodama, Michael K. Axthelm

Research output: Contribution to journalArticle

254 Scopus citations

Abstract

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 progressons. 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.

Original languageEnglish (US)
Pages (from-to)1299-1314
Number of pages16
JournalJournal of Experimental Medicine
Volume200
Issue number10
DOIs
StatePublished - Nov 15 2004

Keywords

  • AIDS
  • CD4 T lymphocytes
  • Immunologic memory
  • Lymphocyte depletion
  • Rhesus macaque

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Fingerprint Dive into the research topics of 'Insufficient production and tissue delivery of CD4<sup>+</sup> memory T cells in rapidly progressive simian immunodeficiency virus infection'. Together they form a unique fingerprint.

  • Cite this

    Picker, L. J., Hagen, S. I., Lum, R., Reed-Inderbitzin, E. F., Daly, L. M., Sylwester, A. W., Walker, J. M., Siess, D. C., Piatak, M., Wang, C., Allison, D. B., Maino, V. C., Lifson, J. D., Kodama, T., & Axthelm, M. K. (2004). Insufficient production and tissue delivery of CD4+ memory T cells in rapidly progressive simian immunodeficiency virus infection. Journal of Experimental Medicine, 200(10), 1299-1314. https://doi.org/10.1084/jem.20041049