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

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267 Scopus citations


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
Issue number10
StatePublished - Nov 15 2004


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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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