Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 200, Issue 10, Pages 1299-1314Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20041049
Keywords
AIDS; CD4(+) T lymphocytes; lymphocyte depletion; immunologic memory; rhesus macaque
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Funding
- NCI NIH HHS [N01-CO-124000] Funding Source: Medline
- NCRR NIH HHS [P51 RR000163, U24-RR018107, U24 RR018107, U42-RR016025, U42 RR016025, P51-RR00163] Funding Source: Medline
- NIAID NIH HHS [R01 AI054292, R01-AI054292] Funding Source: Medline
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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 CD+ 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.
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