Progressive CD4+ central-memory T cell decline results in CD4+ effector-memory insufficiency and overt disease in chronic SIV infection

Afam Okoye, Martin Meier-Schellersheim, Jason M. Brenchley, Shoko I. Hagen, Joshua M. Walker, Mukta Rohankhedkar, Richard Lum, John B. Edgar, Shannon L. Planer, Alfred Legasse, Andrew W. Sylwester, Michael Piatak, Jeffrey D. Lifson, Vernon C. Maino, Donald L. Sodora, Daniel C. Douek, Michael K. Axthelm, Zvi Grossman, Louis J. Picker

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208 Scopus citations


Primary simian immunodeficiency virus (SIV) infections of rhesus macaques result in the dramatic depletion of CD4+ CCR5+ effector-memory T (TEM) cells from extra-lymphoid effector sites, but in most infections, an increased rate of CD4+ memory T cell proliferation appears to prevent collapse of effector site CD4+ TEM cell populations and acute-phase AIDS. Eventually, persistent SIV replication results in chronic-phase AIDS, but the responsible mechanisms remain controversial. Here, we demonstrate that in the chronic phase of progressive SIV infection, effector site CD4+ TEM cell populations manifest a slow, continuous decline, and that the degree of this depletion remains a highly significant correlate of late-onset AIDS. We further show that due to persistent immune activation, effector site CD4+ TEM cells are predominantly short-lived, and that their homeostasis is strikingly dependent on the production of new CD4+ TEM cells from central-memory T (TCM) cell precursors. The instability of effector site CD4+ TEM cell populations over time was not explained by increasing destruction of these cells, but rather was attributable to progressive reduction in their production, secondary to decreasing numbers of CCR5- CD4+ TCM cells. These data suggest that although CD4+ TEM cell depletion is a proximate mechanism of immunodeficiency, the tempo of this depletion and the timing of disease onset are largely determined by destruction, failing production, and gradual decline of CD4+ TCM cells. JEM

Original languageEnglish (US)
Pages (from-to)2171-2185
Number of pages15
JournalJournal of Experimental Medicine
Issue number9
StatePublished - Sep 3 2007

ASJC Scopus subject areas

  • Medicine(all)


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