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

Okoye A, Meier-Schellersheim M, Brenchley JM, Hagen SI, Walker JM, Rohankhedkar M, Lum R, Edgar JB, Planer SL, Legasse A, Sylwester AW, Piatak M, Lifson JD, Maino VC, Sodora DL, Douek DC, Axthelm MK, Grossman Z, Picker LJ - J. Exp. Med. (2007)

Bottom Line: Eventually, persistent SIV replication results in chronic-phase AIDS, but the responsible mechanisms remain controversial.We further show that due to persistent immune activation, effector site CD4(+) T(EM) cells are predominantly short-lived, and that their homeostasis is strikingly dependent on the production of new CD4(+) T(EM) cells from central-memory T (T(CM)) cell precursors.The instability of effector site CD4(+) T(EM) 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(+) T(CM) cells.

View Article: PubMed Central - PubMed

Affiliation: Vaccine and Gene Therapy Institute, Department of Pathology, and the Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006., USA.

ABSTRACT
Primary simian immunodeficiency virus (SIV) infections of rhesus macaques result in the dramatic depletion of CD4(+) CCR5(+) effector-memory T (T(EM)) 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(+) T(EM) 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(+) T(EM) 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(+) T(EM) cells are predominantly short-lived, and that their homeostasis is strikingly dependent on the production of new CD4(+) T(EM) cells from central-memory T (T(CM)) cell precursors. The instability of effector site CD4(+) T(EM) 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(+) T(CM) cells. These data suggest that although CD4(+) T(EM) 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(+) T(CM) cells.

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Proliferating CD4+ and CD8+ memory T cell dynamics in the blood. (A) The fraction of proliferating cells (Ki-67+) is shown over the course of chronic/progressive SIVmac239 infection in four representative RMs that did not receive ART and were followed to an AIDS endpoint. (B) The absolute number of proliferating (Ki-67+) CD4+ and CD8+ memory T cells is shown for the entire course of SIVmac239 infection in the same group of untreated normal progressors described in Fig. 3, and for comparison, a group of SIV(Δnef)-infected nonprogressors followed for 600 d. The pooled Δlog10(%Ki-67+ memory T cells) per 100 d (± SEM) from PID 100 to endpoint (progressors) or PID 100–600 (nonprogressors) is shown for each analysis, along with the p-value delineating the statistical significance of these pooled slopes.
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fig5: Proliferating CD4+ and CD8+ memory T cell dynamics in the blood. (A) The fraction of proliferating cells (Ki-67+) is shown over the course of chronic/progressive SIVmac239 infection in four representative RMs that did not receive ART and were followed to an AIDS endpoint. (B) The absolute number of proliferating (Ki-67+) CD4+ and CD8+ memory T cells is shown for the entire course of SIVmac239 infection in the same group of untreated normal progressors described in Fig. 3, and for comparison, a group of SIV(Δnef)-infected nonprogressors followed for 600 d. The pooled Δlog10(%Ki-67+ memory T cells) per 100 d (± SEM) from PID 100 to endpoint (progressors) or PID 100–600 (nonprogressors) is shown for each analysis, along with the p-value delineating the statistical significance of these pooled slopes.

Mentions: The above data indicate that during chronic infection, the diminished BAL CD4+ TEM cell population is largely comprised of relatively short-lived cells that are highly dependent on new memory cell production and emigration for homeostasis, a finding suggesting that CD4+ memory T cell production dynamics might play a role in the progressive decline of BAL CD4+ TEM cells in chronically infected RMs. As shown in Fig. 5 A, the proliferating (Ki-67+) fraction of CD4+ memory T cells in the blood may indeed fall during chronic infection (RMs nos. 20197 and 20408), but this decline is not uniform, coming very late in some RMs (no. 21064) and not at all in others (no. 20502). However, systemic production is more directly related to the overall number of proliferating cells, and we therefore followed the absolute number of proliferating total memory T cells in the blood throughout the course of infection in eight untreated SIVmac239-infected normal progressors and in four RMs with attenuated (clinically nonprogressive) SIVmac239(Δnef) infection (Fig. 5 B). This analysis demonstrated a highly significant progressive loss of proliferating CD4+ memory T cells in the normal progressors, but not of proliferating CD8+ memory T cells in the same RM. In attenuated SIVmac239(Δnef) infection, the numbers of proliferating CD4+ memory T cells showed a very slight decline over 600 d that did not quite achieve statistical significance.


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

Okoye A, Meier-Schellersheim M, Brenchley JM, Hagen SI, Walker JM, Rohankhedkar M, Lum R, Edgar JB, Planer SL, Legasse A, Sylwester AW, Piatak M, Lifson JD, Maino VC, Sodora DL, Douek DC, Axthelm MK, Grossman Z, Picker LJ - J. Exp. Med. (2007)

Proliferating CD4+ and CD8+ memory T cell dynamics in the blood. (A) The fraction of proliferating cells (Ki-67+) is shown over the course of chronic/progressive SIVmac239 infection in four representative RMs that did not receive ART and were followed to an AIDS endpoint. (B) The absolute number of proliferating (Ki-67+) CD4+ and CD8+ memory T cells is shown for the entire course of SIVmac239 infection in the same group of untreated normal progressors described in Fig. 3, and for comparison, a group of SIV(Δnef)-infected nonprogressors followed for 600 d. The pooled Δlog10(%Ki-67+ memory T cells) per 100 d (± SEM) from PID 100 to endpoint (progressors) or PID 100–600 (nonprogressors) is shown for each analysis, along with the p-value delineating the statistical significance of these pooled slopes.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2118701&req=5

fig5: Proliferating CD4+ and CD8+ memory T cell dynamics in the blood. (A) The fraction of proliferating cells (Ki-67+) is shown over the course of chronic/progressive SIVmac239 infection in four representative RMs that did not receive ART and were followed to an AIDS endpoint. (B) The absolute number of proliferating (Ki-67+) CD4+ and CD8+ memory T cells is shown for the entire course of SIVmac239 infection in the same group of untreated normal progressors described in Fig. 3, and for comparison, a group of SIV(Δnef)-infected nonprogressors followed for 600 d. The pooled Δlog10(%Ki-67+ memory T cells) per 100 d (± SEM) from PID 100 to endpoint (progressors) or PID 100–600 (nonprogressors) is shown for each analysis, along with the p-value delineating the statistical significance of these pooled slopes.
Mentions: The above data indicate that during chronic infection, the diminished BAL CD4+ TEM cell population is largely comprised of relatively short-lived cells that are highly dependent on new memory cell production and emigration for homeostasis, a finding suggesting that CD4+ memory T cell production dynamics might play a role in the progressive decline of BAL CD4+ TEM cells in chronically infected RMs. As shown in Fig. 5 A, the proliferating (Ki-67+) fraction of CD4+ memory T cells in the blood may indeed fall during chronic infection (RMs nos. 20197 and 20408), but this decline is not uniform, coming very late in some RMs (no. 21064) and not at all in others (no. 20502). However, systemic production is more directly related to the overall number of proliferating cells, and we therefore followed the absolute number of proliferating total memory T cells in the blood throughout the course of infection in eight untreated SIVmac239-infected normal progressors and in four RMs with attenuated (clinically nonprogressive) SIVmac239(Δnef) infection (Fig. 5 B). This analysis demonstrated a highly significant progressive loss of proliferating CD4+ memory T cells in the normal progressors, but not of proliferating CD8+ memory T cells in the same RM. In attenuated SIVmac239(Δnef) infection, the numbers of proliferating CD4+ memory T cells showed a very slight decline over 600 d that did not quite achieve statistical significance.

Bottom Line: Eventually, persistent SIV replication results in chronic-phase AIDS, but the responsible mechanisms remain controversial.We further show that due to persistent immune activation, effector site CD4(+) T(EM) cells are predominantly short-lived, and that their homeostasis is strikingly dependent on the production of new CD4(+) T(EM) cells from central-memory T (T(CM)) cell precursors.The instability of effector site CD4(+) T(EM) 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(+) T(CM) cells.

View Article: PubMed Central - PubMed

Affiliation: Vaccine and Gene Therapy Institute, Department of Pathology, and the Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR 97006., USA.

ABSTRACT
Primary simian immunodeficiency virus (SIV) infections of rhesus macaques result in the dramatic depletion of CD4(+) CCR5(+) effector-memory T (T(EM)) 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(+) T(EM) 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(+) T(EM) 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(+) T(EM) cells are predominantly short-lived, and that their homeostasis is strikingly dependent on the production of new CD4(+) T(EM) cells from central-memory T (T(CM)) cell precursors. The instability of effector site CD4(+) T(EM) 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(+) T(CM) cells. These data suggest that although CD4(+) T(EM) 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(+) T(CM) cells.

Show MeSH
Related in: MedlinePlus