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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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Relationship between pvl and survival in SIVmac239 infection. (A) Pvl data is shown for 14 SIVmac239-infected RMs that did not receive ART during their course and were followed to an AIDS endpoint. Profiles are color-coded according to time to endpoint as indicated. Note that the y axis starts at 102 copies/ml (the threshold sensitivity of the viral load assay) rather than 0 (acute-phase viral load data on these RM can be viewed in detail in reference 15). (B) The mean pvl for each RM from postinfection day (PID) 70 to either endpoint (rapid progressors) or PID 350 (normal progressors) is plotted against time to AIDS for all 14 RMs (left) or the 10 normal progressors alone (right). The graph configuration and color-coding are as described for A. Both linear regression (R) and Spearman rank (Rho) correlation coefficients and the p-values for these analyses are indicated in each plot. NS, nonsignificant.
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fig1: Relationship between pvl and survival in SIVmac239 infection. (A) Pvl data is shown for 14 SIVmac239-infected RMs that did not receive ART during their course and were followed to an AIDS endpoint. Profiles are color-coded according to time to endpoint as indicated. Note that the y axis starts at 102 copies/ml (the threshold sensitivity of the viral load assay) rather than 0 (acute-phase viral load data on these RM can be viewed in detail in reference 15). (B) The mean pvl for each RM from postinfection day (PID) 70 to either endpoint (rapid progressors) or PID 350 (normal progressors) is plotted against time to AIDS for all 14 RMs (left) or the 10 normal progressors alone (right). The graph configuration and color-coding are as described for A. Both linear regression (R) and Spearman rank (Rho) correlation coefficients and the p-values for these analyses are indicated in each plot. NS, nonsignificant.

Mentions: SIVmac239 and related CCR5-tropic SIVs are highly pathogenic for Indian origin RMs, inducing rapid disease progression (AIDS in <200 d) in ∼25% of infected animals and normal progression (AIDS in 1–3 yr) in the majority of the remainder (27). Fig. 1 A shows plasma viral loads (pvls) over the course of infection of 14 SIVmac239-infected RMs that did not receive antiretroviral therapy (ART) and were followed to an AIDS endpoint (4 rapid progressors and 10 normal progressors). As reported previously (15), rapid progressors manifest 1–2 log higher pvls than RMs destined for >350 d survival. However, among the latter group, plateau-phase pvls did not distinguish between RMs with considerably different survival periods. Indeed, when the entire study group was included in a correlation analysis of plateau-phase pvls versus time to endpoint, a significant association was observed (by either parametric or nonparametric analysis); however, when the four rapid progressors were excluded from the analysis, this association was no longer apparent (Fig. 1 B). Moreover, in all the normal progressors, pvls remained steady through the development of overt disease. Thus, within the range of viral replication manifested by typical SIV-infected normal progressors, the time to disease was not closely linked to mean pvls over time nor to any late acceleration of viral replication, observations suggesting that the rate of disease progression in these RMs was largely determined by their ability to handle the consequences of chronic viral replication, rather than by differences in viral replication itself.


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)

Relationship between pvl and survival in SIVmac239 infection. (A) Pvl data is shown for 14 SIVmac239-infected RMs that did not receive ART during their course and were followed to an AIDS endpoint. Profiles are color-coded according to time to endpoint as indicated. Note that the y axis starts at 102 copies/ml (the threshold sensitivity of the viral load assay) rather than 0 (acute-phase viral load data on these RM can be viewed in detail in reference 15). (B) The mean pvl for each RM from postinfection day (PID) 70 to either endpoint (rapid progressors) or PID 350 (normal progressors) is plotted against time to AIDS for all 14 RMs (left) or the 10 normal progressors alone (right). The graph configuration and color-coding are as described for A. Both linear regression (R) and Spearman rank (Rho) correlation coefficients and the p-values for these analyses are indicated in each plot. NS, nonsignificant.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2118701&req=5

fig1: Relationship between pvl and survival in SIVmac239 infection. (A) Pvl data is shown for 14 SIVmac239-infected RMs that did not receive ART during their course and were followed to an AIDS endpoint. Profiles are color-coded according to time to endpoint as indicated. Note that the y axis starts at 102 copies/ml (the threshold sensitivity of the viral load assay) rather than 0 (acute-phase viral load data on these RM can be viewed in detail in reference 15). (B) The mean pvl for each RM from postinfection day (PID) 70 to either endpoint (rapid progressors) or PID 350 (normal progressors) is plotted against time to AIDS for all 14 RMs (left) or the 10 normal progressors alone (right). The graph configuration and color-coding are as described for A. Both linear regression (R) and Spearman rank (Rho) correlation coefficients and the p-values for these analyses are indicated in each plot. NS, nonsignificant.
Mentions: SIVmac239 and related CCR5-tropic SIVs are highly pathogenic for Indian origin RMs, inducing rapid disease progression (AIDS in <200 d) in ∼25% of infected animals and normal progression (AIDS in 1–3 yr) in the majority of the remainder (27). Fig. 1 A shows plasma viral loads (pvls) over the course of infection of 14 SIVmac239-infected RMs that did not receive antiretroviral therapy (ART) and were followed to an AIDS endpoint (4 rapid progressors and 10 normal progressors). As reported previously (15), rapid progressors manifest 1–2 log higher pvls than RMs destined for >350 d survival. However, among the latter group, plateau-phase pvls did not distinguish between RMs with considerably different survival periods. Indeed, when the entire study group was included in a correlation analysis of plateau-phase pvls versus time to endpoint, a significant association was observed (by either parametric or nonparametric analysis); however, when the four rapid progressors were excluded from the analysis, this association was no longer apparent (Fig. 1 B). Moreover, in all the normal progressors, pvls remained steady through the development of overt disease. Thus, within the range of viral replication manifested by typical SIV-infected normal progressors, the time to disease was not closely linked to mean pvls over time nor to any late acceleration of viral replication, observations suggesting that the rate of disease progression in these RMs was largely determined by their ability to handle the consequences of chronic viral replication, rather than by differences in viral replication itself.

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