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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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Systemic analysis of T cell populations in SIVmac239-infected RMs with overt immunodeficiency. (A) The absolute number of total, memory, and naive CD4+ and CD8+ T cells in the blood and the percent CD4+ T cells (of total CD3+) in BAL were evaluated by flow cytometry at the time of infection (baseline) and at an AIDS endpoint in 17 SIVmac239-infected RMs: 4 rapid progressors (red) and 13 normal progressors (black). Results are presented as percent change from baseline, with the significance of this change assessed separately for normal and rapid progressors using a mixed-effects statistical model. (B) The percent CD4+ of total T cells in BAL is plotted against the same measurement in small intestinal (jejunal) biopsy cell preparations from RMs with pulmonary lavage examination and small intestinal biopsy within 7 d of each other. The analysis includes 12 plateau-phase SIVmac239-infected RMs (red; median pvl = 550,000 copies/ml), 12 SIVmac239(Δnef)-infected RMs (light blue; median pvl = 180 copies/ml), and 15 SIV− normal control RMs (dark blue). The plot shows a linear regression line with the correlation coefficient and p-value of the correlation indicated in the top left corner. (C) PLNs from 11 SIVmac239-infected normal progressors with AIDS and 10 SIV− control RMs were analyzed by flow cytometry for evidence of relative CD4+ depletion in either the memory or naive compartments. CD3+ T cells, including both CD4+ and CD8+ lineages, were first separated into naive and memory compartments by phenotypic criteria (see Materials and methods), and then the relative fractions of CD4+ cells within these compartments were determined. Results are presented as percent CD4+ (of total naive or memory T cells). The red lines designate the mean percent CD4+ values, with significance of differences between SIV− and SIV+ RMs determined by unpaired t test.
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fig2: Systemic analysis of T cell populations in SIVmac239-infected RMs with overt immunodeficiency. (A) The absolute number of total, memory, and naive CD4+ and CD8+ T cells in the blood and the percent CD4+ T cells (of total CD3+) in BAL were evaluated by flow cytometry at the time of infection (baseline) and at an AIDS endpoint in 17 SIVmac239-infected RMs: 4 rapid progressors (red) and 13 normal progressors (black). Results are presented as percent change from baseline, with the significance of this change assessed separately for normal and rapid progressors using a mixed-effects statistical model. (B) The percent CD4+ of total T cells in BAL is plotted against the same measurement in small intestinal (jejunal) biopsy cell preparations from RMs with pulmonary lavage examination and small intestinal biopsy within 7 d of each other. The analysis includes 12 plateau-phase SIVmac239-infected RMs (red; median pvl = 550,000 copies/ml), 12 SIVmac239(Δnef)-infected RMs (light blue; median pvl = 180 copies/ml), and 15 SIV− normal control RMs (dark blue). The plot shows a linear regression line with the correlation coefficient and p-value of the correlation indicated in the top left corner. (C) PLNs from 11 SIVmac239-infected normal progressors with AIDS and 10 SIV− control RMs were analyzed by flow cytometry for evidence of relative CD4+ depletion in either the memory or naive compartments. CD3+ T cells, including both CD4+ and CD8+ lineages, were first separated into naive and memory compartments by phenotypic criteria (see Materials and methods), and then the relative fractions of CD4+ cells within these compartments were determined. Results are presented as percent CD4+ (of total naive or memory T cells). The red lines designate the mean percent CD4+ values, with significance of differences between SIV− and SIV+ RMs determined by unpaired t test.

Mentions: A major consequence of acute CCR5-tropic SIV infection is destruction of CD4+ memory T cells, particularly CD4+ TEM cells in extra-lymphoid effector sites, and we have previously shown that a strong immunologic correlate of rapid progression is the failure to follow this initial CD4+ TEM cell depletion with a sustained increase in the fraction of proliferating CD4+ memory T cells (15). This increase provides “targets” for SIV (12, 20), but also contributes to the continuous production of new CD4+ TEM cells that limits extra-lymphoid tissue deficits and prevents immunological collapse (15). As it is possible that the same mechanisms extend to chronic progression, we asked first whether CD4+ TEM cell depletion was a specific and uniform feature of SIVmac239-mediated AIDS (Fig. 2). Because almost all bronchoalveolar lavage (BAL) T cells manifest the phenotypic signature, CCR7− and/or CCR5+, of TEM cells (18, 23), the fate of CD4+ T cells in this site provides insight into the extra-lymphoid CD4+ TEM cell compartment. As shown in Fig. 2 A, analysis of 13 normal progressors and 4 rapid progressors demonstrated that overt disease in both settings was uniformly associated with a striking (>99%) decline in CD4+ T cell representation among BAL TEM cells. Because total lymphocyte recovery from BAL in later stages of infection was comparable to or reduced from preinfection (unpublished data), this decline predominantly represents CD4+ TEM cell depletion, rather than CD8+ TEM cell expansion. Importantly, the representation of CD4+ T cells in BAL closely correlated with that of small intestinal lamina propria, another TEM cell–populated effector compartment (18), suggesting that the BAL compartment was an accurate indicator of systemic effector site CD4+ TEM cell representation (Fig. 2 B).


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)

Systemic analysis of T cell populations in SIVmac239-infected RMs with overt immunodeficiency. (A) The absolute number of total, memory, and naive CD4+ and CD8+ T cells in the blood and the percent CD4+ T cells (of total CD3+) in BAL were evaluated by flow cytometry at the time of infection (baseline) and at an AIDS endpoint in 17 SIVmac239-infected RMs: 4 rapid progressors (red) and 13 normal progressors (black). Results are presented as percent change from baseline, with the significance of this change assessed separately for normal and rapid progressors using a mixed-effects statistical model. (B) The percent CD4+ of total T cells in BAL is plotted against the same measurement in small intestinal (jejunal) biopsy cell preparations from RMs with pulmonary lavage examination and small intestinal biopsy within 7 d of each other. The analysis includes 12 plateau-phase SIVmac239-infected RMs (red; median pvl = 550,000 copies/ml), 12 SIVmac239(Δnef)-infected RMs (light blue; median pvl = 180 copies/ml), and 15 SIV− normal control RMs (dark blue). The plot shows a linear regression line with the correlation coefficient and p-value of the correlation indicated in the top left corner. (C) PLNs from 11 SIVmac239-infected normal progressors with AIDS and 10 SIV− control RMs were analyzed by flow cytometry for evidence of relative CD4+ depletion in either the memory or naive compartments. CD3+ T cells, including both CD4+ and CD8+ lineages, were first separated into naive and memory compartments by phenotypic criteria (see Materials and methods), and then the relative fractions of CD4+ cells within these compartments were determined. Results are presented as percent CD4+ (of total naive or memory T cells). The red lines designate the mean percent CD4+ values, with significance of differences between SIV− and SIV+ RMs determined by unpaired t test.
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Related In: Results  -  Collection

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fig2: Systemic analysis of T cell populations in SIVmac239-infected RMs with overt immunodeficiency. (A) The absolute number of total, memory, and naive CD4+ and CD8+ T cells in the blood and the percent CD4+ T cells (of total CD3+) in BAL were evaluated by flow cytometry at the time of infection (baseline) and at an AIDS endpoint in 17 SIVmac239-infected RMs: 4 rapid progressors (red) and 13 normal progressors (black). Results are presented as percent change from baseline, with the significance of this change assessed separately for normal and rapid progressors using a mixed-effects statistical model. (B) The percent CD4+ of total T cells in BAL is plotted against the same measurement in small intestinal (jejunal) biopsy cell preparations from RMs with pulmonary lavage examination and small intestinal biopsy within 7 d of each other. The analysis includes 12 plateau-phase SIVmac239-infected RMs (red; median pvl = 550,000 copies/ml), 12 SIVmac239(Δnef)-infected RMs (light blue; median pvl = 180 copies/ml), and 15 SIV− normal control RMs (dark blue). The plot shows a linear regression line with the correlation coefficient and p-value of the correlation indicated in the top left corner. (C) PLNs from 11 SIVmac239-infected normal progressors with AIDS and 10 SIV− control RMs were analyzed by flow cytometry for evidence of relative CD4+ depletion in either the memory or naive compartments. CD3+ T cells, including both CD4+ and CD8+ lineages, were first separated into naive and memory compartments by phenotypic criteria (see Materials and methods), and then the relative fractions of CD4+ cells within these compartments were determined. Results are presented as percent CD4+ (of total naive or memory T cells). The red lines designate the mean percent CD4+ values, with significance of differences between SIV− and SIV+ RMs determined by unpaired t test.
Mentions: A major consequence of acute CCR5-tropic SIV infection is destruction of CD4+ memory T cells, particularly CD4+ TEM cells in extra-lymphoid effector sites, and we have previously shown that a strong immunologic correlate of rapid progression is the failure to follow this initial CD4+ TEM cell depletion with a sustained increase in the fraction of proliferating CD4+ memory T cells (15). This increase provides “targets” for SIV (12, 20), but also contributes to the continuous production of new CD4+ TEM cells that limits extra-lymphoid tissue deficits and prevents immunological collapse (15). As it is possible that the same mechanisms extend to chronic progression, we asked first whether CD4+ TEM cell depletion was a specific and uniform feature of SIVmac239-mediated AIDS (Fig. 2). Because almost all bronchoalveolar lavage (BAL) T cells manifest the phenotypic signature, CCR7− and/or CCR5+, of TEM cells (18, 23), the fate of CD4+ T cells in this site provides insight into the extra-lymphoid CD4+ TEM cell compartment. As shown in Fig. 2 A, analysis of 13 normal progressors and 4 rapid progressors demonstrated that overt disease in both settings was uniformly associated with a striking (>99%) decline in CD4+ T cell representation among BAL TEM cells. Because total lymphocyte recovery from BAL in later stages of infection was comparable to or reduced from preinfection (unpublished data), this decline predominantly represents CD4+ TEM cell depletion, rather than CD8+ TEM cell expansion. Importantly, the representation of CD4+ T cells in BAL closely correlated with that of small intestinal lamina propria, another TEM cell–populated effector compartment (18), suggesting that the BAL compartment was an accurate indicator of systemic effector site CD4+ TEM cell representation (Fig. 2 B).

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