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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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Effect of infection on CD4+ TEM cell differentiation from proliferating TCM cell precursors. (A) Schema of memory T cell differentiation in RMs (18). (B) The top profiles show CD4+ T cells from one RM with attenuated SIVmac239(Δnef) infection (PID 387; pvl = 5,200 copies/ml) and one with progressive SIVmac239 infection (PID 579; pvl = 3,800,000 copies/ml), indicating the gating of proliferating (Ki-67+) CD4+ memory T cells. The bottom profiles show the representation of TCM cells (CD28+; CCR5−) versus total TEM cells (including CD28+, CCR5+ transitional TEM cells, and CD28−/CCR5dim+ mature TEM cells) within the proliferating CD4+ memory compartment. (C) The figure shows cross-sectional analysis of the fractional representation of total TEM cells (as in A) in 10 SIV− RMs, 7 RMs with early plateau-phase SIVmac239 infection (PID 105; median pvl = 5,300,000 copies/ml), 8 RMs with late plateau-phase SIVmac239 infection (PID 533–878; median pvl = 660,000 copies/ml), and 12 RMs with controlled SIV infection: 9 infected with SIVmac239(Δnef) (PID 154–390; pvls < 400 copies/ml) and 3 spontaneous controllers of SIVmac239 (PID 105–147: pvls < 4,000 copies/ml). Differences were assessed by unpaired t test. (D) The profiles show the fractional representation of TEM cells among proliferating (Ki-67+) CD4+ memory T cells from PLNs from an RM 5 d before SIVmac239 infection, at PID 150 (immediately before ART; pvl = 4,400,000 copies/ml), and at 4 (pvl = 180,000) and 8 d (pvl = 87,000) after ART initiation. (E) The profiles show the fractional representation of TEM cells among proliferating (Ki-67+) CD4+ memory T cells from the blood of an SIVmac239-infected RM at PID 105 (immediately before ART; pvl = 3,000,000 copies/ml) and days 4 (pvl = 220,000 copies/ml), 10 (pvl = 170,000 copies/ml), and 17 (pvl = 24,000 copies/ml) after ART. The arrow indicates the development of a fully mature CD4+ TEM cell population.
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fig6: Effect of infection on CD4+ TEM cell differentiation from proliferating TCM cell precursors. (A) Schema of memory T cell differentiation in RMs (18). (B) The top profiles show CD4+ T cells from one RM with attenuated SIVmac239(Δnef) infection (PID 387; pvl = 5,200 copies/ml) and one with progressive SIVmac239 infection (PID 579; pvl = 3,800,000 copies/ml), indicating the gating of proliferating (Ki-67+) CD4+ memory T cells. The bottom profiles show the representation of TCM cells (CD28+; CCR5−) versus total TEM cells (including CD28+, CCR5+ transitional TEM cells, and CD28−/CCR5dim+ mature TEM cells) within the proliferating CD4+ memory compartment. (C) The figure shows cross-sectional analysis of the fractional representation of total TEM cells (as in A) in 10 SIV− RMs, 7 RMs with early plateau-phase SIVmac239 infection (PID 105; median pvl = 5,300,000 copies/ml), 8 RMs with late plateau-phase SIVmac239 infection (PID 533–878; median pvl = 660,000 copies/ml), and 12 RMs with controlled SIV infection: 9 infected with SIVmac239(Δnef) (PID 154–390; pvls < 400 copies/ml) and 3 spontaneous controllers of SIVmac239 (PID 105–147: pvls < 4,000 copies/ml). Differences were assessed by unpaired t test. (D) The profiles show the fractional representation of TEM cells among proliferating (Ki-67+) CD4+ memory T cells from PLNs from an RM 5 d before SIVmac239 infection, at PID 150 (immediately before ART; pvl = 4,400,000 copies/ml), and at 4 (pvl = 180,000) and 8 d (pvl = 87,000) after ART initiation. (E) The profiles show the fractional representation of TEM cells among proliferating (Ki-67+) CD4+ memory T cells from the blood of an SIVmac239-infected RM at PID 105 (immediately before ART; pvl = 3,000,000 copies/ml) and days 4 (pvl = 220,000 copies/ml), 10 (pvl = 170,000 copies/ml), and 17 (pvl = 24,000 copies/ml) after ART. The arrow indicates the development of a fully mature CD4+ TEM cell population.

Mentions: The overall memory T cell population in blood is composed of three phenotypically distinguishable components:TCM cells, transitional TEM cells, and fully differentiated TEM cells, with both TEM cell subsets expressing CCR5 and being effector site directed (Fig. 6 A) (18). On average, approximately one third of the proliferating CD4+ memory T cell compartment in the blood of uninfected RMs is comprised of CCR5-expressing TEM cell subsets; however, in SIV-infected RMs, this fraction is highly dependent on the degree of pathogenesis. In attenuated SIV infections or wild-type SIV infections in RMs with spontaneous control, we observed a significant increase in the TEM cell fraction of proliferating CD4+ memory cells in comparison to uninfected RMs, consistent with the expected effect of chronic immune activation in driving effector differentiation (28). In contrast, the TEM cell fraction was reduced approximately fourfold throughout pathogenic infection (Fig. 6, B and C). CD4+ TEM cells (predominantly transitional type) were also reduced in PLNs in chronic SIVmac239 infection (Fig. 6 D), indicating that the reduction in proliferating CD4+ TEM cells in the blood was not due to retention in secondary lymphoid tissues. Moreover, effective ART results in an immediate burst of proliferating or recently divided transitional CD4+ TEM cells in the PLNs and blood (Fig. 6, D and E), followed later by mature CD4+ TEM cells (Fig. 6 E), suggesting that although rapid CD4+ TEM cell generation and differentiation is continuously driven by infection-associated immune activation, these new TEM cells and/or their immediate precursors are being destroyed almost as rapidly by direct virus-mediated cytopathogenicity. Importantly, the efficiency of this depletion does not appear to change over the course of chronic infection (compare early vs. late plateau-phase in Fig. 6 C), suggesting that this effect acts as a relatively constant impediment to CD4+ TEM cell production that does not, by itself, explain the progressive decline in CD4 TEM cell populations in extra-lymphoid sites.


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)

Effect of infection on CD4+ TEM cell differentiation from proliferating TCM cell precursors. (A) Schema of memory T cell differentiation in RMs (18). (B) The top profiles show CD4+ T cells from one RM with attenuated SIVmac239(Δnef) infection (PID 387; pvl = 5,200 copies/ml) and one with progressive SIVmac239 infection (PID 579; pvl = 3,800,000 copies/ml), indicating the gating of proliferating (Ki-67+) CD4+ memory T cells. The bottom profiles show the representation of TCM cells (CD28+; CCR5−) versus total TEM cells (including CD28+, CCR5+ transitional TEM cells, and CD28−/CCR5dim+ mature TEM cells) within the proliferating CD4+ memory compartment. (C) The figure shows cross-sectional analysis of the fractional representation of total TEM cells (as in A) in 10 SIV− RMs, 7 RMs with early plateau-phase SIVmac239 infection (PID 105; median pvl = 5,300,000 copies/ml), 8 RMs with late plateau-phase SIVmac239 infection (PID 533–878; median pvl = 660,000 copies/ml), and 12 RMs with controlled SIV infection: 9 infected with SIVmac239(Δnef) (PID 154–390; pvls < 400 copies/ml) and 3 spontaneous controllers of SIVmac239 (PID 105–147: pvls < 4,000 copies/ml). Differences were assessed by unpaired t test. (D) The profiles show the fractional representation of TEM cells among proliferating (Ki-67+) CD4+ memory T cells from PLNs from an RM 5 d before SIVmac239 infection, at PID 150 (immediately before ART; pvl = 4,400,000 copies/ml), and at 4 (pvl = 180,000) and 8 d (pvl = 87,000) after ART initiation. (E) The profiles show the fractional representation of TEM cells among proliferating (Ki-67+) CD4+ memory T cells from the blood of an SIVmac239-infected RM at PID 105 (immediately before ART; pvl = 3,000,000 copies/ml) and days 4 (pvl = 220,000 copies/ml), 10 (pvl = 170,000 copies/ml), and 17 (pvl = 24,000 copies/ml) after ART. The arrow indicates the development of a fully mature CD4+ TEM cell population.
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Related In: Results  -  Collection

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fig6: Effect of infection on CD4+ TEM cell differentiation from proliferating TCM cell precursors. (A) Schema of memory T cell differentiation in RMs (18). (B) The top profiles show CD4+ T cells from one RM with attenuated SIVmac239(Δnef) infection (PID 387; pvl = 5,200 copies/ml) and one with progressive SIVmac239 infection (PID 579; pvl = 3,800,000 copies/ml), indicating the gating of proliferating (Ki-67+) CD4+ memory T cells. The bottom profiles show the representation of TCM cells (CD28+; CCR5−) versus total TEM cells (including CD28+, CCR5+ transitional TEM cells, and CD28−/CCR5dim+ mature TEM cells) within the proliferating CD4+ memory compartment. (C) The figure shows cross-sectional analysis of the fractional representation of total TEM cells (as in A) in 10 SIV− RMs, 7 RMs with early plateau-phase SIVmac239 infection (PID 105; median pvl = 5,300,000 copies/ml), 8 RMs with late plateau-phase SIVmac239 infection (PID 533–878; median pvl = 660,000 copies/ml), and 12 RMs with controlled SIV infection: 9 infected with SIVmac239(Δnef) (PID 154–390; pvls < 400 copies/ml) and 3 spontaneous controllers of SIVmac239 (PID 105–147: pvls < 4,000 copies/ml). Differences were assessed by unpaired t test. (D) The profiles show the fractional representation of TEM cells among proliferating (Ki-67+) CD4+ memory T cells from PLNs from an RM 5 d before SIVmac239 infection, at PID 150 (immediately before ART; pvl = 4,400,000 copies/ml), and at 4 (pvl = 180,000) and 8 d (pvl = 87,000) after ART initiation. (E) The profiles show the fractional representation of TEM cells among proliferating (Ki-67+) CD4+ memory T cells from the blood of an SIVmac239-infected RM at PID 105 (immediately before ART; pvl = 3,000,000 copies/ml) and days 4 (pvl = 220,000 copies/ml), 10 (pvl = 170,000 copies/ml), and 17 (pvl = 24,000 copies/ml) after ART. The arrow indicates the development of a fully mature CD4+ TEM cell population.
Mentions: The overall memory T cell population in blood is composed of three phenotypically distinguishable components:TCM cells, transitional TEM cells, and fully differentiated TEM cells, with both TEM cell subsets expressing CCR5 and being effector site directed (Fig. 6 A) (18). On average, approximately one third of the proliferating CD4+ memory T cell compartment in the blood of uninfected RMs is comprised of CCR5-expressing TEM cell subsets; however, in SIV-infected RMs, this fraction is highly dependent on the degree of pathogenesis. In attenuated SIV infections or wild-type SIV infections in RMs with spontaneous control, we observed a significant increase in the TEM cell fraction of proliferating CD4+ memory cells in comparison to uninfected RMs, consistent with the expected effect of chronic immune activation in driving effector differentiation (28). In contrast, the TEM cell fraction was reduced approximately fourfold throughout pathogenic infection (Fig. 6, B and C). CD4+ TEM cells (predominantly transitional type) were also reduced in PLNs in chronic SIVmac239 infection (Fig. 6 D), indicating that the reduction in proliferating CD4+ TEM cells in the blood was not due to retention in secondary lymphoid tissues. Moreover, effective ART results in an immediate burst of proliferating or recently divided transitional CD4+ TEM cells in the PLNs and blood (Fig. 6, D and E), followed later by mature CD4+ TEM cells (Fig. 6 E), suggesting that although rapid CD4+ TEM cell generation and differentiation is continuously driven by infection-associated immune activation, these new TEM cells and/or their immediate precursors are being destroyed almost as rapidly by direct virus-mediated cytopathogenicity. Importantly, the efficiency of this depletion does not appear to change over the course of chronic infection (compare early vs. late plateau-phase in Fig. 6 C), suggesting that this effect acts as a relatively constant impediment to CD4+ TEM cell production that does not, by itself, explain the progressive decline in CD4 TEM cell populations in extra-lymphoid sites.

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