Profound CD4+/CCR5+ T cell expansion is induced by CD8+ lymphocyte depletion but does not account for accelerated SIV pathogenesis

Afam Okoye, Haesun Park, Mukta Rohankhedkar, Lia Coyne-Johnson, Richard Lum, Joshua M. Walker, Shannon L. Planer, Alfred W. Legasse, Andrew Sylwester, Michael Piatak, Jeffrey D. Lifson, Donald L. Sodora, Francois Villinger, Michael Axthelm, Joern E. Schmitz, Louis Picker

Research output: Contribution to journalArticle

56 Citations (Scopus)

Abstract

Depletion of CD8+ lymphocytes during acute simian immunodeficiency virus (SIV) infection of rhesus macaques (RMs) results in irreversible prolongation of peak-level viral replication and rapid disease progression, consistent with a major role for CD8+ lymphocytes in determining postacute-phase viral replication set points. However, we report that CD8+ lymphocyte depletion is also associated with a dramatic induction of proliferation among CD4+ effector memory T (T EM) cells and, to a lesser extent, transitional memory T (T TrM) cells, raising the question of whether an increased availability of optimal (activated/proliferating), CD4+/CCR5+ SIV "target" cells contributes to this accelerated pathogenesis. In keeping with this, depletion of CD8+ lymphocytes in SIV- RMs led to a sustained increase in the number of potential CD4+ SIV targets, whereas such depletion in acute SIV infection led to increased target cell consumption. However, we found that the excess CD4+ TEM cell proliferation of CD8+ lymphocyte-depleted, acutely SIV-infected RMs was completely inhibited by interleukin (IL)-15 neutralization, and that this inhibition did not abrogate the rapidly progressive infection in these RMs. Moreover, although administration of IL-15 during acute infection induced robust CD4+ TEM and TTrM cell proliferation, it did not recapitulate the viral dynamics of CD8+ lymphocyte depletion. These data suggest that CD8+ lymphocyte function has a larger impact on the outcome of acute SIV infection than the number and/or activation status of target cells available for infection and viral production.

Original languageEnglish (US)
Pages (from-to)1575-1588
Number of pages14
JournalJournal of Experimental Medicine
Volume206
Issue number7
DOIs
StatePublished - Jul 6 2009

Fingerprint

Lymphocyte Depletion
Simian Immunodeficiency Virus
T-Lymphocytes
Virus Diseases
Macaca mulatta
Interleukin-15
Lymphocytes
Cell Proliferation
Virus Activation
Infection
Disease Progression

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Profound CD4+/CCR5+ T cell expansion is induced by CD8+ lymphocyte depletion but does not account for accelerated SIV pathogenesis. / Okoye, Afam; Park, Haesun; Rohankhedkar, Mukta; Coyne-Johnson, Lia; Lum, Richard; Walker, Joshua M.; Planer, Shannon L.; Legasse, Alfred W.; Sylwester, Andrew; Piatak, Michael; Lifson, Jeffrey D.; Sodora, Donald L.; Villinger, Francois; Axthelm, Michael; Schmitz, Joern E.; Picker, Louis.

In: Journal of Experimental Medicine, Vol. 206, No. 7, 06.07.2009, p. 1575-1588.

Research output: Contribution to journalArticle

Okoye, A, Park, H, Rohankhedkar, M, Coyne-Johnson, L, Lum, R, Walker, JM, Planer, SL, Legasse, AW, Sylwester, A, Piatak, M, Lifson, JD, Sodora, DL, Villinger, F, Axthelm, M, Schmitz, JE & Picker, L 2009, 'Profound CD4+/CCR5+ T cell expansion is induced by CD8+ lymphocyte depletion but does not account for accelerated SIV pathogenesis', Journal of Experimental Medicine, vol. 206, no. 7, pp. 1575-1588. https://doi.org/10.1084/jem.20090356
Okoye, Afam ; Park, Haesun ; Rohankhedkar, Mukta ; Coyne-Johnson, Lia ; Lum, Richard ; Walker, Joshua M. ; Planer, Shannon L. ; Legasse, Alfred W. ; Sylwester, Andrew ; Piatak, Michael ; Lifson, Jeffrey D. ; Sodora, Donald L. ; Villinger, Francois ; Axthelm, Michael ; Schmitz, Joern E. ; Picker, Louis. / Profound CD4+/CCR5+ T cell expansion is induced by CD8+ lymphocyte depletion but does not account for accelerated SIV pathogenesis. In: Journal of Experimental Medicine. 2009 ; Vol. 206, No. 7. pp. 1575-1588.
@article{94399d4d93154b1583c6348122fd6406,
title = "Profound CD4+/CCR5+ T cell expansion is induced by CD8+ lymphocyte depletion but does not account for accelerated SIV pathogenesis",
abstract = "Depletion of CD8+ lymphocytes during acute simian immunodeficiency virus (SIV) infection of rhesus macaques (RMs) results in irreversible prolongation of peak-level viral replication and rapid disease progression, consistent with a major role for CD8+ lymphocytes in determining postacute-phase viral replication set points. However, we report that CD8+ lymphocyte depletion is also associated with a dramatic induction of proliferation among CD4+ effector memory T (T EM) cells and, to a lesser extent, transitional memory T (T TrM) cells, raising the question of whether an increased availability of optimal (activated/proliferating), CD4+/CCR5+ SIV {"}target{"} cells contributes to this accelerated pathogenesis. In keeping with this, depletion of CD8+ lymphocytes in SIV- RMs led to a sustained increase in the number of potential CD4+ SIV targets, whereas such depletion in acute SIV infection led to increased target cell consumption. However, we found that the excess CD4+ TEM cell proliferation of CD8+ lymphocyte-depleted, acutely SIV-infected RMs was completely inhibited by interleukin (IL)-15 neutralization, and that this inhibition did not abrogate the rapidly progressive infection in these RMs. Moreover, although administration of IL-15 during acute infection induced robust CD4+ TEM and TTrM cell proliferation, it did not recapitulate the viral dynamics of CD8+ lymphocyte depletion. These data suggest that CD8+ lymphocyte function has a larger impact on the outcome of acute SIV infection than the number and/or activation status of target cells available for infection and viral production.",
author = "Afam Okoye and Haesun Park and Mukta Rohankhedkar and Lia Coyne-Johnson and Richard Lum and Walker, {Joshua M.} and Planer, {Shannon L.} and Legasse, {Alfred W.} and Andrew Sylwester and Michael Piatak and Lifson, {Jeffrey D.} and Sodora, {Donald L.} and Francois Villinger and Michael Axthelm and Schmitz, {Joern E.} and Louis Picker",
year = "2009",
month = "7",
day = "6",
doi = "10.1084/jem.20090356",
language = "English (US)",
volume = "206",
pages = "1575--1588",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "7",

}

TY - JOUR

T1 - Profound CD4+/CCR5+ T cell expansion is induced by CD8+ lymphocyte depletion but does not account for accelerated SIV pathogenesis

AU - Okoye, Afam

AU - Park, Haesun

AU - Rohankhedkar, Mukta

AU - Coyne-Johnson, Lia

AU - Lum, Richard

AU - Walker, Joshua M.

AU - Planer, Shannon L.

AU - Legasse, Alfred W.

AU - Sylwester, Andrew

AU - Piatak, Michael

AU - Lifson, Jeffrey D.

AU - Sodora, Donald L.

AU - Villinger, Francois

AU - Axthelm, Michael

AU - Schmitz, Joern E.

AU - Picker, Louis

PY - 2009/7/6

Y1 - 2009/7/6

N2 - Depletion of CD8+ lymphocytes during acute simian immunodeficiency virus (SIV) infection of rhesus macaques (RMs) results in irreversible prolongation of peak-level viral replication and rapid disease progression, consistent with a major role for CD8+ lymphocytes in determining postacute-phase viral replication set points. However, we report that CD8+ lymphocyte depletion is also associated with a dramatic induction of proliferation among CD4+ effector memory T (T EM) cells and, to a lesser extent, transitional memory T (T TrM) cells, raising the question of whether an increased availability of optimal (activated/proliferating), CD4+/CCR5+ SIV "target" cells contributes to this accelerated pathogenesis. In keeping with this, depletion of CD8+ lymphocytes in SIV- RMs led to a sustained increase in the number of potential CD4+ SIV targets, whereas such depletion in acute SIV infection led to increased target cell consumption. However, we found that the excess CD4+ TEM cell proliferation of CD8+ lymphocyte-depleted, acutely SIV-infected RMs was completely inhibited by interleukin (IL)-15 neutralization, and that this inhibition did not abrogate the rapidly progressive infection in these RMs. Moreover, although administration of IL-15 during acute infection induced robust CD4+ TEM and TTrM cell proliferation, it did not recapitulate the viral dynamics of CD8+ lymphocyte depletion. These data suggest that CD8+ lymphocyte function has a larger impact on the outcome of acute SIV infection than the number and/or activation status of target cells available for infection and viral production.

AB - Depletion of CD8+ lymphocytes during acute simian immunodeficiency virus (SIV) infection of rhesus macaques (RMs) results in irreversible prolongation of peak-level viral replication and rapid disease progression, consistent with a major role for CD8+ lymphocytes in determining postacute-phase viral replication set points. However, we report that CD8+ lymphocyte depletion is also associated with a dramatic induction of proliferation among CD4+ effector memory T (T EM) cells and, to a lesser extent, transitional memory T (T TrM) cells, raising the question of whether an increased availability of optimal (activated/proliferating), CD4+/CCR5+ SIV "target" cells contributes to this accelerated pathogenesis. In keeping with this, depletion of CD8+ lymphocytes in SIV- RMs led to a sustained increase in the number of potential CD4+ SIV targets, whereas such depletion in acute SIV infection led to increased target cell consumption. However, we found that the excess CD4+ TEM cell proliferation of CD8+ lymphocyte-depleted, acutely SIV-infected RMs was completely inhibited by interleukin (IL)-15 neutralization, and that this inhibition did not abrogate the rapidly progressive infection in these RMs. Moreover, although administration of IL-15 during acute infection induced robust CD4+ TEM and TTrM cell proliferation, it did not recapitulate the viral dynamics of CD8+ lymphocyte depletion. These data suggest that CD8+ lymphocyte function has a larger impact on the outcome of acute SIV infection than the number and/or activation status of target cells available for infection and viral production.

UR - http://www.scopus.com/inward/record.url?scp=67650457719&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67650457719&partnerID=8YFLogxK

U2 - 10.1084/jem.20090356

DO - 10.1084/jem.20090356

M3 - Article

C2 - 19546246

AN - SCOPUS:67650457719

VL - 206

SP - 1575

EP - 1588

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

IS - 7

ER -