Magnitude and complexity of rectal mucosa HIV-1-specific CD8+ T-cell responses during chronic infection reflect clinical status

J. William Critchfield, Delandy H. Young, Timothy L. Hayes, Jerome V. Braun, Juan Carlos Garcia, Richard B Pollard, Barbara Shacklett

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

Background: The intestinal mucosa displays robust virus replication and pronounced CD4+ T-cell loss during acute human immunodeficiency virus type 1 (HIV-1) infection. The ability of HIV-specific CD8+ T-cells to modulate disease course has prompted intensive study, yet the significance of virus-specific CD8+ T-cells in mucosal sites remains unclear. Methods and Findings: We evaluated five distinct effector functions of HIVgag-specific CD8+ T-cells in rectal mucosa and blood, individually and in combination, in relationship to clinical status and antiretroviral therapy (ART). In subjects not on ART, the percentage of rectal Gag-specific CD8+ T-cells capable of 3, 4 or 5 simultaneous effector functions was significantly related to blood CD4 count and inversely related to plasma viral load (PVL) (p,0.05). Polyfunctional rectal CD8+ T-cells expressed higher levels of MIP-1β and CD107a on a per cell basis than mono- or bifunctional cells. The production of TNFα, IFN-γ, and CD107a by Gag-specific rectal CD8+ T-cells each correlated inversely (p<0.05) with PVL, and MIP-1β expression revealed a similar trend. CD107a and IFN-γ production were positively related to blood CD4 count (p<0.05), with MIP-1β showing a similar trend. IL-2 production by rectal CD8+ T-cells was highly variable and generally low, and showed no relationship to viral load or blood CD4 count. Conclusions: The polyfunctionality of rectal Gag-specific CD8+ T-cells appears to be related to blood CD4 count and inversely related to PVL. The extent to which these associations reflect causality remains to be determined; nevertheless, our data suggest a potentially important role for mucosal T-cells in limiting virus replication during chronic infection.

Original languageEnglish (US)
Article numbere3577
JournalPLoS One
Volume3
Issue number10
DOIs
StatePublished - Oct 30 2008

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T-cells
Human immunodeficiency virus 1
Viruses
mucosa
HIV-1
Mucous Membrane
T-lymphocytes
T-Lymphocytes
Infection
infection
CD4 Lymphocyte Count
viral load
Viral Load
Blood
blood
Virus Replication
virus replication
Plasmas
therapeutics
Virus Diseases

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Magnitude and complexity of rectal mucosa HIV-1-specific CD8+ T-cell responses during chronic infection reflect clinical status. / Critchfield, J. William; Young, Delandy H.; Hayes, Timothy L.; Braun, Jerome V.; Garcia, Juan Carlos; Pollard, Richard B; Shacklett, Barbara.

In: PLoS One, Vol. 3, No. 10, e3577, 30.10.2008.

Research output: Contribution to journalArticle

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abstract = "Background: The intestinal mucosa displays robust virus replication and pronounced CD4+ T-cell loss during acute human immunodeficiency virus type 1 (HIV-1) infection. The ability of HIV-specific CD8+ T-cells to modulate disease course has prompted intensive study, yet the significance of virus-specific CD8+ T-cells in mucosal sites remains unclear. Methods and Findings: We evaluated five distinct effector functions of HIVgag-specific CD8+ T-cells in rectal mucosa and blood, individually and in combination, in relationship to clinical status and antiretroviral therapy (ART). In subjects not on ART, the percentage of rectal Gag-specific CD8+ T-cells capable of 3, 4 or 5 simultaneous effector functions was significantly related to blood CD4 count and inversely related to plasma viral load (PVL) (p,0.05). Polyfunctional rectal CD8+ T-cells expressed higher levels of MIP-1β and CD107a on a per cell basis than mono- or bifunctional cells. The production of TNFα, IFN-γ, and CD107a by Gag-specific rectal CD8+ T-cells each correlated inversely (p<0.05) with PVL, and MIP-1β expression revealed a similar trend. CD107a and IFN-γ production were positively related to blood CD4 count (p<0.05), with MIP-1β showing a similar trend. IL-2 production by rectal CD8+ T-cells was highly variable and generally low, and showed no relationship to viral load or blood CD4 count. Conclusions: The polyfunctionality of rectal Gag-specific CD8+ T-cells appears to be related to blood CD4 count and inversely related to PVL. The extent to which these associations reflect causality remains to be determined; nevertheless, our data suggest a potentially important role for mucosal T-cells in limiting virus replication during chronic infection.",
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AB - Background: The intestinal mucosa displays robust virus replication and pronounced CD4+ T-cell loss during acute human immunodeficiency virus type 1 (HIV-1) infection. The ability of HIV-specific CD8+ T-cells to modulate disease course has prompted intensive study, yet the significance of virus-specific CD8+ T-cells in mucosal sites remains unclear. Methods and Findings: We evaluated five distinct effector functions of HIVgag-specific CD8+ T-cells in rectal mucosa and blood, individually and in combination, in relationship to clinical status and antiretroviral therapy (ART). In subjects not on ART, the percentage of rectal Gag-specific CD8+ T-cells capable of 3, 4 or 5 simultaneous effector functions was significantly related to blood CD4 count and inversely related to plasma viral load (PVL) (p,0.05). Polyfunctional rectal CD8+ T-cells expressed higher levels of MIP-1β and CD107a on a per cell basis than mono- or bifunctional cells. The production of TNFα, IFN-γ, and CD107a by Gag-specific rectal CD8+ T-cells each correlated inversely (p<0.05) with PVL, and MIP-1β expression revealed a similar trend. CD107a and IFN-γ production were positively related to blood CD4 count (p<0.05), with MIP-1β showing a similar trend. IL-2 production by rectal CD8+ T-cells was highly variable and generally low, and showed no relationship to viral load or blood CD4 count. Conclusions: The polyfunctionality of rectal Gag-specific CD8+ T-cells appears to be related to blood CD4 count and inversely related to PVL. The extent to which these associations reflect causality remains to be determined; nevertheless, our data suggest a potentially important role for mucosal T-cells in limiting virus replication during chronic infection.

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