Abstract
BackgroundThe 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 FindingsWe 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.ConclusionsThe 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.
Highlights
A significant body of work has demonstrated the contribution of HIV-specific CD8+ T-cell responses to immunological control of HIV infection [1,2,3]
The polyfunctionality of rectal Gag-specific CD8+ T-cells appears to be related to blood CD4 count and inversely related to plasma viral load (PVL)
We report that HIV-specific CD8+ T-cell responses in rectal mucosa of patients on long-term suppressive antiretroviral therapy (ART) are characterized by low magnitude and a marked qualitative shift towards monofunctional responses when compared to patients not on ART
Summary
A significant body of work has demonstrated the contribution of HIV-specific CD8+ T-cell responses to immunological control of HIV infection [1,2,3]. Mathematical models based upon the ability of CTL to clear virally infected cells predicted an inverse relationship between blood CTL frequency and HIV plasma viral load in the absence of antiretroviral therapy [4]. Subsequent studies did not produce a consensus on this point: one study reported a positive correlation between plasma viral load and the total HIV-specific, Env-, and Nef-specific CD8+ T-cell frequency [7], while at least two others found no numerical relationship [8,9]. Additional light has been shed on this issue by reports documenting a unique relationship between the breadth and/or magnitude of Gagspecific CD8+ T-cell responses (but not Env, Pol or Nef-specific responses) and plasma viremia and/or blood CD4 count [10,11,12,13,14,15,16]. 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
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