High CD8+ T Cell Activation Marks a Less Differentiated HIV-1 Specific CD8+ T Cell Response that Is Not Altered by Suppression of Viral Replication

Jason D Barbour,Terence Ho,Elizabeth Sinclair,Lishomwa C Ndhlovu,Jay A Levy,Qi Xuan Tan,Lorrie Epling,Frederick M Hecht,Barry M Bredt

doi:10.1371/journal.pone.0004408

Jason D Barbour, Terence Ho + Show 7 more

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https://doi.org/10.1371/journal.pone.0004408

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Abstract

BackgroundThe relationship of elevated T cell activation to altered T cell differentiation profiles, each defining features of HIV-1 infection, has not been extensively explored. We hypothesized that anti-retroviral suppression of T cell activation levels would lead to alterations in the T cell differentiation of total and HIV-1 specific CD8+ T cell responses among recently HIV-1 infected adults.Methodology/Principal FindingsWe performed a longitudinal study simultaneously measuring T cell activation and maturation markers on both total and antigen-specific T cells in recently infected adults: prior to treatment; after the initiation of HAART; and after treatment was halted. Prior to treatment, HIV-1 Gag–specific CD8+ T cells were predominantly of a highly activated, intermediate memory (CD27+CD28−) phenotype, while CMV pp65-specific CD8+ T cells showed a late memory (CD27−CD28−), low activation phenotype. Participants with the highest fraction of late memory (CD27−CD28−) HIV-1-specific CD8+ T cells had higher CD4+ T cell counts (rho = +0.74, p = 0.004). In turn, those with the highest fraction of intermediate memory (CD27+ CD28−) HIV-1 specific CD8+ T cells had high total CD8+ T cell activation (rho = +0.68, p = 0.01), indicating poorer long-term clinical outcomes. The HIV-1 specific T cell differentiation profile was not readily altered by suppression of T cell activation following HAART treatment.Conclusions/SignificanceA more differentiated, less activated HIV-1 specific CD8+ T cell response may be clinically protective. Anti-retroviral treatment initiated two to four months after infection lowered T cell activation but had no effect on the differentiation profile of the HIV-1-specific response. Intervention during the first month of acute infection may be required to shift the differentiation phenotype of HIV-1 specific responses to a more clinically favorable profile.

Highlights

Elevated CD8+ T cell activation is established early in HIV-1 infection [1], is a hallmark of HIV-1 disease [2] and predicts subsequent poor clinical outcome in a manner independent of viral load [1]
The magnitude of IFN-c and IFN-c/IL-2 CD8+ T cell responses to HIV-1 Gag were lower than the response to CMV pp65 at visit 1, and subsequent study time points during and after anti-retroviral therapy (Fig. 2)
At study visit 1, during early untreated infection, we examined the relationship between the CD8+ T cell activation level and maturation profile of total and HIV-1 Gag specific T cell responses (Figure 5)

Summary

Introduction

Elevated CD8+ T cell activation is established early in HIV-1 infection [1], is a hallmark of HIV-1 disease [2] and predicts subsequent poor clinical outcome in a manner independent of viral load [1]. Elevated CD8+ T cell activation, and not viral load, distinguish pathogenic from non-pathogenic lentiviral infections [3,4,5,6]. These observations have lead to a general consensus that CD8+ T cell activation plays an important role in the pathogenesis of immunodeficiency. We hypothesized that a block in T cell maturation may be related to elevated activation on HIV-1 specific CD8+ T cells, and be relieved by suppression of T cell activation levels by anti-retroviral treatment (ART). We hypothesized that anti-retroviral suppression of T cell activation levels would lead to alterations in the T cell differentiation of total and HIV-1 specific CD8+ T cell responses among recently HIV-1 infected adults

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