Date Published: May 6, 2008
Publisher: Public Library of Science
Author(s): Hendrik Streeck, Zabrina L Brumme, Michael Anastario, Kristin W Cohen, Jonathan S Jolin, Angela Meier, Chanson J Brumme, Eric S Rosenberg, Galit Alter, Todd M Allen, Bruce D Walker, Marcus Altfeld, Sarah Rowland-Jones
Abstract: BackgroundVirus-specific CD8+ T lymphocytes play a key role in the initial reduction of peak viremia during acute viral infections, but display signs of increasing dysfunction and exhaustion under conditions of chronic antigen persistence. It has been suggested that virus-specific CD8+ T cells with a “polyfunctional” profile, defined by the capacity to secrete multiple cytokines or chemokines, are most competent in controlling viral replication in chronic HIV-1 infection. We used HIV-1 infection as a model of chronic persistent viral infection to investigate the process of exhaustion and dysfunction of virus-specific CD8+ T cell responses on the single-epitope level over time, starting in primary HIV-1 infection.Methods and FindingsWe longitudinally analyzed the polyfunctional epitope-specific CD8+ T cell responses of 18 patients during primary HIV-1 infection before and after therapy initiation or sequence variation in the targeted epitope. Epitope-specific CD8+ T cells responded with multiple effector functions to antigenic stimulation during primary HIV-1 infection, but lost their polyfunctional capacity in response to antigen and up-regulated programmed death 1 (PD-1) expression with persistent viremic infection. This exhausted phenotype significantly decreased upon removal of stimulation by antigen, either in response to antiretroviral therapy or by reduction of epitope-specific antigen load in the presence of ongoing viral replication, as a consequence of in vivo selection of cytotoxic T lymphocyte escape mutations in the respective epitopes. Monofunctionality increased in CD8+ T cell responses directed against conserved epitopes from 49% (95% confidence interval 27%–72%) to 76% (56%–95%) (standard deviation [SD] of the effect size 0.71), while monofunctionality remained stable or slightly decreased for responses directed against escaped epitopes from 61% (47%–75%) to 56% (42%–70%) (SD of the effect size 0.18) (p < 0.05).ConclusionThese data suggest that persistence of antigen can be the cause, rather than the consequence, of the functional impairment of virus-specific T cell responses observed during chronic HIV-1 infection, and underscore the importance of evaluating autologous viral sequences in studies aimed at investigating the relationship between virus-specific immunity and associated pathogenesis.
Partial Text: During acute viral infections, antigen-specific CD8+ T cells control viral replication, leading to a clearance or significant reduction of viremia with subsequent development of robust and fully differentiated memory CD8+ T cells. However, in some cases, the immune response is unable to completely clear a viral infection during acute infection. This inability leads to viral persistence, which is often associated with the subsequent development of chronic viral disease. Under conditions of chronic antigen persistence, virus-specific CD8+ T cells gradually lose their ability to proliferate, to secrete a diverse profile of cytokines, and they display progressively dysfunctional cytotoxic activity [1–4], ultimately leading to exhaustion or even anergy of these cells . The functional exhaustion of virus-specific T cells has been best characterized in lymphocytic choriomeningitis virus (LCMV) infection of mice [5–7], and has also been described in several chronic human infections, such as HIV, hepatitis B virus (HBV), or hepatitis C virus (HCV) infection [8–10]. Therefore, CD8+ T cell responses in chronic viral infections are characterized by an increasing degree of functional impairment, and this defect has been proposed as one reason for the incapability of the host to clear the persisting infection.
The identification of correlates of protective immunity in HIV-1 infection has largely remained elusive . Recent studies have reported that effective virus-specific CD8+ T cells display a “polyfunctional” capacity, including the ability to secrete multiple cytokines and chemokines in response to antigenic stimulation in HIV-1–infected individuals with chronic long-term nonprogressive infection . These data suggest an important role for the ability of antigen-specific CD8+ T cells to secrete multiple cytokines/chemokines in the control over viral replication. However, the preserved functionality of HIV-1–specific CD8+ T cells that is observed in chronically infected individuals who control HIV-1 viremia could represent either the cause of control over viral replication or the consequence of low viremia. The longitudinal studies in individuals identified during primary HIV-1 infection presented here suggest that the functional profile of an epitope-specific CD8+ T cell response is largely determined by the duration and intensity of antigenic exposure, and is therefore mainly a consequence of viremia.