Abstract
We tested the hypothesis that therapeutic vaccination against HIV-1 can increase the frequency and suppressive function of regulatory, CD4+ T cells (Treg), thereby masking enhancement of HIV-1-specific CD8+ T cell response. HIV-1-infected subjects on antiretroviral therapy (N = 17) enrolled in a phase I therapeutic vaccine trial received 2 doses of autologous dendritic cells (DC) loaded with HIV-1 peptides. The frequency of CD4+CD25hiFOXP3+ Treg in blood was determined prior to and after vaccination in subjects and normal controls. Polyfunctional CD8+ T cell responses were determined pre- and post-vaccine (N = 7) for 5 immune mediators after in vitro stimulation with Gag peptide, staphylococcal enterotoxin B (SEB), or medium alone. Total vaccine response (post-vaccine–pre-vaccine) was compared in the Treg(+) and Treg-depleted (Treg-) sets. After vaccination, 12/17 subjects showed a trend of increased Treg frequency (P = 0.06) from 0.74% to 1.2%. The increased frequency did not correlate with CD8+ T cell vaccine response by enzyme linked immunosorbent assay for interferon γ production. Although there was no significant change in CD8+ T cell polyfunctional response after vaccination, Treg depletion increased the polyfunctionality of the total vaccine response (P = 0.029), with a >2-fold increase in the percentage of CD8+ T cells producing multiple immune mediators. In contrast, depletion of Treg did not enhance polyfunctional T cell response to SEB, implying specificity of suppression to HIV-1 Gag. Therapeutic immunization with a DC-based vaccine against HIV-1 caused a modest increase in Treg frequency and a significant increase in HIV-1-specific, Treg suppressive function. The Treg suppressive effect masked an increase in the vaccine-induced anti-HIV-1-specific polyfunctional response. The role of Treg should be considered in immunotherapeutic trials of HIV-1 infection.
Highlights
The ability of regulatory T cells (Treg) to control the immune response to infections can have serious implications in the body’s capability to eradicate invading pathogens
Despite the inconsistent frequency results, functional studies have demonstrated that Treg isolated from both peripheral blood and lymphoid tissues of HIV-1 infected individuals show strong suppressor activity and that they suppress HIV-1-specific effector functions of T cells. [2,9,10] Treg isolated from HIVinfected patients have been shown to suppress HIV-1-specific CD8+ T cell interferon c (IFNc) and tumor necrosis factor a (TNFa) secretion as well as Gag-specific cytolytic activity. [11]
Recent studies of HIV-1-infected individuals with natural immune control have shown that an effective immune response is characterized by the presence of a polyfunctional CD8+ T cell response to the virus. [13,14,16,20] Since the control of HIV-1 has been shown to be more dependent on the quality and specificity of the CD8+ T cell response rather than the quantity of the response alone, [15] we evaluated CD8+ T cell polyfunctional response in a previously completed dendritic cells (DC)-HIV-1 peptide vaccine trial
Summary
The ability of regulatory T cells (Treg) to control the immune response to infections can have serious implications in the body’s capability to eradicate invading pathogens. The frequency and function of Treg in the peripheral blood and lymphatic tissues of patients with HIV-1 infection have been explored, no consistent results have emerged It is uncertain whether Treg mainly protect against or contribute to persistent HIV-1 infection and consequent disease progression. A nested case-control study by Cao et al [8] showed significant expansion of Treg and increase in T cell activation in subjects with rapidly progressing HIV-1 infection. Despite the inconsistent frequency results, functional studies have demonstrated that Treg isolated from both peripheral blood and lymphoid tissues of HIV-1 infected individuals show strong suppressor activity and that they suppress HIV-1-specific effector functions of T cells. Despite the inconsistent frequency results, functional studies have demonstrated that Treg isolated from both peripheral blood and lymphoid tissues of HIV-1 infected individuals show strong suppressor activity and that they suppress HIV-1-specific effector functions of T cells. [2,9,10] Treg isolated from HIVinfected patients have been shown to suppress HIV-1-specific CD8+ T cell interferon c (IFNc) and tumor necrosis factor a (TNFa) secretion as well as Gag-specific cytolytic activity. [11]
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