Regulatory function of cytomegalovirus-specific CD4+CD27-CD28- T cells.

CMV infection is characterized by high of frequencies of CD27-CD28- T cells. Here we demonstrate that CMV-specific CD4+CD27-CD28- cells are regulatory T cells (TR). CD4+CD27-CD28- cells sorted from CMV-stimulated PBMC of CMV-seropositive donors inhibited de novo CMV-specific proliferation of autologous PBMC in a dose-dependent fashion. Compared with the entire CMV-stimulated CD4+ T-cell population, higher proportions of CD4+CD27-CD28- TR expressed FoxP3, TGFbeta, granzyme B, perforin, GITR and PD-1, lower proportions expressed CD127 and PD1-L and similar proportions expressed CD25, CTLA4, Fas-L and GITR-L. CMV-CD4+CD27-CD28- TR expanded in response to IL-2, but not to CMV antigenic restimulation. The anti-proliferative effect of CMV-CD4+CD27-CD28- TR significantly decreased after granzyme B or TGFbeta inhibition. The CMV-CD4+CD27-CD28- TR of HIV-infected and uninfected donors had similar phenotypes and anti-proliferative potency, but HIV-infected individuals had higher proportions of CMV-CD4+CD27-CD28- TR. The CMV-CD4+CD27-CD28- TR may contribute to the downregulation of CMV-specific and nonspecific immune responses of CMV-infected individuals.

T cell responses of HIV-infected children after administration of inactivated or live attenuated influenza vaccines.

Live-attenuated influenza vaccine (LAIV) prevents significantly more cases of influenza in immune-competent children than the trivalent inactivated vaccine (TIV). We compared the T cell responses to LAIV or TIV in HIV-infected children. IFN-gamma-ELISPOT for the three vaccine-contained influenza strains, two mismatched strains, and phytohemagglutinin (PHA), was performed at 0, 4, and 24 weeks postimmunization in 175 HIV-infected children randomly assigned to LAIV or TIV. The contribution of CD8 T cells to the influenza-specific response (CD8-ELISPOT) was evaluated by CD8-cell depletion. CD8 T cells accounted for > or =87% of the total influenza-ELISPOT. At baseline, total influenza-ELISPOT and CD8-ELISPOT values were similar or higher in TIV compared with LAIV recipients. Four and 24 weeks after TIV, total influenza-ELISPOT and CD8-ELISPOT results were significantly lower than baseline results (p < or = 0.001). Responses to PHA also tended to decrease at 4 weeks after TIV (p = 0.06), but rebounded to baseline levels at 24 weeks. Four weeks after LAIV, total influenza-ELISPOT responses to vaccine-contained strains A H3N2 and B significantly decreased. Other ELISPOT values at 4 weeks and all values at 24 weeks were similar to the baseline values. At 4 and 24 weeks, TIV compared to LAIV administration resulted in a significantly greater decrease in influenza-specific ELISPOT values for vaccine-contained influenza A strains (p < or = 0.02). Responses to PHA also tended to decrease more in TIV recipients (p = 0.07). HIV-infected children immunized with TIV had significant and persistent decreases in ELISPOT responses to influenza. LAIV administration suppressed ELISPOT responses less. The clinical significance of these findings deserves further study.

Anti-influenza serum and mucosal antibody responses after administration of live attenuated or inactivated influenza vaccines to HIV-infected children.

BACKGROUND: Live-attenuated influenza vaccine (LAIV) prevents more cases of influenza in immune-competent children than the trivalent inactivated vaccine (TIV). We compared the antibody responses to LAIV or TIV in HIV-infected children. METHODS: Blood and saliva obtained at enrollment, 4 and 24 weeks postimmunization from 243 HIV-infected children randomly assigned to TIV or LAIV were analyzed. RESULTS: Both vaccines increased the anti-influenza neutralizing antibodies at 4 and 24 weeks postimmunization. At 4 weeks postimmunization, TIV recipients had 2-fold to 3-fold higher neutralizing antibody titers than LAIV recipients, but the proportions of subjects with protective titers (≥ 1:40) were similar between treatment groups (96%-100% for influenza A and 81%-88% for influenza B). Both vaccines increased salivary homotypic IgG antibodies, but not IgA antibodies. Both vaccines also increased serum heterosubtypic antibodies. Among HIV-specific characteristics, the baseline viral load correlated best with the antibody responses to either vaccine. We used LAIV-virus shedding as a surrogate of influenza infection. Influenza-specific humoral and mucosal antibody levels were significantly higher in nonshedders than in shedders. CONCLUSIONS: LAIV and TIV generated homotypic and heterosubtypic humoral and mucosal antibody responses in HIV-infected children. High titers of humoral or mucosal antibodies correlated with protection against viral shedding.

Virologic and immunologic correlates with the magnitude of antibody responses to the hepatitis A vaccine in HIV-infected children on highly active antiretroviral treatment.

BACKGROUND: HIV-infected individuals mount poor antibody responses to vaccines. We sought to identify the immunologic and virologic factors associated with a robust response to hepatitis A virus (HAV) vaccine in children on highly active antiretroviral treatment. METHODS: One hundred fifty-two pediatric highly active antiretroviral treatment recipients immunized against HAV at weeks 0 and 24 had anti-HAV antibodies, CD4+, CD8+, and CD19+ cell percent assessed at weeks 0 and 32. Subgroups had HIV viremia, B- and T-cell subpopulations, and cell-mediated immunity (CMI) to HAV and other stimulants measured. RESULTS: Anti-HAV antibodies after complete vaccination correlated positively with CD4+ percent and CD19+ percent and negatively with viremia and CD8+ percent at baseline, but not at 32 weeks. There were no significant correlations between anti-HAV antibodies and B- or T-cell-naïve, memory, or activated subpopulations or non-HAV CMI. Compared with children who remained HAV-CMI-negative, those who mounted HAV-CMI in response to vaccination had higher anti-HAV antibody titers and CD19+ CD21+ CD27+ memory B cell percent at 32 weeks, but no other differences. CONCLUSIONS: In HIV-infected children on highly active antiretroviral treatment, control of viral replication and conserved or reconstituted CD19+ and CD4+ cell numbers and function determine a robust antibody response to anti-HAV primary immunization. Our data support a bidirectional B- and T-cell cooperation in the response to the HAV vaccine.

Continuous improvement in the immune system of HIV-infected children on prolonged antiretroviral therapy.

BACKGROUND: The goal of HAART is to promote reconstitution of CD4+ T cells and other immune responses. We evaluated the extent and the kinetics of immune reconstitution in HIV-infected children over 144 weeks of successful HAART. METHODS: Thirty-seven children receiving their first HAART regimen had plasma HIV RNA; T cells and subpopulations; T-cell rearrangement excision circles (TREC) DNA; candida, HIVCD4 and HIVCD8 enzyme-linked immunospot measured at regular intervals. RESULTS: Plasma HIV RNA became undetectable in 81% of patients at 24 weeks and remained undetectable in 77% at 144 weeks. In contrast, CD4+% continuously increased. Distribution of T-cell subpopulations changed rapidly during the first 48 weeks of HAART and more slowly thereafter. At 144 weeks, total, naive and activated CD4+% and naive CD8+% of HIV-infected children were not significantly different from those of healthy age-matched controls, whereas total and activated CD8+% remained elevated. CD4 and CD8 TREC content increased only during the first 48 weeks of HAART. They positively correlated with each other and with total CD4+%, naive CD4+% and naive CD8+%. Candida and HIVCD4 enzyme-linked immunospot increased over time reaching peak values at 48 weeks and 144 weeks, respectively. HIVCD8 enzyme-linked immunospot decreased in magnitude over 144 weeks of HAART but retained its breadth. Baseline CD4+% positively correlated with CD4+% and with functional immune reconstitution at week 144, whereas baseline TREC correlated with TREC at week 144. CONCLUSION: HIV-infected children acquired normal distribution of CD4 T cells and other subpopulations and recovered CD4-mediated HIV immunity after 144 weeks of HAART.

Phenotypic and functional characterization of ex vivo T cell responses to the live attenuated herpes zoster vaccine.

To define the phenotypic characteristics and kinetics of T cell responses to a shingles vaccine in elderly individuals, 20 subjects > or =60 years of age received two doses of vaccine or placebo 6 weeks apart. VZV-specific T cell phenotypes and intracellular cytokines were determined by flow cytometry on blood mononuclear cells obtained pre-vaccination and up to 6 months after the second immunization. Results were compared with responses of five unvaccinated young adults. Pre-vaccination, elderly individuals had significantly lower VZV-specific effectors and cytokine-producing T cells compared with young adults. The vaccine significantly increased VZV-specific Th1, memory, early effector, and cutaneous homing receptor-bearing T cells.

Cytomegalovirus-specific immunity and protection against viremia and disease in HIV-infected patients in the era of highly active antiretroviral therapy.

To define the immune correlates of protection against cytomegalovirus (CMV) end-organ disease, CMV-specific interferon (IFN)- gamma enzyme-linked immunospot (ELISPOT) and CD8(+) and CD4(+) intracellular IFN- gamma synthesis assays were performed for subjects with CD4(+) cell counts of < or =50 cells/ microL who were enrolled in a prospective observational study of CMV infection in the era of highly active antiretroviral therapy. Of 87 subjects, 46 developed viremia, 14 developed end-organ disease, and 20 died. Positive ELISPOT assay results, but not positive results for CD4(+) or CD8(+) intracellular IFN- gamma synthesis, were associated with delayed development of viremia and CMV end-organ disease or death. CMV viremia did not appear to boost CMV-specific immunity. ELISPOT assays may be used to identify HIV-infected patients who might benefit from anti-CMV prophylactic interventions.