Cross-reactive memory CD4+ T cells alter the CD8+ T-cell response to heterologous secondary dengue virus infections in mice in a sequence-specific manner.

Center for Infectious Disease and Vaccine Research, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA.
Viral immunology (Impact Factor: 1.45). 07/2009; 22(3):215-9. DOI: 10.1089/vim.2008.0089
Source: PubMed


Dengue virus is the causative agent of dengue fever and the more-severe dengue hemorrhagic fever (DHF). Human studies suggest
that the increased risk of DHF during secondary infection is due to immunopathology partially mediated by cross-reactive memory
T cells from the primary infection. To model T cell responses to sequential infections, we immunized mice with different sequences
of dengue virus serotypes and measured the frequency of peptide-specific T cells after infection. The acute response after
heterologous secondary infections was enhanced compared with the acute or memory response after primary infection. Also, the
hierarchy of epitope-specific responses was influenced by the specific sequence of infection. Adoptive-transfer experiments
showed that memory T cells responded preferentially to the secondary infection. These findings demonstrate that cross-reactive
T cells from a primary infection alter the immune response during a heterologous secondary infection.

Download full-text


Available from: Coreen M Beaumier
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Dengue virus (DENV) causes the most significant mosquito-borne viral disease in the world in terms of illness, death, and economic cost, due to the lack of an approved vaccine or antiviral. Infections with one of the four serotypes of DENV (DENV1-4) can result in diseases ranging from an acute, self-limiting febrile illness (dengue fever, DF) to life-threatening dengue hemorrhagic fever (DHF) or dengue shock syndrome (DSS), yet exactly how viral and host factors contribute to the severe disease is unknown. Clinical observations have provided information on DENV pathogenesis, but the lack of an adequate animal model has hindered research on this important human pathogen. A mouse model is ideal for investigating host-pathogen interactions due to the immunological tools available, however, wild-type mice are resistant to DENV-induced disease. Therefore, the mouse models for DENV infection developed to date include infection of severely immunocompromised mice, non-physiologic routes of infection, and mouse-human chimeras, which all have their limitations. An inbred mouse model in which mice develop signs of human DENV-induced disease is needed to investigate the contribution of various immune components to protection and pathogenesis of DENV infections, and to test the efficacy of DENV vaccines and antivirals.
    Preview · Article · Aug 2008 · Antiviral research
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Three independent, phase 1 clinical trials were conducted in Australia and in USA to assess the safety and immunogenicity of sanofi pasteur dengue vaccine candidates. In this context, Dengue 1-4 and Yellow Fever 17D-204 (YF 17D)-specific CD4 and CD8 cellular responses induced by tetravalent chimeric dengue vaccines (CYD) were analyzed in flavivirus-naive or flavivirus-immune patients. Tetravalent CYD vaccine did not trigger detectable changes in serum pro-inflammatory cytokines, whatever the vaccinees immune status, while inducing significant YF 17D NS3-specific CD8 responses and dengue serotype-specific T helper responses. These responses were dominated by serotype 4 in naive individuals, but a booster vaccination (dose #2) performed 4 months following dose #1 broadened serotype-specific responses. A similar, broader response was seen after primary tetravalent immunization in subjects with pre-existing dengue 1 or 2 immunity caused by prior monovalent live-attenuated dengue vaccination. In all three trials, the profile of induced response was similar, whatever the subjects' immune status, i.e. an absence of Th2 response, and an IFN-gamma/TNF-alpha ratio dominated by IFN-gamma, for both CD4 and CD8 responses. Our results also showed an absence of cross-reactivity between YF 17D or Dengue NS3-specific CD8 responses, and allowed the identification of 3 new CD8 epitopes in the YF 17D NS3 antigen. These data are consistent with the previously demonstrated excellent safety of these dengue vaccines in flavivirus-naive and primed individuals.
    Full-text · Article · Sep 2008 · Vaccine
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The four serotypes of dengue virus (DENV1-4) are causative agents of dengue fever and dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). Previous DENV infection is a risk factor for DHF/DSS during subsequent infection by a different serotype. Nonetheless, most primary and secondary DENV infections are asymptomatic. To investigate the possible mechanisms of immune protection in vivo, 129/Pas mice lacking IFN-alpha/beta and -gamma receptors (AG129) were used to model secondary infection using both DENV1-DENV2 and DENV2-DENV4 sequences. At intervals between sequential infections of 4 to 52 weeks, protection against secondary heterologous DENV infection was observed. Passive transfer of DENV-immune serum was protective against replication of heterologous challenge virus in all tissues tested, whereas adoptive transfer of DENV-immune cells significantly protected mice from replication of the challenge virus only when a lower inoculum was administered. These findings are relevant for understanding both natural and vaccine-induced immunity to DENV.
    Preview · Article · Oct 2008 · Virology
Show more