Both Mucosal and Systemic Routes of Immunization with the Live, Attenuated NYVAC/Simian Immunodeficiency Virus SIVgpe Recombinant Vaccine Result in Gag-Specific CD8+ T-Cell Responses in Mucosal Tissues of Macaques

Basic Research Laboratory, National Cancer Institute, Bethesda, Maryland 20892, USA.
Journal of Virology (Impact Factor: 4.65). 12/2002; 76(22):11659-76. DOI: 10.1128/JVI.76.22.11659-11676.2002
Source: PubMed

ABSTRACT As most human immunodeficiency virus (HIV) infection occurs via mucosal surfaces, an important goal of vaccination may be the induction of virus-specific immune responses at mucosal sites to contain viral infection early on. Here we designed a study in macaques carrying the major histocompatibility complex class I Mamu-A(*)01 molecule to assess the capacity of the highly attenuated poxvirus NYVAC/simian immunodeficiency virus (SIV) SIV(gpe) vaccine candidate administered by the intranasal, intramuscular, or intrarectal route to induce mucosal immunity. All macaques, including one naive macaque, were exposed to SIV(mac251) by the intrarectal route and sacrificed 48 h after infection. The kinetics of immune response at various time points following immunization with NYVAC/SIV(gpe) and the anamnestic response to SIV(mac251) at 48 h after challenge were assessed in blood, in serial rectal and vaginal biopsy samples, and in tissues at euthanasia with an SIV(mac) Gag-specific tetramer. In addition, at euthanasia, antigen-specific cells producing gamma interferon or tumor necrosis factor alpha from the jejunum lamina propria were quantified in all macaques. Surprisingly, antigen-specific CD8(+) T cells were found in the mucosal tissues of all immunized macaques regardless of whether the vaccine was administered by a mucosal route (intranasal or intrarectal) or systemically. In addition, following mucosal SIV(mac251) challenge, antigen-specific responses were mainly confined to mucosal tissues, again regardless of the route of immunization. We conclude that immunization with a live vector vaccine results in the appearance of CD8(+) T-cell responses at mucosal sites even when the vaccine is delivered by nonmucosal routes.

  • Source
    • "Furthermore, up to 50% of the vaccine-induced tetramerpositive CD8+ T lymphocytes in peripheral blood expressed the gut-homing molecule, α4β7, suggesting that systemic administration of recombinant HSV may be able to elicit mucosal immunity. These data are consistent with the finding of a recombinant NYVAC-SIV vaccine being able to induce anti-SIV CD8+ T cells in the rectal and vaginal mucosa even when administered via the intramuscular route (Stevceva et al., 2002). Since mucosal priming can further accentuate mucosal immunity (Bertley et al., 2004; Egan et al., 2004; Evans et al., 2003), the ability to deliver recombinant HSV vectors via mucosal routes may be an added advantage of this vaccine approach. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The immunogenicity and protective capacity of replication-defective herpes simplex virus (HSV) vector-based vaccines were examined in rhesus macaques. Three macaques were inoculated with recombinant HSV vectors expressing Gag, Env, and a Tat-Rev-Nef fusion protein of simian immunodeficiency virus (SIV). Three other macaques were primed with recombinant DNA vectors expressing Gag, Env, and a Pol-Tat-Nef-Vif fusion protein prior to boosting with the HSV vectors. Robust anti-Gag and anti-Env cellular responses were detected in all six macaques. Following intravenous challenge with wild-type, cloned SIV239, peak and 12-week plasma viremia levels were significantly lower in vaccinated compared to control macaques. Plasma SIV RNA in vaccinated macaques was inversely correlated with anti-Rev ELISPOT responses on the day of challenge (P value<0.05), anti-Tat ELISPOT responses at 2 weeks post challenge (P value <0.05) and peak neutralizing antibody titers pre-challenge (P value 0.06). These findings support continued study of recombinant herpesviruses as a vaccine approach for AIDS.
    Virology 01/2007; 357(2):199-214. DOI:10.1016/j.virol.2006.08.007 · 3.28 Impact Factor
  • Source
    • "Published by Elsevier Inc. doi:10.1016/j.virol.2005.01.003 chronic HIV/SIV infection in different tissues (Barouch et al., 2002; Hel et al., 2001a; Kuroda et al., 1999b; Mothe et al., 2002; O'Connor et al., 2002; Schmitz et al., 2001; Stevceva et al., 2002a; Veazey et al., 2003). Some compartments such as GALT (Hel et al., 2001a), liver (Schmitz et al., 2000), spleen, bone marrow (Kuroda et al., 2000), vaginal mucosa (Stevceva et al., 2002a), and central nervous system (Moniuszko et al., 2003) appear to have a higher frequency of virus-specific CD8+ T cells than peripheral blood. The impact of regional CTLs on the containment of viral replication has been investigated previously in plasma and secondary lymphoid organs of four SIV-infected macaques, and no correlation was found between the percentage of virus-specific CTLs and the magnitude of viral replication (Kuroda et al., 1999b). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Plasma virus in human immunodeficiency virus type 1/simian immunodeficiency virus (HIV-1/SIV) infection most likely results from the combination of viruses produced in different tissues. As immunological pressure may be higher in effector sites than secondary lymphoid tissues, we investigated quantitative and qualitative changes in viral RNA in blood and tissues of 10 Mamu-A*01-positive SIV-infected macaques in parallel with the frequency of CD8+ T cells recognizing the dominant Gag181-189 CM9 epitope. The plasma virus level in these macaques directly correlated with the viral RNA levels in lymph nodes, spleen, lungs, colon, and jejunum. In contrast, the frequency of the Gag181-189 CM9 tetramer did not correlate with SIV RNA levels in any compartment. We investigated the presence of viral immune escape in RNA from several tissues. The complete substitution of wild-type genotype with viral immune-escape variant within the Gag181-189 CM9 epitope was associated with low tetramer response in all tissues and blood of two macaques. In one macaque, the replacement of wild type with an immune-escape mutant was asynchronous. While the mutant virus was prevalent in blood and effector tissues (lungs, jejunum, and colon), secondary lymphoid organs such as spleen and lymph nodes still retained 80% and 40%, respectively, of the wild-type virus. These results may imply that there are differences in the immunological pressure exerted by cytotoxic T lymphocytes (CTLs) in tissue compartments of SIVmac251-infected macaques.
    Virology 04/2005; 333(1):159-68. DOI:10.1016/j.virol.2005.01.003 · 3.28 Impact Factor
  • Source
    • "A number of efforts have been made to develop a vaccine that elicits a mucosal immune response against SIV. Induction of SIV-specific IgA and cytotoxic T lymphocytes (CTL) in vaginal and rectal mucosal surfaces have been demonstrated with particulate antigens (Klavinskis et al., 2000), microencapsulated killed virus (Israel et al., 1999; Lerner et al., 1996), and immunization with DNA vaccine or live attenuated viral vectors encoding viral antigens or noninfectious virions (Baig et al., 2002; Stevceva et al., 2002; Wang et al., 2000). In most mucosal vaccine trials, immunogens in the form of a DNA vaccine or live attenuated virus are administered directly into mucosal sites, i.e., vaginal, rectal, or intranasal (Belyakov et al., 1998; Klavinskis et al., 1999, 2000). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Clostridium perfringens is a normal bacterial flora of the small and large intestines of humans and other animals. The current study investigates the potential use of a noncytotoxic C. perfringens as an oral vaccine vehicle for expression and intestinal delivery of a large amount of SIV antigens. Here we report the construction of a recombinant C. perfringens vaccine vector expressing high levels of SIV p27 during sporulation. Following oral administration of this recombinant C. perfringens vaccine vector to mice, large amounts of intact p27 protein were detected in the terminal ileum where the majority of Peyer's Patches (PPs) are located. Furthermore, dendritic cells (DCs) beneath the mucosal surface in the PPs were able to capture SIV p27 antigen, when PPs were exposed to C. perfringens expressing SIV p27 antigen. In addition, uptake of C. perfringens was able to induce maturation of mouse DCs. These results support the potential use of C. perfringens as an oral SIV/HIV vaccine vector.
    Virology 12/2004; 329(2):226-33. DOI:10.1016/j.virol.2004.08.018 · 3.28 Impact Factor
Show more