T-cell-mediated immune effector mechanisms play an important role in the containment of human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) replication after infection. Both vaccination-and infection-induced T-cell responses
Given the mucosal transmission of HIV-1, we compared whether a mucosal vaccine could induce mucosal cytotoxic T lymphocytes (CTLs) and protect rhesus macaques against mucosal infection with simian/human immunodeficiency virus (SHIV) more effectively than the same vaccine given subcutaneously. Here we show that mucosal CTLs specific for simian immunodeficiency virus can be induced by intrarectal immunization of macaques with a synthetic-peptide vaccine incorporating the LT(R192G) adjuvant. This response correlated with the level of T-helper response. After intrarectal challenge with pathogenic SHIV-Ku2, viral titers were eliminated more completely (to undetectable levels) both in blood and intestine, a major reservoir for virus replication, in intrarectally immunized animals than in subcutaneously immunized or control macaques. Moreover, CD4+ T cells were better preserved. Thus, induction of CTLs in the intestinal mucosa, a key site of virus replication, with a mucosal AIDS vaccine ameliorates infection by SHIV in non-human primates.
IntroductionThe induction and maintenance of immune responses to antigens is tightly regulated. Activation of T cells requires the interaction between the T-cell receptor and the antigen presented on the surface of an antigen-presenting cell (APC; first signal) and engagement of CD28 (second signal) by the costimulatory molecules B7-1 (CD80) and B7-2 (CD86). 1,2 Costimulation is particularly important for the initial T-cell response, promoting proliferation and survival. Following antigen stimulation, both CD28 and its negative regulatory, cytotoxic T lymphocyte antigen-4 (CTLA-4), are up-regulated on the cell surface and compete for their ligands, B7-1 and B7-2. CTLA-4 binds to both B7-1 and B7-2 with higher (10-to 20-fold) affinity than CD28, 3,4 and, in contrast to CD28, CTLA-4 suppresses T-cell activation. However, competition with CD28 for the costimulatory molecules is not likely to be the main mechanism responsible for CTLA-4 immunoregulatory activity. [5][6][7] Several lines of evidence suggest that expression of CTLA-4 by CD25 ϩ CD4 ϩ regulatory T (T reg ) cells plays a role in controlling peripheral T-cell tolerance and differentiation. 8,9 T reg cells are CD4 ϩ T lymphocytes that express high levels of the interleukin-2 (IL-2) receptor ␣-chain (CD25), and constitutively express CTLA-4. T reg cells inhibit the proliferation of T cells through contactdependent or cytokine-mediated (IL-10, transforming growth factor- [TGF-]) inhibition of T-cell responses. 10 T reg cells can induce activation of the enzyme IDO in APCs via CTLA-4-mediated ligation of CD80/CD86. 11,12 IDO confers immunosuppressive activity to APCs. 11,12 Two mechanisms have been suggested as mediators of the T-cellsuppressive action of IDO 13 : degradation and consequent reduction of tryptophan, an essential amino acid required for T-cell proliferation; and generation of inhibitory tryptophan metabolites. Blocking CTLA-4 signals with monoclonal antibodies may provide an important tool to influence the host immune response in clinical settings. For example, synergy between anti-CD25 and anti-CTLA-4 monoclonal antibodies has been shown to be effective in antitumor therapy. 14,15 T reg cells may suppress a potentially successful adaptive host immune response to a pathogen. [16][17][18][19][20][21] In the case of HIV infection, CTLA-4 expression is higher in patients with advanced clinical symptoms compared with asymptomatic individuals, 22,23 and the frequency of CTLA-4-expressing CD25 ϩ CD4 ϩ T reg cells is increased in lymphoid tissues in untreated individuals infected with HIV-1. 24 Primary infection of macaques with simian immunodeficiency virus (SIV) is associated with an increase in T reg cells, IDO, TGF-, and IL-10. 25 Similarly, chronic SIV infection is associated with an accumulation of T reg cells in lymphoid tissues, including the gut, and an increased level of immunosuppressive cytokines (A. B., M. V., A. H., D. F., J. N., Valentina Cecchinato, G. F., G. M. S., and C. C., our unpublished results, October 2006).Here, we examined...
Macaques infected with the SIV strain SIVmac251 develop a disease closely resembling human AIDS characterized by high viremia, progressive loss of CD4+ T cells, occurrence of opportunistic infection, cachexia, and lymphomas. We report in this study that vaccination with the genetically attenuated poxvirus vector expressing the structural Ags of SIVmac (NYVAC-SIV-gag, pol, env) in combination with priming with DNA-SIV-gag, env resulted in significant suppression of viremia within 2 mo after mucosal exposure to the highly pathogenic SIVmac251 in the majority of vaccinated macaques. The control of viremia in these macaques was long lasting and inversely correlated to the level of both pre- and postchallenge Gag-specific lymphoproliferative responses, as well as to the level of total SIV-specific CD4+ T lymphocyte responses at the peak of acute viremia as detected by intracellular cytokine-staining assay. Viremia containment also correlated with the frequency of the immunodominant Gag181–189CM9 epitope-specific CD8+ T cells present before the challenge or expanded during acute infection. These data indicate, for the first time, the importance of vaccine-induced CD4+ Th cell responses as an immune correlate of viremia containment. The results presented in this work also further demonstrate the potential of a DNA-prime/attenuated poxvirus-boost vaccine regimen in an animal model that well mirrors human AIDS.
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