Immune-response profiles induced by human immunodeficiency virus type 1 vaccine DNA, protein or mixed-modality immunization: increased protection from pathogenic simian–human immunodeficiency virus viraemia with protein/DNA combination

Abstract

Current data suggest that prophylactic human immunodeficiency virus type 1 (HIV) vaccines will be most efficacious if they elicit a combination of adaptive humoral and T-cell responses. Here, we explored the use of different vaccine strategies in heterologous prime–boost regimes and evaluated the breadth and nature of immune responses in rhesus monkeys induced by epidermally delivered plasmid DNA or recombinant HIV proteins formulated in the AS02A adjuvant system. These immunogens were administered alone or as either prime or boost in mixed-modality regimes. DNA immunization alone induced cell-mediated immune (CMI) responses, with a strong bias towards Th1-type cytokines, and no detectable antibodies to the vaccine antigens. Whenever adjuvanted protein was used as a vaccine, either alone or in a regime combined with DNA, high-titre antibody responses to all vaccine antigens were detected in addition to strong Th1- and Th2-type CMI responses. As the vaccine antigens included HIV-1 Env, Nef and Tat, as well as simian immunodeficiency virus (SIV)mac239 Nef, the animals were subsequently exposed to a heterologous, pathogenic simian–human immunodeficiency virus (SHIV)89.6p challenge. Protection against sustained high virus load was observed to some degree in all vaccinated groups. Suppression of virus replication to levels below detection was observed most frequently in the group immunized with protein followed by DNA immunization, and similarly in the group immunized with DNA alone. Interestingly, control of virus replication was associated with increased SIV Nef- and Gag-specific gamma interferon responses observed immediately following challenge.

Acute-phase CD4+ T-cell proliferation and CD152 upregulation predict set-point virus replication in vaccinated simian–human immunodeficiency virus strain 89.6p-infected macaques

“…However, these cells had low (20-30 %) Ki-67 expression and thus seemed to be less activated (not shown). No correlation with set-point virus load was observed, which, together with the preservation of antiviral immune responses reported previously (Koopman et al, 2008), contradicts a role for regulatory T-cellmediated immune suppression in this model.…”

“…The typical pattern of early post-infection upregulation of activation, proliferation and CD152 marker expression lead us to plot these parameters against the previously reported early post-infection HIV/SIV-specific immune responses (Koopman et al, 2008). As demonstrated in Table 1, an inverse correlation between antigen-specific IFN-c production, measured at 2, 8 or 12 weeks p.i., and peak levels of Ki-67 and CD152 expression was observed, whilst comparison with peak-level HLA-DR expression did not reach statistical significance.…”

“…(Andersson et al, 2005;Epple et al, 2006;Estes et al, 2006;Nilsson et al, 2006). Although in the lymph node 5-25 % of CD4 + T cells were found to express CD152, there was no correlation with virus load (not shown), in stark contrast to what was seen at peak expression in the blood.The typical pattern of early post-infection upregulation of activation, proliferation and CD152 marker expression lead us to plot these parameters against the previously reported early post-infection HIV/SIV-specific immune responses (Koopman et al, 2008). As demonstrated in Table 1, an inverse correlation between antigen-specific IFN-c production, measured at 2, 8 or 12 weeks p.i., and peak levels of Ki-67 and CD152 expression was observed, whilst comparison with peak-level HLA-DR expression did not reach statistical significance.…”

“…A unique opportunity is thus provided to study immune activation and its relationship to the establishment of a set-point virus load in the absence of memory T-cell loss. In this study, a cohort of SHIV 89.6p -infected animals, derived from a previous vaccine-evaluation study (Koopman et al, 2008), that showed various levels of control of virus replication was evaluated for activationand proliferation-marker expression through the successive stages of acute and chronic infection. In addition, CD4 + memory/naive subset composition and expression of CD152, which can provide an inhibitory signal that counteracts cell activation, were studied.…”

“…All animals were housed at the Biomedical Primate Research Center, Rijswijk, The Netherlands, according to international guidelines for nonhuman primate care and use. The animals had participated in a previous vaccine study (Koopman et al, 2008). In brief, five groups of six rhesus macaques had been immunized at weeks 0, 8, 16 and 24 with either the pRix57 DNA vector encoding HIV-1 W6.1D Env (gp120), SIV Nef and HIV-1 Tat, or a combination of HIV-1 W6.1D Env, HIV-1 Nef and Tat and SIV Nef proteins formulated in the AS02A Adjuvant System.…”