Neurokinin Receptors

DCs were first treated for 24 h with Ad5 vector alone or with Ad5 IC

DCs were first treated for 24 h with Ad5 vector alone or with Ad5 IC. by Ad5 IC was mediated by the Fc receptor IIa and Toll-like receptor 9 interactions. DCs treated with Ad5 IC also induced significantly higher activation of Ad5-specific CD8 T cells equipped with cytolytic machinery. In contrast to Ad5 vectors alone, Ad5 IC caused significantly enhanced HIV contamination in DCCT cell cocultures. The present results indicate that Ad5 IC activates a DCCT cell axis that, together with the possible persistence of the Ad5 vaccine in seropositive individuals, may set up a permissive environment for HIV-1 contamination, which could account for the increased Relebactam acquisition of HIV-1 contamination among Ad5 seropositive vaccine recipients. The detection of high frequencies of HIV-1Cspecific CD4 and CD8 T cells in HIV-1Cinfected subjects with nonprogressive disease (1), the demonstration that CD8 T cells are key players in vivo in the control of SIV replication (2), and the association of polyfunctional CD4 and CD8 T cells with better control of computer virus replication (1, 3, 4) provided the rationale for developing T cell vaccine strategies that, although they are unlikely to prevent contamination, may eventually control HIV replication after contamination (5). The T cell vaccines that have joined clinical evaluation include adenovirus (Ad) and poxvirus vectors (6, 7). Ad vectors were used either alone or in combination with DNA-based vaccines. Each of these approaches has induced vigorous T cell responses (8, 9) and has partially controlled SIV replication in nonhuman primates (6). The high seroprevalence to some Ad serotypes in target populations remains a major issue for these vectors (7, 8). On the basis of the encouraging preclinical and phase I/II clinical programs, a trivalent Ad5-gag/pol/nef vaccine candidate joined a phase II test-of-concept-efficacy study called STEP in December 2004 and enrolled 3,000 high-risk HIV seronegative subjects. The primary objectives of the study were to determine the effects of the vaccine around the reduction of the acquisition of contamination and on the reduction of the set-point viremia. Late last year, STEP was prematurely terminated because of a lack of efficacy and because of the observation of a twofold increase in the incidence of HIV acquisition among vaccinated recipients with high Ad5 neutralizing antibodies (Abdominal muscles [NAbs]) titers compared with placebo recipients ( Several hypotheses have been proposed to explain the increased acquisition of HIV contamination including the following: unique microenvironment of the mucosal compartment where the mechanisms for increased Relebactam acquisition to HIV contamination likely operate; generation of enhancing Abs that facilitate HIV contamination; and vector-mediated activation of Ad5-specific CD4 T cells that become Relebactam ideal targets for HIV contamination. It is important to mention that Ads are not cleared after contamination, and numerous clinical reports have exhibited that Ads cause latent Relebactam infections that are normally well controlled by the host (10). Therefore, the administration of an Ad5 vector, its persistence, and continual exposure may have an impact on both Ad-specific Abs generation and T cell responses. In this study, we developed a series of ex vivo strategies to delineate the immunological events that may have operated among vaccine recipients with preexisting immunity to Ad5. In particular, we investigated the effects of Ad5 immune complex (IC) exposure on DCs, Ad5-specific CD4 and CD8 T cell responses, and enhancement of HIV contamination. RESULTS AND Conversation Effects of Ad5 IC on DCs Ad5-specific memory T cells and Ad5 NAbs are an important component of Ad5 preexisting immunity (11), and conversation between Ad5 BZS vector and NAbs certainly occurs rapidly after the administration of vectors in vivo. Ad5 IC are also well characterized in vitro (12, 13). Thus, we investigated the effects of Ad5 IC on DCs. For these purposes, we generated Ad5 IC by mixing Ad5 vectors with sera made up of Ad5 NAbs..