Systemic and Mucosal T-Lymphocyte Activation Induced by Recombinant Adenovirus Vaccines in Rhesus Monkeys

The administration of vectors designed to elicited cell-mediated immune responses may have other consequences that are clinically significant. To explore this possibility, we evaluated T-cell activation during the first 2 months after recombinant adenovirus serotype 5 (rAd5) prime or boost immunizations in rhesus monkeys. We also evaluated the kinetics of T-lymphocyte activation in both the systemic and the mucosal compartments after rAd5 administration in monkeys with preexisting immunity to Ad5. The rAd5 immunization induced lower-frequency Gag epitope-specific CD8⁺ T cells in the colonic mucosa than in the peripheral blood. There was evidence of an expansion of the simian immunodeficiency virus Gag-specific CD8⁺ T-cell responses, but not the Ad5 hexon-specific T-cell responses, following a homologous rAd5 boost. A striking but transient T-lymphocyte activation in both the systemic and the mucosal compartments of rhesus monkeys was observed after rAd5 immunization. These findings indicate that the administration of a vaccine vector such as Ad5 can induce a global activation of T cells.Considerable effort has been invested in the development of vaccine strategies for eliciting cell-mediated immune responses to human immunodeficiency virus (HIV). Studies in simian immunodeficiency virus (SIV)/SHIV-infected nonhuman primates and HIV-infected humans demonstrated a central role for cell-mediated immune responses in the containment of HIV replication (1, 12). These findings led to the hypothesis that vaccine-elicited cell-mediated immunity might contribute to improved control of HIV in infected individuals. Studies in the SIV and SHIV/macaque models have supported this hypothesis, demonstrating a decrease in peak plasma virus RNA levels during primary infection, protection against memory CD4⁺ T-cell lymphocyte loss, and prolonged survival of monkeys that had vaccine-elicited cell-mediated immunity to the virus prior to challenge (8, 15, 16).Despite promising results in preclinical nonhuman primate studies, a prophylactic HIV vaccine trial of the Merck recombinant adenovirus serotype 5 (rAd5) vector expressing HIV gag, pol, and nef genes (STEP trial) was recently halted due to a 2.3-fold increase of HIV acquisition in vaccinees with preexisting neutralizing antibodies (NAbs) to Ad5 (2, 9, 10). This finding raised the possibility that T lymphocytes that are activated in response to vaccination might represent an increased pool of potential targets for HIV infection, and the persistence of such activated cells may increase the susceptibility of the vaccinated individual to acquiring an HIV infection (5, 11). HIV replicates most readily in activated, CCR5⁺CD4⁺ T lymphocytes. It has been suggested that vaccines that elicit potent cellular immune responses may also activate subpopulations of CD4⁺ T lymphocytes. In fact, in the aftermath of the failed STEP trial, it was proposed that the activation of Ad5-specific T cells in individuals with prior Ad5 immunity may have contributed to their increased acquisition of HIV after vaccination.The contribution of cellular activation in mucosal tissues to acquisition of HIV remains unexplored (2). HIV transmission occurs most often across mucosal barriers. There is increasing evidence that CD4⁺ T lymphocytes are among the first cells infected during the transmission event (4). Activation of mucosal populations of lymphocytes as a consequence of vaccination could contribute to increasing the incidence of HIV transmission at a mucosal site.To examine these issues, the present study was initiated to explore vaccine-induced activation of T-lymphocyte populations in rhesus monkeys. The character and kinetics of the activation of both circulating and mucosal T-lymphocyte populations were evaluated after immunization with a variety of immunogens. These experiments demonstrate a striking but transient T-lymphocyte activation induced by adenovirus-based vaccine vectors in both the systemic and mucosal compartments of rhesus monkeys.