Elicitation of simian immunodeficiency virus-specific cytotoxic T lymphocytes in mucosal compartments of rhesus monkeys by systemic vaccination

Abstract

Since most human immunodeficiency virus (HIV) infections are initiated following mucosal exposure to the virus, the anatomic containment or abortion of an HIV infection is likely to require vaccine-elicited cellular immune responses in those mucosal sites. Studying vaccine-elicited mucosal immune responses has been problematic because of the difficulties associated with sampling T lymphocytes from those anatomic compartments. In the present study, we demonstrate that mucosal cytotoxic T lymphocytes (CTL) specific for simian immunodeficiency virus (SIV) and simian HIV can be reproducibly sampled from intestinal mucosal tissue of rhesus monkeys obtained under endoscopic guidance. These lymphocytes recognize peptide-major histocompatibility complex class I complexes and express gamma interferon on exposure to peptide antigen. Interestingly, systemic immunization of monkeys with plasmid DNA immunogens followed by live recombinant attenuated poxviruses or adenoviruses with genes deleted elicits high-frequency SIV-specific CTL responses in these mucosal tissues. These studies therefore suggest that systemic delivery of potent HIV immunogens may suffice to elicit substantial mucosal CTL responses.

FIG. 1.

Immunohistochemically stained serial sections from distal colon (A) and jejunum (B) of a SIVmac-infected rhesus monkey demonstrating distribution of CD8⁺ lymphocytes. Bar, 200 μm.

FIG. 2.

IFN-γ expression by p11C tetramer⁺ CD3⁺ CD8⁺ T lymphocytes from peripheral blood and distal-colonic mucosal lymphocytes of a SHIV 89.6P-infected rhesus monkey. Tetramer-binding peripheral blood (A to C) and distal-colonic mucosal (D to F) CD8⁺ T lymphocytes stain with monoclonal anti-IFN-γ antibody after exposure in vitro to PMA plus ionomycin (B and E) or the Gag epitope peptide p11C (C and F). Percentages of p11C tetramer⁺ CD3⁺ CD8⁺ T lymphocytes positive for IFN-γ are shown in each panel.