Route of Adenovirus-Based HIV-1 Vaccine Delivery Impacts the Phenotype and Trafficking of Vaccine-Elicited CD8 ⁺ T Lymphocytes

Abstract

Candidate HIV-1 vaccine regimens utilizing intramuscularly (i.m.) administered recombinant adenovirus (rAd)-based vectors can induce potent mucosal cellular immunity. However, the degree to which mucosal rAd vaccine routing might alter the quality and anatomic distribution of vaccine-elicited CD8 ؉ T lymphocytes remains unclear. We show that the route of vaccination critically impacts not only the magnitude but also the phenotype and trafficking of antigen-specific CD8 ؉ T lymphocytes in mice. I.m. rAd immunization induced robust local transgene expression and elicited high-frequency, polyfunctional CD8 ؉ T lymphocytes that trafficked broadly to both systemic and mucosal compartments. In contrast, intranasal (i.n.) rAd immunization led to similarly robust local transgene expression but generated low-frequency, monofunctional CD8 ؉ T lymphocytes with restricted anatomic trafficking patterns. Respiratory rAd immunization elicited systemic and mucosal CD8؉ T lymphocytes with phenotypes and trafficking properties distinct from those elicited by i.m. or i.n. rAd immunization. Our findings indicate that the anatomic microenvironment of antigen expression critically impacts the phenotype and trafficking of antigen-specific CD8 ؉ T lymphocytes.Acute human immunodeficiency virus type 1 (HIV-1) infection is accompanied by a massive, irreversible destruction of memory CD4ϩ T lymphocytes, particularly within the intestinal mucosa (11,26,30,42), as a result of the high proportion of effector/memory target cells within the intestinal lamina propria. Chronic HIV-1 infection is characterized by inflammation within the intestinal mucosa, breakdown of epithelialbarrier integrity, and translocation of gut microflora from the intestinal lumen (10, 24). These processes may drive systemic inflammation and contribute to HIV-1 disease progression. Therefore, vaccination strategies that enhance mucosal cellular immunity and attenuate the mucosal immunopathology of HIV-1 infection would be desirable.Recombinant adenovirus (rAd) vectors are potent inducers of cellular immunity (3, 12, 25), and we have recently demonstrated that intramuscular (i.m.) rAd immunization transiently activates peripheral antigen-specific CD8 ϩ T lymphocytes and allows them to migrate to mucosal surfaces and establish potent, durable mucosal cellular immunity (22). Moreover, we have shown that an i.m. delivered heterologous rAd primeboost regimen prevented the destruction of CD4 ϩ T lymphocytes within the intestinal mucosa and attenuated disease progression following simian immunodeficiency virus (SIV) challenge (29). Notably, this vaccine regimen did not contain the SIV Env protein, indicating that cellular mucosal immunity likely played a critical role in abrogating mucosal CD4 ϩ Tlymphocyte destruction.While our laboratory and others have observed potent mucosal CD8 ϩ T-lymphocyte responses after i.m. immunization with rAd vectors (2, 21, 28, 41) and other vaccine modalities (40-41), other studies have suggested that mucosal routing of vaccine vectors may opti...

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Prime-boost vaccination with Bacillus Calmette Guerin and a recombinant adenovirus co-expressing CFP10, ESAT6, Ag85A and Ag85B of Mycobacterium tuberculosis induces robust antigen-specific immune responses in mice

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Lack of IL‐7 and IL‐15 signaling affects interferon‐γ production by, more than survival of, small intestinal intraepithelial memory CD8+ T cells

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