Evaluation of mucosal T cell immunity following HIV-1 prime-boost immunization

Abstract

Vaccination is one of the most important contributions to human health and has produced a dramatic reduction in infectious disease deaths over the last 100 years. However, there is still no successful vaccine for HIV-1 that provides full protection against infection. Because HIV-1 primarily infects the mucosae, there is strong opinion that more effective mucosal HIV-1 vaccines eliciting robust immunity at mucosal sites will be a key requirement for a successful vaccine. This thesis evaluates mucosal HIV-specific CD8{u207A} T cell responses following prime-boost immunization with a novel HIV-1 vaccine that encodes an IL-13 inhibitor (IL-13R{u03B1}2). Vaccination with this IL-13R{u03B1}2 vaccine has been shown previously to elicit high systemic HIV-specific CD8{u207A} T cell response with great T cell avidity. However, the responses induced at mucosae were not known. HIV-specific CD8{u207A} T cell immunity is known for its critical role in controlling HIV-1 replication and preventing CD4{u207A} T cell depletion. To examine the potential ability of IL-13R{u03B1}2 vaccine in generating robust mucosal immunity, IFN-{u03B3} expression and K{u1E0F}Gag{u2081}{u2089}{u2087}{u208B}{u2082}{u2080}{u2085} -specific binding CD8{u207A} T cells were evaluated. By inhibiting host IL-13 through the co-expressed of vaccine encoded IL-13R{u03B1}2, significantly enhanced mucosal (Peyer's patch, genito-rectal nodes and lung tissue) HIV-specific CD8{u207A} T cell responses were observed. The enhanced CD8{u207A} T cell response were sustained from acute phase to memory phase, as examined at 3 days, 2 weeks and 8 weeks post vaccine boost. This leads to the conclusion that i.n. / i.m. IL-13R{u03B1}2 prime-boost vaccination can generate strong sustained HIV-specific CD8{u207A} T cell response in mucosae. The expression of different homing molecules on CD8{u207A} T cells determines the selective trafficking and localization. {u03B1}{u2084}{u03B2}{u2087} and CCR9 are gut-specific homing markers with well characterized effects on trafficking T cells that home to the gut. To examine the potential ability of the IL-13R{u03B1}2 vaccine to elicitHIV-specific CD8{u207A} T cells that reside in the gut. The expression of {u03B1}{u2084}{u03B2}{u2087} and CCR9 on K{u1E0F}Gag{u2081}{u2089}{u2087}{u208B}{u2082}{u2080}{u2085} -specifictetramer binding CD8{u207A} T cells was measured. The results demonstrate that IL-13R{u03B1}2 vaccine elicits significantly enhanced {u03B1}{u2084}{u03B2}{u2087}{u207A}CCR9{u207A} HIV-specific CD8{u207A} T cells in Peyer's patch, which suggests that an HIV-1 vaccine delivered with i.n./ i.m. prime-boost strategy, that temporarily inhibits IL-13, may be an attractive approach to enhance protective immunity against HIV-1 in the gut. Show more