The lack of an effective HIV vaccine calls for efforts to investigate the
mechanism of protective immunity against AIDS viruses. It has been previously
demonstrated that the live replication-competent modified vaccinia virus Tiantan
(MVTT) is superior to non-replication vaccinia MVA in inducing high levels of
neutralizing antibodies against SARS-CoV infection via mucosal vaccination.
Therefore, the hypothesis was that MVTT could be a better HIV vaccine vector
given its highly attenuated phenotypes such as no neurovirulence and safe in severe
combined immunodeficiency disease (SCID) mice. Here, a recombinant MVTT
expressing SIVmac239 Gag-Pol and Env (rMVTTSIVgpe) was constructed and its
immunogenicity was assesed when administered via different routes using
homologous prime-boost strategies or in heterologous regimens boosted with a
recombinant adenovirus-based vaccine inserted matched SIVmac239 genes
(rAd5SIVgpe). Results show that the heterologous prime-boost immunization with
rMVTTSIVgpe and rAd5SIVgpe induces significantly greater humoral and T cell
responses specific to SIV Gag, Pol and Env than homologous inoculations in mice
with remarkable improvements in quality and quantity.
The further study comparing different combinations of rMVTTSIVgpe and
rAd5SIVgpe demonstrates that the rMVTTSIVgpe prime-rAd5SIVgpe boost regimens
elicit systemic CD8+ T cell responses with augmented magnitude and
polyfunctionality, as compared with rAd5SIVgpe-rMVTTSIVgpe and
rAd5SIVgpe-rAd5SIVgpe regimens. Priming with rMVTTSIVgpe also increases
frequencies of gut-homing Gag-specific CD8+ T cells (CCR9+47+ and
CCR6+47+) and levels of CD8+ T cell ELISPOT responses against Gag, Pol and
Env in mesenteric lymph nodes (MLNs) post-boost. The mucosal route of
immunization is essential for rMVTTSIVgpe to induce rectal IgG with detectable
neutralizing activity against SIVmac1A11. Furthermore, the regimen involving
mucosal prime with rMVTTSIVgpe followed by systemic boost with rAd5SIVgpe
proves to be efficient in protecting monkeys from mucosal challenge of a high dose
of SIVmac239, a CCR5-tropic strain with high pathogenicity and
neutralization-resistance. SIV-specific T cell ELISPOT responses specific to Gag
and Pol but not Env and the frequency of Gag-specific IFN-+TNF-+CD8+
effector memory T cells (TEM) are likely associated with virological control after
challenge. Mucosal immunity induced by this vaccination strategy also has
important implications to the effectiveness of protection against disease
progression.
A hypothesis was generated that removal of non-protective but immune
dominant determinant of SIVmac239 Env may drive antibody responses to
protective domains. It was found that the neutralization-resistance of SIVmac239
could be partially explained by its high immunogenicity in eliciting CD4-induced
neutralizing antibodies, which are unable to protect the CCR5-binding site due to
the conformational masking and steric restriction. It was discovered that the
immunodominance of CD4-induced neutralizing antibodies on SIV envelope is
determined by a single highly conserved N-linked glycosylation site (N277) in the
C2 domain. Substitution of this N-linked site abolishes viral entry and the
immunogenicity of the CD4i domain while promotes V2-specific antibody
responses, which have recently been identified as an important immunological
correlate to HIV-1/SIV protection. Our findings demonstrate the concept that B cell
immunodominance is relative and eliminating the dominant antigenic region can
result in redirection of B cell recognition, which have critical implications for
immunogen design and the development of protective antibody-based HIV vaccine. / published_or_final_version / Microbiology / Doctoral / Doctor of Philosophy
| Identifer | oai:union.ndltd.org:HKU/oai:hub.hku.hk:10722/193064 |
| Date | January 2012 |
| Creators | 唐娴, Tang, Xian |
| Publisher | The University of Hong Kong (Pokfulam, Hong Kong) |
| Source Sets | Hong Kong University Theses |
| Language | English |
| Detected Language | English |
| Type | PG_Thesis |
| Rights | The author retains all proprietary rights, (such as patent rights) and the right to use in future works., Creative Commons: Attribution 3.0 Hong Kong License |
| Relation | HKU Theses Online (HKUTO) |
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