Oral Abstract Session 01 - Global HIV Vaccine Enterprise

Topic 8: Mucosal Immunity
P08.07
Induction of HIV Mucosal Immunity at Distal Sites
After Encapsulation of NOD1 and NOD2 Ligands in
Biodegradable Nanocarriers
V. Pavot 1 , N. Rochereau 2 , V. Lahaye 1 , C. Genin 2 , E. Perouzel 3 ,
T. Lioux 3 , C. Primard 1 , T. Delair 4 , S. Paul 2 , B. Verrier 1
1 IBCP-CNRS, Lyon, France; 2 GIMAP, Saint Etienne, France;
3 Cayla Invivogen, Toulouse, France; 4 University of Lyon - IMP,
Lyon, France
Background: The use of TLR ligands as mucosal adjuvant for
vaccine administration is already largely described; wherease
the use of NOD-like receptors ligands is still investigated. As
activation of intracytoplasmic NOD like-receptors is able to induce
production of pro-inflammatory molecules, we have evaluated if
their co-delivery into biodegradable nanocarriers carrying HIV-
Gag antigens could amplify the mucosal immune responses in
mice at the vaginal and intestinal (HIV replication site)
Methods: We used Poly(Lactic Acid) (PLA) nanoparticles (NPs)
(~200 nm) for co-delivery of p24 and NOD ligands. As NOD likereceptors
are mainly expressed by antigen presenting cells, we
first assessed the capacity of free or encapsulated ligands to
induce monocyte derived dendritic cells (MoDCs) maturation.
Then, as NOD like-receptors are principally expressed at the
intestinal level we compared by oral immunization of BALB/c
mice encapsulated ligands co-delivered with PLA-p24 NPs. To
assess the adjuvant effect, p24-specific cellular and humoral
responses were analyzed on splenocytes and in vaginal washes,
faeces and sera.
Results: The state of MoDCs maturation was characterized
by the expression of CD80, CD83 and CD86. We showed that
encapsulation of NOD1 or NOD2 ligand increases significantly
their expression, compared to the effect of free ligands, probably
due to a better uptake of encapsulated ligands
By analyzing humoral immune responses, we observed that coadministration
of p24 and NOD2 ligand by two different NPs was
the most efficient formulation to induce anti-p24 IgG and IgA
responses in faeces. By contrast co-formulation of p24 and NOD1
ligand in the same NP induced a better CD8 IFNγ response.
Conclusion: Encapsulation of NOD ligands into PLA nanoparticles
seems to favour their action on DCs maturation, their coadministration
with PLA-p24 NPs inducing an adjuvant effect.
Use of those ligands as mucosal adjuvant deserve further
experiments and we are investigating the mechanisms involved
and increasing delivery efficacy after co-encapsulations.
P08.08
AIDS Vaccine 2012
Posters
Anti-gp41 Antibodies Inhibit Infection and
Transcytosis of HIV-1 Infectious Molecular Clones
Expressing Transmitted/Founder Envelopes
S. Jain 2 , C. Ochsenbauer 1 , J.C. Kappes 1 , K.L. Rosenthal 2
1 University of Alabama at Birmingham, Birmingham, AL, USA;
2 McMaster University, Hamilton, Canada
Background: Prophylactic vaccine strategies against HIV-1 must
effectively prevent virus transmission, infection and cell-to-cell
spread during the earliest stages of acute infection. Since the
genital mucosa is the primary site of entry, mucosal defense
is critical for early control of infection. Recent identification of
transmitted/founder (T/F) HIV-1 genomes has demonstrated a
consistent genetic bottleneck during mucosal transmission and
suggests that T/F viruses may exhibit distinct phenotypes. HIV-1
Env gp41-specific responses are among the first to be generated
in natural HIV infection.
Methods: Previously, we developed chimeric virus-like particle
(VLP) immunogens that elicit potent systemic and mucosal
antibodies against two highly conserved regions of gp41, by
employing an optimized immunization strategy. The ELDKWA
and QARVLAVERY epitopes are found with the membrane
proximal external region (MPER) and the coiled coil region of
gp41, respectively. Importantly, the epitope-specific IgG and
IgA fractions derived from immunized mice were shown to be
effective in neutralizing and preventing transcytosis of HIV in
vitro. In particular, the QARVLAVERY epitope is remarkably
conserved and induced unusually high and early levels of anti-
QARV IgA, making it an attractive candidate for generation of
broadly reactive mucosal antibodies.
Results: In this study, we assessed the effectiveness of mucosal
and systemic mouse antibodies elicited against these gp41
epitopes to inhibit T/F Env function. For this, we employed
recombinant infectious molecular clones (Env-IMC) of HIV-1 that
encode mucosally transmitted/founder env genes. Our results
show that the gp41-specific IgG and IgA fractions effectively
prevented the infection of TZM-bl cells and inhibited HIV
transcytosis in an assay measuring the passage of infectious
virus across an epithelial monolayer. Interestingly, the T/F Env-
IMC tested were more sensitive to the antibodies than the R5
lab-adapted strains included as controls.
Conclusion: These results highlight the potential of gp41-based
immunogens to impart effective mucosal protection in the
earliest stages of HIV transmission and infection.
193
POSTERS