Oral Abstract Session 01 - Global HIV Vaccine Enterprise

Topic 8: Mucosal Immunity
P08.15
Human Intestinal Beta Defensins Inhibit Viral
Replication and Are Diminished in Chronic Untreated
HIV Infection
B. Corleis 1 , W.G. Gostic 1 , J.A. Johnson 1 , D.S. Kwon 1
1 Massachusetts General Hospital, Boston, MA, USA
Background: One of the hallmarks of HIV infection is an early
and dramatic depletion of CD4 T cells in the intestinal lamina
propria. This loss of T cells is accompanied by intestinal epithelial
cell disruption resulting in the translocation of luminal bacterial
products, persistent systemic immune activation and resultant
disease progression. Beta defensins are cationic antimicrobial
polypeptides produced by intestinal epithelial cells and
phagocytes that are a part of the innate immune response. They
have a pivotal role in maintenance of immune homeostasis in
the gut. Although beta defensins have been reported to inhibit
bacterial and viral replication in vitro, their role in HIV infection
has been incompletely characterized.
Methods: We investigated anti-viral activity and production of
defensins in intestinal mucosal biopsies, stool and plasma from
individuals with chronic untreated HIV (chronic progressors),
immunologically controlled HIV (elite controllers) and HIV
uninfected individuals using ELISA, immunohistochemistry,
quantitative PCR and viral inhibition assays.
Results: Plasma levels of beta defensins were increased in the HIV
controller group compared to HIV progressors, whereas levels
of beta defensins were significantly decreased in biopsies from
chronic progressors. Beta defensin release was induced by HIV
in ex vivo cultured intestinal cells. Recombinant beta defensins
inhibited HIV replication in vitro.
Conclusion: Beta defensins are upregulated by HIV and inhibit viral
replication in vitro. Chronic progressors, however, had diminished
levels of beta defensins in gut biopsies and in the plasma. We
propose that beta defensins are induced in HIV infection and
have a role in inhibiting viral replication and preventing intestinal
epithelial cell disruption. In chronic infection, however, their
release is diminished, likely due to epithelial damage in the
setting of persistent viremia and mucosal inflammation.
P08.16
AIDS Vaccine 2012
Posters
Improved Systemic and Mucosal Antibody Responses
with a CCR10 Ligand Adjuvant
N. Hutnick 1 , D.J. Myles 1 , A. Ginsberg 1 , A.S. Khan 2 , J. Yan 2 ,
Z. Moldoveanu 3 , J. Mestecky 3 , P.A. Marx 4 , M. Kutzler 5 ,
D.B. Weiner 1
1 University of Pennsylvania, Philadelphia, PA, USA; 2 Inovio
Pharmaceuticals, Blue Bell, PA, USA; 3 University of Alabama,
Birminham, AL, USA; 4 Tulane University, Covington, LA, USA;
5 Drexel University, Philadelphia, PA, USA
Background: The induction of potent mucosal immune
responses will be critical for an effective HIV vaccine, However, a
major limitation of current vaccine development is the ability to
induce mucosal antibodies by a systemic, non-replicating vector.
To address this inadequacy, we have hypothesized that encoding
instructions for immune cell targeting to the mucosa in the form
of MEC, a mucosal chemokine adjuvant delivered as a plasmid
can redirect immune responses in vivo. MEC (CCL28) is normally
expressed by epithelium in the skin, lungs, and intestines and it
functions to attract CCR10 expressing plasmablasts locally.
Methods: IIndian rhesus macaques were vaccinated using EP
delivery with either a pcon SIVmac239 gag, pol, SIVsm unmatched
E660 env vaccine delivered IM alone (n=5), with CCL28 (MEC,
n=5) or a plasmid expressed H1 HA Influenza vaccine alone (n=4)
or with MEC (n=4). SIV Vaccinated animals and 6 naïve controls
were challenged vaginally twice weekly for four weeks with
500TCID50 SIVsmE660.
Results: The inclusion of a CCR10 ligand adjuvant enhanced
vaginal and serum IgG and IgA titers compared with DNA alone.
In Flu vaccinated animals functional HAI antibody titers were
significantly elevated and above the 1:40 titer required for
protection in humans with just a single dose of H1HA delivered
with the MEC adjuvant. Following SIV challenge monkeys
vaccinated with a CCR10 adjuvant showed 89% protection from
the establishment of infection compared 40% with DNA alone
with only 16% of the naïve animals.
Conclusion: Mucosal and systemic antibody responses were
enhanced with the inclusion of a CCR10 ligand adjuvant. Dose
sparing was also observed. DNA vaccination alone improved
challenge outcome, and this was further enhanced by the
inclusion of a CCR10 ligand adjuvant. The inclusion of mucosal
homing chemokines represents a novel approach to induce
improved mucosal immune responses by non-live systemic
immunization of relevance to HIV infection.
197
POSTERS