Oral Abstract Session 01 - Global HIV Vaccine Enterprise

POSTERS
Posters
Topic 8: Mucosal Immunity
P08.09
Systemic Administration of a Broadly-Neutralizing
IgG Antibody to Generate HIV-Neutralization
Responses in Breast Milk
G.G. Fouda 1 , J. Amos 1 , K. Beck 1 , S. Smith 1 , X. Wang 2 , K. Reimann 2 ,
S. Permar 1
1 Duke Human Vaccine Institute, Durham, NC, USA; 2 Beth Israel
Deaconess Medical Center, Boston, MA, USA
Background: Postnatal acquisition of HIV during breastfeeding is
responsible for almost half of 350,000 pediatric HIV infections
occurring yearly. Thus, there is an urgent need to develop
immunologic interventions to impede breast milk transmission
of HIV, including immunization and passive infusion strategies.
We previously observed that functional antibody responses in
milk of HIV- infected mothers mirror that in plasma, suggesting
that inducing strong systemic IgG responses may lead to virus
inhibition in milk. Therefore, we investigated the kinetics of
binding and neutralizing antibodies in plasma and milk of
passively- infused lactating rhesus monkeys.
Methods: The broadly neutralizing antibody b12 engineered in
a rhesus IgG1 backbone was administered intravenously to four
hormone-induced, lactating female rhesus monkeys at a dose
of 5mg/kg. Milk and blood was collected frequently until 72 h
post infusion, then weekly for 4 weeks. Levels of the infused
antibody and the neutralizing activity in the milk and systemic
compartments were measured at each time-point.
Results: The b12 IgG levels peaked 1 hour post-infusion in
plasma and 24 to 72h post-infusion in milk. The median peak b12
antibody levels were 87,503 ng/ml (range 62,548 to 101,525 ng/
ml) in plasma and 47 ng/ml (range 16 to 202 ng/ml) in milk. The
peak in plasma neutralization was 1 to 6 hours post-infusion and
the neutralization titer slowly declined after 24 hours. The peak
neutralization titer in milk (median ID50: 70, range: 50-103) was
approximately two logs lower than in plasma (median ID50: 2313,
range: 1875-3128) and occurred within 24 hours post-infusion
in 3 of 4 animals. There was a significant correlation between
neutralization titers in milk and plasma (r=0.48, p=0.01).
Conclusion: The neutralizing activity detected in milk following
systemic administration of a broadly- neutralizing IgG antibody
supports the induction of strong systemic anti-HIV IgG responses
to generate HIV inhibitory antibodies in breast milk.
194
AIDS Vaccine 2012
P08.10
The Humanized BLT Mouse to Study HIV
Transmission
M. Deruaz 1 , T.T. Murooka 1 , T. Dudek 2 , V.D. Vrbanac 1 , T. Tivet 1 ,
K.C. Bankert 1 , T.M. Allen 2 , A.M. Tager 1 , A.D. Luster 1
1 Massachusetts General Hospital, Harvard Medical School,
Charlestown, MA, USA; 2 Ragon Institute of MGH, MIT and
Harvard, Charlestown, MA, USA
Background: Worldwide, the majority of HIV-1 infections are
acquired by vaginal transmission. Studies in SIV-1 infected nonhuman
primates have shown that SIV-1 infection takes hold
initially in a small population of CCR5+ cells in the in female
lower genital tract (FLGT) where the infection expands first
locally before disseminating to the draining lymph node (LN) to
establish a systemic infection. Our goal is to use humanized BLT
mice to address whether the infection paradigm established for
SIV-1 in non-human primates holds true during HIV-1 infection
in vivo.
Methods: We studied the kinetics of infection during the first
two weeks after intravaginal HIV-1 exposure by measuring the
presence of virus in the FLGT, LNs and blood after 2, 6, 10 and 12
days post infection (p.i.) by qPCR and flow cytometry.
Results: Our results show that similar to the non-human primate
model, the presence of virus is first detected by qRT-PCR in the
FLGT as soon as day 2 p.i., followed by the LN at day 6 p.i. and the
blood at day 12 p.i.. Similar but delayed kinetics were observed
using p24 staining by flow cytometry, with positive staining of T
cells located in the FLGT at day 6 p.i., in the draining LN between
day 6 and day 10, and in the non draining LN at day 12 p.i..
Conclusion: Our data suggests that HIV-1 transmission and initial
replication in BLT mice following intravaginal exposure occurs
first locally in the LGT and then disseminates to the draining LN.
The virus then spreads to the non-draining LNs and subsequently
into the blood, suggesting that BLT mice have an “eclipse phase”
following HIV infection similar to what have been described for
SIV infection of macaques and HIV infection of humans.