Oral Abstract Session 01 - Global HIV Vaccine Enterprise

POSTERS
Posters
Topic 2: Animal Models and Preclinical Trials
P02.07
Modelling the Neuropathological Consequences of
HIV Vaccines That Confer Partial Protection
D. Ferguson 1 , S. Clarke 1 , C. Ham 1 , A. Das 2 , B. Berkhout 2 ,
A. Meiser 3 , S. Patterson 3 , N. Berry 1 , N. Almond 1
1 National Institute of Biological Standards and Control - HPA,
Potters Bar, United Kingdom (Great Britain); 2 Academic
Medical Centre, University of Amsterdam, Amsterdam,
Netherlands; 3 Imperial College, London, United Kingdom
(Great Britain)
Background: Effective management of peripheral viral loads
with anti-retroviral drugs can delay or halt CD4 cell loss for
decades. However, patients still face the potential of developing
significant HIV-1 associated neurocognitive disorders (HAND).
Challenges obtaining relevant clinical samples limit the detailed
investigation of the aetiology and neuropathology of HAND and
therefore we do not understand the impact of vaccines that
confer partial protection on long term neuropathology.
Methods: We are using immunohistochemical analysis of brain
sections from the experimental infection of macaques with SIV
to model neuropathology in situations where peripheral viral
loads are under effective control.
Results: We have established that chronic infection with
attenuated SIV, where peripheral viral loads are below detection,
still results in pathological changes (astrogliosis, microglial
activation, viral persistence). We have now extended these
studies using a unique conditional live attenuated, doxycycline
dependent virus, SIVrtTA. Removal of doxycycline 3 weeks after
infection, at the end of the primary viremia results in detectable
neuropathological changes in astrocytes, oligodendrocytes,
microglia and perivascular macrophage 40 weeks later.
We are also investigating the effects of vaccines that confer
partial protection on the neuropathology of wild-type SIV
infection. A vaccine study using SIV Gag based vaccines
comprising three primes with rDNAgag followed by a rAdgag
boost resulted in significant delay in acquisition of SIVmac251
administered by low-dose intra-rectal challenge. Furthermore,
there was a significant blunting of the primary viremia, but
no significant suppression of set-point viral loads compared
with naive challenge controls. We are determining the impact
of vaccination on the frequency of virus infected cells in the
brain collected 20-30 weeks after infection and also comparing
the frequency and intensity of neuropathological changes in
infected vaccinated and control macaques.
Conclusion: These data will enable us to establish the likely
neurological benefit of vaccines that do not provide protection
against detectable infection.
110
AIDS Vaccine 2012
P02.08
Optimizing Delivery of HIV-1 Conserved Region-
Derived Immunogen for Induction of T and B Cell
Responses in Rhesus Macaques
M. Rosario 1 , G. Koopman 1 , A. Mbewe-Mvula 1 , M.L. Knudsen 1 ,
E.D. Quakkelaar 1 , N. Borthwick 1 , R. Wagner 1 , D.A. Price 1 ,
P. Liljestrom 1 , C.J. Melief 1 , J.W. Drijfhout 1 , S. Colloca 1 ,
A. Nicosia 1 , T. Hanke 1
1 University of Oxford, Oxford, United Kingdom (Great Britain)
Background: The complexity of candidate HIV-1 vaccine
formulations is increasing due to extreme challenges faced when
trying to prevent or control HIV-1 infection.
Methods: Immunogen HIVconsv based on the most conserved
regions of the HIV-1 proteome was used to explore combinations
of seven distinct vaccines modalities in heterologous prime-boost
regimens delivered to rhesus macaques to optimize induction of
T cell and antibody responses. These include plasmid DNA (P),
Semliky Forest virus replicons delivered as DNA (DREP; D) or
virus particles (VREP; V), modified vaccinia virus Ankara (MVA;
M), adenoviruses of human (HAdV-5; A) and chimpanzee origin
(ChAdV-63; C) and adjuvanted synthetic long peptides (SLP; S).
Results: A number of observations were made. Thus, a very potent
combination for induction of HIV-1-specific T cells was an adenovirus
vector (A or C) followed by poxvirus M. S boost broadened T cell
responses, but did not prime T cells efficiently. D was a stronger prime
than P. PPP was the best prime for T cells, while PSS was best for
induction of antibodies. Even very complex regimen PPPAMSSCMV
continued to recruit new T cell clones into the response to a single
epitope, although a ceiling for immunodominant responses was
reached; subdominant responses could be boosted up to the last V
delivery. Finally, PPSS, but not SSSS could protect 2/6 animals from
SIVmac251 acquisition.
Conclusion: These results will guide initial design of human trials.
So far, human studies in Oxford testing CM, PPPCM and PPPMC
regimen concur with observations made in rhesus macaques.