Summary Statement: ADARC Program Project on HIV/SIV Vaccine Development

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1 P01 A143042-01 4 SEP
Ho, David D.
and CD8 suppressor factors. Breakthrough viruses from these earlier
experiments will be characterized phenotypically and genotypically. An
additional 14 macaques will be immunized with nef-deleted SIVmac and
challenged 5 weeks or 25 weeks later in an attempt to characterize more fully
the cell-mediated immune response. In addition, the kinetics of replication
and tissue localization of the immunizing virus will be determined. Eight of
the nine protected animals from their earlier study will be re-challenged with
either pathogenic or non-pathogenic SHIV89.6. Animals previously immunized
with nef-deleted SIVmac will be treated with PMPA to determine whether active
replication of the attenuated virus is necessary to maintain protection.
Furthermore,-the immunized macaques will be challenged mucosally to determine
whether prot ction is still holding. In an attempt to assess the role of CTLs
in protection, immunized monkeys will be challenged with a SIV expressing
ICP47, an inhibitor of TAP.
Subtype C has become the most prevalent globally HIV-1 genetic subtype with
epicenters in southern AfrieeTndla, and southwestern t is
anticipated that y su C viruses will dominate well in e
next c king the choice of these strains for vaccine work timely
nd highly elevan. - - -
China rica for the proposed studies, with the long-term goal of
conducting vaccine trials in these countries when suitable products are made.
Emphasis will be placed on viruses that are non-syncytium-inducing and
macrophage-tropic since these are the strains that*utilize the co-receptor
CCR5 and are preferentially transmitted. Lastly, based on subtype C env, a
new SHIV/macaque model will be developed to test multiple immunogens and
vaccine concepts. Three specific aims are proposed in this project, namely:
(i) genotypic, phenotypic, and antigenic characterization of subtype C
isolates of HIV-1 and selection of vaccine strains; (ii) subtype C envelope
expression and modification, and construction of subtype C envelops SHIVs; and
(iii) testing in macaques.
In Projiect 3, the applicants plan to pursue the development of new immunogens
suitable for the priming phase, based on both modified vaccinia Ankara (MVA)
and DNA constructs, and to test them for immunogenicity in macaques. The
applicants further intend to evaluate in guinea pigs and macaques multiple
different designs for soluble protein boosts, including pseudovirions and
various forms of monomeric and oligomeric envelope glycoproteins. The most
promising priming and boosting components will be combined and subsequently
evaluated in macaques, culminating in assessment of their ability to protect
the animals from infection with SHIVs containing the env of subtype C HIV-1
strains. The four specific aims of Project 3 are: (i) construction of
recombinant vaccinia viruses and pseudovirions; (ii) construction of DNA
vaccines; (iii) testing of immunogens, adjuvants, and liposomes in vitro and
in animals; and (iv) testing of the prime-boost strategy for immunogenicity
and SHIV protection in macaques.
The Program Project is composed of three individual projects and three
separate core facilities to support those projects. Core functions have been

Continued