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

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1 P01 A143042-01 15 SEP
Ho, David D.
is proposed, movement away from a "nodal" construct is sought by design. In
the opinion of this reviewer, this aim should be eliminated; 1
(2) Specific Aim 3: Although the purpose of the investigatork in this project
is to develop their own SHIV/macaque model, they should test their vaccine
first in the available and relatively standardized clade B model, and only if
they are not successful, they should test for envelope specificity. In the
opinion of this reviewer, constructing more SHIVs forethe sake of having more
SHIVs at this time is a waste of effort, and in the long run makes it more
difficult to compare laboratory-to-laboratory results.
In summary, this project is aimed at repeating what others have already done
and contributes little new. Furthermore, there is little presented in this
project to suggest that the investigators have a strategy to move relatively
quickly into human testing of a potential vaccine.
REVIEWER C: A maior strength of this project and of the entire Program is the
commitment to develop a SHIV based on HIV subtype C. The applicants already
have a number of clade C viruses in the laboratory and propose to obtain more,
especially from South Africa and China. The criteria by which they will
select their clade C viruses for vaccine evaluation are defined and defensible
(e.g., macrophage-tropic, using CCR-5 co-receptor, susceptible to
neutralization with broadly neutralizing MAbs, displaying minimal genetic
divergence from other subtype C viruses, and immunogenic in guinea pigs).
Developing a SHIV which fulfills their criteria and replicates well in
macaques may prove difficult, but given the large number of isolates already
in-hand and the commitment of the investigators towards this goal, it is not
impossible. The investigators state that they would like to use viruses from
China or South Africa in several parts of the proposed studies, in part
because they have connections with both countries and believe clinical trials
of candidate vaccines could be readily set up. However, there are no letters
of collaboration from anyone in either of these two country. The applicants
propose severai dai-erent ways to make the envelope gene product more
immunogenic including deglycosylation, loop removal, and using the oligomeric
form. These seem to be standard procedures and should not prove difficult.
Lastly, the investigators will construct SHIVs with HIV subtype C envelopes.
Some of these SHIVs will contain wild-type sequence while others will have
modified envelopes (e.g., deglycosylated, loop-deleted). As a back-up the
a icants propose to use a subtype C envelope SHIV already generated by Dr.
Liciw. This existing subtype C SHIV will also serve as a control in several
o e in vitro assessme of the new SHIVs. However, there is no letter of
S collaboration from Dr. _ iw (Is this available from the repository).
Results from the applid~~sk' laboratory as well as from other groups suggest
that immunity to env may not be necessary for protective immunity in the SIV
or SHIV models. Depending on the results of the challenge experiment proposed
in Project 1, should more attention be placed on determining non-envelope
mechanisms of protection and ways to make.agg/pol more immunogenic?
The investigators have outstanding qualifications to conduct the proposed
work.

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