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

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1 P01 AI43042-01 14 SEP
Ho, David D.
functional envelope protein will be assessed by a single-round pseudotyped
luciferase reporter virus assay. Immunogenicity in guinea pigs will be
determined.
In Specific Aim 3, promising env genes will be used to construct SHIVs. Cell
tropism and co-receptor usage will be determined. Macaques will be infected
intravenously and vaginally and will be monitored for viral load, immune
response, lymphocyte counts, and signs of immunodeficiency. These experiments
seem logical and relatively straightforward. Interesting data regarding the
structure, function, and immunogenicity of HIV envelope genes is likely to be
generated which should be useful for the development of HIV vaccines.
SHowever, this Program Project application is written in such a way as to make
it very difficult to determine who will work on Project 2.-hose mentioned in
the Budget Justification Section seem well qualified.
REVIEWER B: The objective of this project is to develop an envelope immunogen
to stimulate neutralizing antibodies based on selecting a deglycosylated
and/or loop-deleted envelope protein.
The strengths of the project are as follows:
(1) Specific Aim 1: A macrophage-tropic CCR5 utilizing strain will be used
which would appear to be appropriate for a vaccine aimed at preventing mucosal
transmission. The investigators plan to choose as a vaccine donor strain one
that contains epitopes that react with broadly neutralizing MAbs as a
predictor of an env construct that elicits broadly neutralizing antibodies -
this is a good choice. Standard procedures will be used for genotype and
phenotype characterization allowing cross laboratory comparisons;
(2) Specific Aim 2: The objective is to create an envelope protein that
elicits better neutralizing antibodies by removing of variable loops and
specific glycosylation sites (or combination of), and then testing in guinea
p~igs for immunogenicity. (NOTE: the investigators are well aware of the
limitations of using this model to screen vaccine products and will take that
into account before going further into primates). Both monomeric and
oligomeric constructs will be used. Standard procedures will be followed for
expression of envelope, maintenance of conserved glycosylation sites, the
generation of loop deletions and glycosylation mutants, the generation of
oligomeric proteins, and the efficiency of viral entry and replication. The
"hottest" strain will then be used to construct a SHIV.
However, the project as written is seriously flawed, namely:
(1) Specific Aim 1l There isno" i'ng novel proposed, or that has not yet been
done. Although an argument is made for choosing a "nodal" strain as
important, another argument can be made for jUs the opposite. Nevertheless,
it 1 keJ y MakesttYTe di ference since divergence occurs naturally and
steadily, thereby suggesting that it has little to do with infectivity which
would select towards less genotype diversity; diversity has been shown very
likely to be important in virus survivability within a host, and thus little
effort should be spent on strain selection. Also, since envelope modification

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