CCR5 Ligand Levels and Immune Response to HIV Vaccines

ZRG 1 VACC (01) 2 1 RO1 A152038-01
November 2001 Garzino-Demo, Alfredo
problems associated with working with frozen cells. Overall, concerns about the
reliability of the proposed assays, especially when performed on cryopreserved
specimens and the lack of a well-established basis for correlations and data
interpretation, dampened the enthusiasm for the proposed work.
DESCRIPTION: (Provided by Applicant): RANTES, macrophage inflammatory protein
(MIP)-la and MIP-lb potently inhibit HIV by binding to the CCR5 coreceptor,
which is the major host determinant for primary infection. Accordingly, our
studies, along with those of other groups, show that the release of these
inhibitors is associated with natural resistance to HIV infection in high-risk
individuals. Similarly, the increased production of the same chemokines is
correlated with protection from SIV or SHIV infection in vaccinated primates.
These observations introduce the possibility that the release of these
chemokines provides a component of vaccine-induced innate immunity against HIV.
Our preliminary data showing readily detectable increases in CCR5 ligands in
PBMC cultures stimulated with vaccine antigen indicates this possibility can be
explored using ELISA-based detection methods. Therefore, studies to determine
changes in antigen induced chemokine release in vaccines are clearly warranted.
In this project, we will develop, standardize and apply methods for the
rigorous analyses of CCR5 ligand release from antigen stimulated cells that
will be suitable for screening vaccinees. These analyses will for the first
time incorporate the means to measure LD78b versus MIP-la and the natural
isoforms of RANTES. The latter molecules are important to distinguish sine the
-2 isoform has been associated with a more potent antiviral effect in vitro.
The application of the assay system will provide a far more complete and
detailed profile of chemokine release that will be relevant to vaccine
development and testing and to the exploration of the hypothesis that HIV
suppressive chemokine might play a role in providing protection against HIV
infection.
CRITIQUE 1:
SIGNIFICANCE: The role of B chemokines in HIV pathogenesis has firmly been
established since the original description of these molecules' ability to block
HIV entry. This application will attempt to expand on a significant literature
on this topic by refining the assays for B chemokines and extending them to the
additional chemokines LD78B and -2 isoforms of RANTES not evaluated in previous
studies. The impact of the results of these studies will be limited as the
proposal for the most part is simply dealing with technical advances in assay
development. The aim to evaluate chemokine levels from HIV vaccine recipients
will simply provide correlative data with CTL and neutralization assays and not
further our understanding of potential mechanisms of chemokine production in
protective immune responses to HTV. The overall results of the proposed studies
wilEl not significantly advance our understanding of the role of chemokines in
HIV disease.
APPROACH: The experimental design simply proposes technical advances in
measurements of B chemokines and would not add to a more complete mechanistic
understanding of the role of chemokines in HIV disease. The outcome of these
studies will simply provide descriptive data on chemokine levels in HIV vaccine
recipients. One question that was brought out by the investigators not dealt
with experimentally was to clearly define the positive (ability to block HIV
infection) or negative (increased rate of infection by chemotaxis of infected