HIV-Inhibiting Chemokines: Critical Host Factors in AIDS

ZRG-1 AARR-02 (01) 5 1R01A148384-01A1
July 2000 GARZINO-DEMO, A
There is little specific experimental criticism of aim one. The assays are
straightforward and the investigators have employed the most up to date methods
of detection. One might argue that intracellular cytoplasmic chemokine staining
would yield more interesting data on a per cell level, but this assay is not
available for all chemokines analyzed here. A more serious concern is the
failure of the investigator to consider variations within the patient
population that effect there ultimate read out. These include confounding
variables such as drug abuse. Criticisms of aim two from the previous
submission have largely been addressed by the elimination of the fusion assay.
The new approach will be to isolate virus and test for infectivity with the
U373 indicator line. How the investigator will distinguish rare species that
infect alternative receptors from a larger population shift is unclear. That
is, the investigator has not clarified how he will evaluate the viral
population as a whole. This is particularly relevant in situations of early
phase changes when unique chemokine receptor binding virus may represent only
small fraction of the total population. The investigator also has not yet
specified which additional chemokine receptors will be tested. Lastly, the
ability to establish a correlation between patterns of chemokine production in
aim one with shifts in co-receptor utilization do not of themselves provide
definitive arguments for the former driving the latter.
Innovation: The project addresses an interesting hypothesis. It uses
straightforward concepts and methods. Solid, but not particularly innovative.
Investigator: The investigator is junior but experienced in all the
methodologies. He has established good collaborations to complete the studies
as outlined.
Environment: The environment at the University of Maryland Biotechnology
Institute is well positioned to enable the investigator to complete the studies
as outlined.
OVERALL EVALUATION: This is the second submission of a new proposal from a
first time ROl investigator. 1m rovements to th rant have been made from the
previous submission Nevertheless, the fundamental concern raise in t e
initial review remains - that being that the experimental analysis is
sufficiently broad in scope such that the generation of data to prove the
primary hypothesis that alterations in chemokine receptor levels affect disease
progression and drive co-receptor utilization will most likely not be met. The
strengths of the proposal are the qualifications of the investigator, the
streamlined experimental approach, and the resources on hand to collect both
subject samples and to conduct experimental determinations. In view of these
comments the grant does not fall in the upper tier of those viewed in the
present cycle. Because of the speculative nature the investigator should
consider reducing the number of years requested and the support to perform
these studies.
CRITIQUE 3:

Significance: Ine ability of chemokines to inhibit HIV replication. in vitro has
been well documented. However, it has been difficult to produce definitive
evidence for an in vivo role of chemokines, although several studies in both
humans and monkeys have provided an intriguing correlations. There is therefore