HIV-Inhibiting Chemokines: Critical Host Factors in AIDS

ZRG-1 AARR-02 (01) 4 1R01A148384-01A1
July 2000 GARZINO-DEMO, A
which proposes an important analysis: a longitudinal study of the impact of
beta-chemokines on HIV disease progression and on the selection of viral
variants in vivo. The proposal has strengths: work from this Investigator has
been instrumental in defining this. question; the environment of the IHV in
particular and of the greater Baltimore area (including participants of the
MACS cohort) in general are strong and would be contributory to successful
pursuit of the study; and, not,least importantly, a definitive statement
arising from these studies might provide clues about better ways to treat HIV
disease in the future. These strengths are, however, overweighed by fundamental
flaws in the design of the study and in the methodologies proposed for use. In
view of these concerns, the revised protocol is placed in the lower half of
submissions reviewed in this session.
CRITIQUE 2:
Significance: This proposal addresses a highly significant area of HIV
pathogenesis. The proposal, seeks to understand the role that chemokine
production plays in the regulation of HIV progression and pathogenesis. The
proposal advances several specu'lative aims, which are intended to utilize
samples from the MACS cohort, in the analysis of chemokine production of the
HIV progression.
Approach: In the first aim the investigators will examine temporal
relationships between levels of secreted HIV inhibitory chemokine and the
progression of HIV infection. The hypothesis is that individuals that
demonstrate a higher and/or sustained level of chemokine release will show a
lower rate of disease progression. Patients in the cohort will be followed in ay
longitudinal fashion, individual PBMC will be obtained from subjects and these
cells/sera analyzed for the production of multiple alpha andbeta chemokines. In
the second aim the investigator proposes to study the relationship between
chemokine production and the evolution of viral coreceptors. The hypothesis
here is that the production of a particular chemokine may saturate or down
regulate this receptor and drive virus to the utilization of an alternative
receptor for infection.
There are several concerns of a general nature that override the specific
experimental criticisms: 1) The overall approach assumes that levels of
chemokines produced by in vitro activated PBMC is reflective of the in vivo
production of chemokines during infection. This does not take into account
production by alternative cells or alternative sites. The assumption is also
that cell activation is required for measurement of chemokine production. The
preliminary data show that non activated cells may produce substantial amounts
of theseJfactors__and indeed one could. argue thatmeasurement of the endogenou s
non-activated levels of expression are more - or at least as - relevant to
analysis of disease progression. 2) The second assumption is that a correlation
can be established at any level between chemokine production and multi
factorial disease. For example, it is known that activation of lymphocytes up
regulates chemokine production, and yet cells from infected patients show
altered patterns of activation depending on the status of disease. Therefore,
if one &ees a lower level of beta chemokine production as disease progresses
can one safely assume that this is the positive property driving disease, or
simply a consequence of increase production during enhanced proliferation.