CCR5 Ligands in HIV Vaccines

LABORATORY METHODS TO ASSESS RESPONSES TO HIV VACCINE
CANDIDATES
CCR5 ligands in HIV vaccinees
PA NUMBER: PA-99-044
P.I. Alfredo Garzino-Demo
RANTES, macrophage inflammatory protein (MIP)-la and MIP-1( are potent
and specific inhibitors of HIV (1), and their release is associated with protection from
HIV infection in both SIV immunization animal models and in human clinical studies (2 -11). These inhibitors bind to one of the major coreceptor molecules for HIV-1, CCR-5,
which is most involved in primary infection events (12-16). The ability of these
chemokines to prevent infection, which thus renders them functional equivalent of
neutralizing antibodies, has logically led to the hypothesis that high levels of RANTES,
MIP-lia or MIP-1 (3 release should be associated with resistance to primary and/or
advanced HIV infection (1,17-20). In accordance with this idea, the overproduction of
these molecules has been associated with resistance to primary HIV infection in
exposed/uninfected individuals (7-10), lower maternal transmission of virus (11), and to
an overall better clinical status in HIV-infected individuals on or off antiviral therapy
(21-29).
We recently showed that peripheral blood mononuclear cells (PBMC) from
asymptomatic HIV+ subjects from the Multicenter AIDS Cohort Study (MACS)
produced high levels of MIP-la and MIP-1f3 when stimulated with HIV antigen. The
levels of these two chemokines were significantly higher in the asymptomatic HIV+
subjects than in uninfected controls and in subjects with clinical AIDS (28). However, it
is particularly significant that the overproduction of these chemokines also occurred in
response to non-HIV antigens (28). Such findings suggest that some individuals have an
inherent or innate capacity to overproduce certain chemokines in response to general
immune stimuli. In accordance with this idea, the majority of other studies have
correlated chemokine production with more favorable clinical status using
nonspecifically activated cells. In addition, another study has shown that activated cells
from exposed-uninfected individuals released abnormally high levels of 1 chemokines in
response to phytohemagglutinin relative to controls in a group of hemophiliac subjects
who otherwise resistant to infection with hepatitis C virus, to which they were also
exposed through the same transfusions (7).
It is particularly noteworthy that vaccine studies are also showing a similar
correlation between the overproduction of chemokines and protection from experimental
virus challenge. During their attempts to identify correlates of protection, Lehner et al.,
Heeney et al., Wang et al., and Ahmed et al. measured RANTES, MIIP-la and MmP-lb