Immunotherapy for Infectious Diseases

224 Kilby and Bucy
can infect human cells. HIV isolates categorized as non-syncytium-inducing (NSI) are
most often implicated in the sexual transmission of infection. NSI viruses typically
require the presence of the �-chemokine receptor CCR5 in addition to CD4 (48,49).
CCR5 is the natural receptor for RANTES, macrophage inflammatory protein (MIP)-1�,
and MIP-�, mediators of inflammatory reactions and chemotaxis. Syncytium-inducing
(SI) or T-tropic viral strains, often associated with more rapid disease progression in the
setting of advanced HIV infection and AIDS, tend to utilize the �-chemokine receptor
CXCR4 (also called fusin) (50). The natural ligand for CXCR4 is stromal-derived factor
(SDF-1), a protein constituitively expressed in many tissues that may mediate cellular
trafficking such as the homing of lymphocytes into inflamed tissues or the repopulation
of transplanted stem cells into bone marrow (51,52).
It may be possible to alter host expression of the chemokine receptors. For example,
a gene therapy strategy involving expression of a modified CXCR4 molecule (an
intrakine) demonstrated antiviral effects against T-tropic HIV in vitro, possibly because
the altered CXCR4 was effectively trapped in the endoplasmic reticulum and not
appropriately expressed on the cell surface for HIV binding (53). At the present time,
there is insufficient information about the normal role chemokines play in inflammatory
responses and other physiologic processes. The discovery of the role of CCR5
receptors in HIV was owing in part to the recognition of a relatively common mutation
in the CCR5 gene, a 32-bp deletion (�32) that results in lack of cell surface
expression of the chemokine receptor among individuals who have been multiply
exposed to HIV yet not infected with the virus (17,49,54). Thus there is evidence that
individuals homozygous for the �32CCR5 mutation are substantially protected from
becoming infected, although these individuals do not have an obvious deleterious phenotype
associated with the defective expression of CCR5.
However, evidence related to the effects of alterations in the CXCR4 pathway raises
theoretical concerns. Knockout mice that cannot express SDF-1, the ligand for CXCR4,
undergo abnormal fetal development (cardiac and B-cell lymphopoesis defects) and die
perinatally (55). Another theoretical concern is that effectively blocking one of the
chemokine receptors may provide selection pressure for the outgrowth of viruses utilizing
alternative receptors. One undesirable scenario is that selectively inhibiting NSI
viruses, by administering one of the �-chemokines, for example, may ultimately drive
the evolution of viral strains within an individual to SI CXCR4-utilizing viruses, which
are associated with more rapid clinical progression and CD4 depletion.
However, the most straightforward approach to blocking chemokine receptors would
be to administer the natural ligands or other small molecules that may serve as competitive
inhibitors. A recent in vitro study demonstrates that a specific isoform of MIP-1�
may be the most potent CCR5 agonist and may be a candidate for clinical studies (56).
Recent in vitro investigations involving the bicyclam AMD3100 provide further data to
support the feasibility of blocking HIV-1 entry via the the CCR5 receptor (57). An
example of a synthetic compound that appears to block HIV-1 entry via CXCR4 receptor
inhibition is T22, an 18-amino acid peptide (58). A smaller derivative, termed T134
(14 amino acids), exhibits greater potency and less cytotoxicity in vitro (59).
The subsequent step in the viral entry process, gp41-mediated membrane fusion, has
potential as a more universal therapeutic target because it may be utilized by all HIV
isolates regardless of cellular tropism or antigenic variations. Synthetic peptides corre-