Immunotherapy for Infectious Diseases

202 Jacobson
is reduced (54,55). A single amino acid change in an epitope can result in escape
from antibody neutralization (58–60). Given the high rate of mutation of HIV, this is
a significant risk.
CD4-Immunoglobulin Fusion Compounds
Similar to antibody neutralization, the concentrations of recombinant soluble CD4
(rsCD4) required for in vitro inhibition of clinical HIV-1 isolates are 200–2700 times
greater than those required for inhibition of laboratory strains (61,62). Intravenous doses of
rsCD4 need to achieve serum concentrations associated with 90–95% in vitro inhibition of
the particular clinical isolate to have an in vivo antiviral effect, as measured by quantitative
plasma viral cultures (63). One CD4-immunoglobulin product, created by the fusion of
rsCD4 with the heavy chain of IgG had no detectable antiviral activity in one clinical study
(64), but concentrations able to neutralize most clinical isolates may not have been achieved.
A CD4-IgG2 fusion protein, with the Fv portions of both heavy and light chains of the IgG2 molecule replaced by the V1 and V2 domains of CD4, has been found to neutralize most
clinical HIV-1 isolates, with inhibitory concentration of 90% (IC90) values less than 40
�g/mL for 26 of 28 isolates tested (47). CD4-IgG2 protected 20 of 21 hu-PBL-SCID mice
from challenge with the laboratory isolate HIV-1LAI and the clinical isolates HIV-1JR-CSF and HIV-1AD6 (65). Phase I clinical studies of this preparation are under way.
Anti-Receptor and Anti-Coreceptor Antibodies
An alternate approach for using antibodies to inhibit HIV replication is to create monoclonal
antibodies targeting the CD4 receptor and the chemokine CCR5 and CXCR4 coreceptors
used by HIV for cell fusion and entry. Anti-CD4 monoclonal antibodies inhibit HIV
infection of lymphocytes and macrophages at both CD4-gp120 binding and postbinding
steps and block HIV-induced cell-cell fusion and syncytium formation (66–68). A murine
monoclonal antibody (mu5A8), subsequently humanized, has been developed against the
second domain of CD4 (69,70). Its antiviral activity is synergistic with anti-gp120 antibodies
(71). The epitope on the second domain of CD4 targeted by this antibody is not
involved in MHC class II-mediated immune functions, and the antibody does not promote
clearance of CD4 cells in vivo (69,70). Thus, this potential treatment appears safe and is
likely to proceed to clinical trials. The monoclonal antibody B4 also targets the CD4 molecule,
and its binding to CD4 is enhanced in the presence of chemokine receptor peptides
(72). Hence, its binding to the CD4 receptor on the T-cell surface may be affected by coreceptor
interactions (72). It neutralizes against infection with primary HIV-1 isolates (72).
Similarly, it is possible to design anti-CCR5 antibodies that interfere with HIV binding
but do not inhibit chemokine binding and intracellular signaling (73). HIV-1 and
chemokines bind to different sites on CCR5 (73). Monoclonal antibodies targeting the
N-terminus region and the second extracellular loop of CCR5 inhibit HIV infection of
cells but not chemokine activity (73). Whether antibodies that target CXCR4 safely can
be developed has yet to be shown.
Antibody-Dependent Cellular Cytotoxicity
Another mechanism whereby humoral immunity could affect the course of HIV
infection is through ADCC (74,75). This process consists of programming of mononuclear
cells to lyse HIV-infected cells bound to HIV-specific antibody. A different mech-