Immunotherapy for Infectious Diseases

200 Jacobson
changes of gp120 alter the ability of antibodies to bind and neutralize the virus (23).
Various envelope sites are also heavily glycosylated, further affecting virus-antibody
interactions (25). In general, HIV gp120 is a less effective neutralization target in its
natural (“primary viral isolate”) state than when laboratory-adapted to grow in immortalized
CD4 lymphocyte cell lines. The primary gp120 epitopes sensitive to neutralization
are on V2, V3, C4, and the conformationally dependent overlapping regions that
make up the CD4 binding site (26). The gp41 glycoprotein, a transmembrane element
non-covalently bound to gp120, is involved in virus-cell fusion and also serves as a
neutralization target (27).
HIV infection of a cell involves binding to the CD4 receptor, binding to a chemokine
coreceptor, fusion with the cell, and then entry into the cell. During each step, the HIV
envelope structure undergoes conformational changes. Recent evidence suggests that
the transient envelope structures arising during cell binding and fusion may be more
susceptible to antibody neutralization and could serve as targets for immunization
strategies (28).
Neutralization Epitopes
It has long been known that the V3 loop contains neutralizable epitopes (29,30).
Antibodies to this region of the viral envelope are produced early in the course of infection
(31) and are associated with delayed progression of disease (32) and reduced
maternal-infant transmission of infection (33). They appear to function by inhibiting
coreceptor binding and virus-cell fusion (34). Anti-V3 monoclonal antibodies protect
chimpanzees against HIV-1 infection (35), and anti-V3 antibodies elicited by vaccination
are associated with protection in animal studies (36). Several anti-V3 monoclonal
antibodies have been created (Table 1), but the hypervariability of this region hinders
its usefulness as a target for immunologic control by passive or active vaccination
strategies (30,36). However, some studies have suggested that some anti-V3 antibodies
are more broadly neutralizing (37,38). Nevertheless, clinical HIV isolates appear
to be more resistant to the effects of anti-V3 monoclonal antibodies than T-cell
laboratory-adapted strains (36,39).
The V2 region and CD4 binding domain on gp120 and the gp41 glycoprotein are
better targets for neutralization of clinical viral isolates of HIV (36). Monoclonal antibodies
against the CD4 binding domain and V2 region have been created and shown
to have neutralizing activity against “primary” viral isolates (40–43). The gp41 molecule
is more conserved than gp120 (44). Monoclonal antibody 2F5 binds to the amino
acid sequence ELDKWA on the ectodomain of gp41 and is broadly reactive against
clinical HIV isolates (45). Seventy-two percent of isolates from different clades contain
this amino acid sequence (45). The decapeptide GCSGKLICTT has been identified
as another conserved epitope on gp41 that serves as a neutralizing antibody target
in laboratory strains of HIV (44). Clinical isolates need to be tested. The monoclonal
antibody 2G12 recognizes a discontinuous epitope on gp120 that includes domains in
C2, C3, C4, and V4 (46). It also has demonstrated broad neutralizing activity against
clinical HIV isolates (47). In a blinded study of a panel of clinical HIV isolates involving
several laboratories, the monoclonal antibodies 2F5, 2G12, and b12 showed significant
neutralizing activity against almost all isolates tested (48).