Biology Reference
In-Depth Information
deletions in small loop to enhance the exposure of conserved neutral-
ization epitopes that are shielded from the immune system (unpub-
lished observations).
Structural Information on gp41
Four crystal structures of HIV/SIV gp41 cores are available; all of
these structures are similar and represent a post-fusion conformation
of gp41.
175
It seems that in prefusion state, in the native and untrig-
gered conformation, the surface of gp41 is shielded by gp120, and
thus is not accessible for antibody recognition. Upon binding of CD4
and co-receptor, both gp120 and gp41 undergo extensive conforma-
tional changes that expose the gp41 in an extended fusion intermedi-
ate conformation to position the fusion peptides for insertion into the
host membrane, during which gp41 is perhaps most vulnerable from
host antibody binding. In a proof of concept study, LaCasse and col-
leagues have shown that it is possible to target the fusion interme-
diate for vaccine application.
176
In the study they immunized the
animals with fusion intermediates, and demonstrated that post immu-
nization sera neutralized 24 out of 25 primary isolated tested.
Furthermore, it has been shown that the peptides derived from the
sequences of HR1 and HR2 blocked the membrane fusion process of
HIV.
76,177
Most likely, these peptides bind to the gp41 fusion inter-
mediates during the conformational changes, and therefore prevent
the membrane fusion and viral internalization. Now the most impor-
tant question is how to exploit the potential of fusion intermediates
for vaccine development. The most important constraint is exploiting
these fusion intermediates for vaccine application is that the struc-
ture of gp41 in fusion intermediate conformation is not known.
Therefore, structural information of a longer or full-length gp41 pro-
tein will be helpful to understand the influence on overall gp41 struc-
ture and function of the segments that were omitted in the present
crystal structures of gp41 core. In addition, detailed structure studies
of gp41 variants in conjunction with functional characterization of
antigenicity of the forms can drive a better understanding of the
structural epitopes to productively drive antigen development.
