Development of HIV-1 vaccines has been hampered by the virus’s ability to rapidly evolve through structural changes to its envelope glycoprotein (Env) that allow it to evade host antibody responses during persistent infections. A particularly interesting candidate for vaccine development is the viral glycoprotein gp120, which binds to CD4 on host cells to create a second co-receptor site needed for entry into the cell. Although HIV-infected individuals make many neutralizing antibodies to this co-receptor site, these antibodies are largely ineffective. Now, Forsell et al. show that in both primates and rabbits, antibodies are only induced in the presence of primate CD4 binding to gp120. They suggest that naive B cells require gp120 to bind to primate CD4 in order to recognize the co-receptor site, and that the conformation of this interaction is an important determinant of HIV-1 immunogenicity.

Forsell
M. N.
,
Dey
B.
,
Mörner
A.
,
Svehla
K.
,
O’dell
S.
,
Högerkorp
C. M.
,
Voss
G.
,
Thorstensson
R.
,
Shaw
G. M.
,
Mascola
J. R.
, et al. 
. (
2008
).
B cell recognition of the conserved HIV-1 co-receptor binding site is altered by endogenous primate CD4
.
PLoS Pathog.
4
,
e1000171
.