Structural Biology of CD4 and CDS Involvement in the Cellular 
Immune Response 
One of these is the major determinant for HIV 
binding to CD4. 
Structure of a CDS Fragment 
Although the function of CDS is quite analogous 
to that of CD4, the architecture of the two mole- 
cules is different. CDS is a disulfide-bridged dimer, 
whereas unactivated CD4 is monomeric, and each 
^CDS chain has only one immunoglobulin-like do- 
main rather than four. This single domain is Hnked 
to the transmembrane segment by a 50-residue 
stretch that is highly glycosylated. 
Dan Leahy has expressed a soluble fragment of 
CDS composed of the immunoglobulin-like do- 
main and half of the stalk region. He has recently 
solved a crystal structure of this molecule, and 
this shows that the CDS dimer is organized very 
much as in the variable domain tips of antibodies. 
The stalk region from this molecule is disordered 
in these crystals, a feature compatible with a role 
as flexible tether to the membrane surface. 
Interactions with MHC Molecules 
Although a direct physical interaction between 
isolated CD4 or CDS molecules and their respec- 
tive MHC partners has not been demonstrated, 
these interactions are expected to be very weak. 
Otherwise, in light of the high polyvalency in 
cell-cell interactions, unwanted adhesion would 
be expected. Less-direct evidence for these inter- 
actions, however, is available from suitably con- 
structed cell biology experiments. 
In the case of CD4, Rafick Sekaly and his col- 
leagues at the Clinical Research Institute of Mon- 
treal have used point mutations on human CD4 to 
identify residues involved in the interaction with 
class II molecules. These mutated residues map 
to exposed residues on one face of the D1D2 
structural model. Further analyses are still in 
progress. 
In the case of the CDS-class I interaction, we 
have been able to model a plausible mode of asso- 
ciation between the positively charged CDS mol- 
ecule and the largely negative site localized to 
the a3 domain of the class I MHC molecule. This 
putative interaction is also consistent with results 
from a mutational study by Paula Kavathis at Yale 
University. 
CD4 and AIDS 
The hallmark of AIDS (acquired immune defi- 
ciency syndrome) is the immunodeficiency 
brought on by elimination of CD4"^ T cells. We 
continue in our efforts to understand molecular 
details of the interaction between CD4 and HIV 
that are involved in viral entry. Seong-Eon Ryu is 
completing his refinement of the D1D2 frag- 
ment, Reza Beigi is analyzing the structures of 
mutant proteins with abnormal HIV-binding 
properties, and Peter Kwong has characterized an 
antibody fragment that permits full HIV binding 
to CD4 but inhibits infection. This antibody, 
which binds to the D3 domain, indicates an in- 
volvement of CD4 flexibility in HIV entry. Peter 
Kwong is also attempting to crystallize the viral 
coat protein gpl20 and various complexes with 
this crucial component of the system. 
182 
