mals that transmit the mutant gene to their off- 
spring. 
II. Interaction of Retroviruses with Receptors. 
Entry of HIV into target cells involves high-affin- 
ity binding of the viral envelope glycoprotein to 
CD4, fusion of the viral membrane to cellular mem- 
branes, and uncoating of the virus. Work in Dr. 
Littman's laboratory has focused on the role of CD4 
in viral binding and, more recently, on defining 
molecules other than CD4 that are required for 
entry. These studies have been extended to develop 
retroviruses that can be targeted to specific tissues 
and that can be used to isolate genes encoding the 
cell surface virus receptors. 
HIV displays enormous polymorphism, making 
the prospect of developing immunological agents 
to combat infection quite daunting. The region of 
the virus that is exempt from significant variability 
is the domain of the envelope glycoprotein, gpl20, 
that interacts with the receptor, the CD4 glycopro- 
tein. This interaction is likely to be the key to a 
number of potential antiviral therapies. Amino acid 
residues in CD4 that interact with gpl20 have been 
identified by analyzing the ability of numerous CD4 
point mutants to bind to gpl20 and to anti-CD4 
monoclonal antibodies. Two regions predicted to 
lie in close proximity to each other in the immuno- 
globulin-like amino-terminal domain of CD4 are in- 
volved in HIV binding. Monoclonal antibodies were 
found to bind in the same region, but none of the 
antibodies coincided with gpl20 in their require- 
PUBLICATIONS 
ments for binding to CD4 mutants. This approach 
may facilitate screening of anti-CD4 monoclonal an- 
tibodies that have binding sites for CD4 similar to 
the binding site on gpl20; such antibodies may be 
useful for preparing anti-HIV vaccines. The design 
of drugs that block the virus-receptor interaction 
will be facilitated by an understanding of the three- 
dimensional nature of the binding. To this end, sol- 
uble complexes of CD4 and gpl20 have been pre- 
pared for crystal analysis in collaboration with 
Dr. Robert Stroud (University of California at San 
Francisco). 
A number of observations suggest that a mole- 
cule other than CD4 is required for fusion of HIV 
to cellular plasma membranes. The same or other 
molecules may also be sufficient for viral entry in 
some cell lines that lack CD4. To identify other 
genes required for HIV entry, Dr. Littman and his 
colleagues have prepared retroviruses containing 
the HIV envelope glycoprotein and encoding 
selectable markers; cells that have intact receptors 
for HFV can be selected by virtue of their ability to 
internalize these viruses. This approach is also 
being used to prepare viruses bearing the envelope 
glycoprotein of HTLV-I; these viruses are being em- 
ployed to identify the receptor for HTLV-I and 
HTLV-II. 
Dr. Littman is also Assistant Professor of Microbi- 
ology and Immunology and of Biochemistry and 
Biophysics at the University of California at San 
Francisco. 
Articles 
Norment, A.M., and Littman, D.R. 1988. A second subunit of CD8 is expressed in human T cells. EMBO J 
7:3433-3439. 
Norment, A.M., Lonberg, N., Lacy, E., and Littman, D.R. 1989- Alternatively spliced mRNA encodes a secreted 
form of human CD8a. J Immunol 142:3312-3319. 
Norment, A.M., Salter, R.D., Parham, P, Engelhard, VH., and Littman, D.R. 1988. Cell-cell adhesion mediated 
by CD8 and MHC class I molecules. Nature 336:79-81. 
Salter, R.D., Norment, A.M., Chen, B.R, Clayberger, C, Krensky A.M., Littman, D R. , and Parham, P 1989. 
Polymorphism in the domain of HLA-A molecules affects binding to CD8. Nature 338:345-347. 
White, J. M., and Littman, D.R. 1989. Viral receptors of the immunoglobulin superfamily. Cell 56:725-728. 
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