prepare mice defective in expression of the 
iymphoid-specific CD2 glycoprotein. A substantial 
number of studies have suggested that the CD2 mol- 
ecule, which interacts with several different ligands 
on antigen-presenting and target cells, has an essen- 
tial role in T cell signal transduction and in lysis of 
target cells. The CD2-negative mice were found to 
be normal in all facets of immune system develop- 
ment and function, suggesting that the function 
of the highly conserved CD2 molecule may be 
redundant. 
Mechanism of HIV Entry and Pathogenesis 
HIV entry into target cells involves high-affinity 
binding of the viral envelope glycoprotein (gpl 20) 
to CD4, fusion of the viral membrane to cellular 
membranes, and uncoating of the virus. A number of 
observations indicate that viral binding to CD4 is 
not sufficient for its fusion to cellular plasma mem- 
branes. Retroviruses containing the HIV envelope 
glycoprotein and encoding selectable markers have 
been prepared as a tool for identifying additional 
factors involved in HIV entry. Only cells that bear 
these molecules as well as CD4 can internalize the 
virus and survive selection. This system is being 
used to complement genetic and biochemical ap- 
proaches aimed at identifying additional host cell 
molecules required for HIV entry. 
The selectable retrovirus system has also been 
used to study the effect of mutations in the envelope 
glycoproteins of HIV and of the related simian im- 
munodeficiency virus (SIV). Mutations in the V3 
loop of gpl 20 from HIV have been shown to influ- 
ence virus-cell fusion after binding to CD4; analysis 
of mutations in this region argues that it is not a 
target of cellular proteases, as has been proposed by 
several groups. Growth of SIV in cultured human 
cells selects for rapidly replicating virus with a trun- 
cated envelope cytoplasmic domain. Using select- 
able HIV cores, Dr. Littman's group has shown that 
decreased infectivity of virus bearing full-length SIV 
envelopes is due to decreased envelope assembly 
onto particles and to lower fusogenic activity when 
compared with truncated envelopes. 
The mechanism through which HIV infection re- 
sults in loss of CD4^ helper T cells is not yet under- 
stood. Since few CD4^ cells are infected, it is likely 
that most of them die as a result of an indirect pro- 
cess. Mice in which helper T cell development and 
function are dependent on the human, rather than 
mouse, CD4 molecule have been developed, as de- 
scribed above. Although these animals cannot be in- 
fected with HIV, they are being used to test several 
hypotheses on the mechanism of HIV immunopath- 
ogenesis. For example, interaction of CD4 on helper 
cells with soluble or cell-bound envelope glycopro- 
tein may sensitize these cells for autoimmune cytol- 
ysis or for the activation of a programmed cell death 
pathway. These mechanisms have been shown to oc- 
cur in vitro and are now being tested in vivo using 
the murine model system developed in Dr. Littman's 
laboratory. (The projects described above on mecha- 
nisms of HIV entry were supported by a grant from 
the National Institutes of Health.) 
Dr. Littman is also Associate Professor of Micro- 
biology and Immunology and of Biochemistry 
and Biophysics at the University of California, 
San Francisco. 
Articles 
KiUeen, N., Moriarty, A., Teh, H.-S., and Littman, 
D.R. 1992. Requirement for CD8-MHC class I in- 
teraction in positive and negative selection of de- 
veloping T ceWs. J Exp Med 176:89-97. 
Landau, N.R., and Littman, D.R. 1992. Packaging 
system for rapid production of murine leukemia 
virus vectors with variable tropism. / Virol 
66:5110-5113. 
Page, K.A., Stearns, S.M., and Littman, D.R. 1992. 
Analysis of mutations in the V3 domain of gpl 60 
that affect fusion and infectivity. / Virol 66:524- 
533. 
Pelchen-Matthews, A., Boulet, I., Littman, D.R., 
Fagard, R., and Marsh, M. 1992. The protein tyro- 
sine kinase p56'''* inhibits CD4 endocytosis by 
preventing entry of CD4 into coated pits. / Cell 
Biol 117:279-290. 
Poulin, L., Evans, L.A., Tang, S.B., Barboza, A., Legg, 
H., Littman, D.R., and Levy, J. A. 1991. Several 
CD4 domains can play a role in human immunode- 
ficiency virus infection in cells./ F/ro/ 65:4893- 
4901. 
Sawada, S., and Littman, D.R. 1991. Identification 
and characterization of a T-cell-specific enhancer 
adjacent to the murine CD4 gene. Mol Cell Biol 
11:5506-5515. 
Teitell, M., Mescher, M.F., Olson, C.A., Littman, 
D.R., and Kronenberg, M. 1991- The thymus leu- 
kemia antigen binds human and mouse CD8. / 
Exp Med 174:1131-1138. 
van Oers, N.S.C., Garvin, A.M., Davis, C.B., For- 
bush, K.A., Carlow, D.A., Littman, D.R., Perl- 
mutter, R.M., and Teh, H.-S. 1992. Disruption of 
CD8-dependent negative and positive selection of 
thymocytes is correlated with a decreased associa- 
tion between CDS and the protein tyrosine ki- 
nase, p56'''''. Eur J Immunol 22:735-743- 
IMMUNOLOGY 345 
