Interestingly, expression of Nef reduces CD4 ex- 
pression on T cells to such a degree that they are no 
longer permissive to infection by HIV-1 virions, al- 
though a transfected HIV-1 provirus is expressed 
normally. It is hypothesized that Nef normally func- 
tions to facilitate the efficient release of infectious 
HIV-1 or SIV virions by preventing the premature 
interaction of viral envelope proteins with CD4 ex- 
pressed in either the endoplasmic reticulum or on 
the surface of the infected cell. 
HIV-1 Cell Tropism 
Isolates of HIV- 1 can be divided into two distinct 
groups based on their ability to infect primary hu- 
man macrophages. Previously it was shown that this 
tissue tropism was primarily regulated by the se- 
quence of a small, disulfide-bonded protein loop 
found within the HIV-1 envelope protein. More re- 
cently it has been demonstrated that this so-called 
V3 loop also regulates the efficiency with which 
HIV-1 virions in culture are neutralized by soluble, 
recombinant CD4 protein. Inability to grow in mac- 
rophages was tightly correlated with high sensitivity 
to soluble CD4. 
It is believed that CD4 neutralizes HIV-1 virions 
by inducing a conformational shift in the HIV-1 en- 
velope protein that leads to shedding of the gpl20 
component. It is therefore hypothesized that the se- 
quence of the V3 loop modulates the nature of this 
conformational shift, thereby influencing not only 
the sensitivity of HIV-1 virions to soluble CD4 but 
also the nature of the interaction of the HIV- 1 enve- 
lope with specific cell surface proteins subsequent 
to initial binding of the virion to cell surface CD4. 
Gene Therapy Approaches to AIDS 
Previously Dr. Cullen's laboratory described mu- 
tant forms of the HIV- 1 Rev protein that retain the 
ability to bind to, and multimerize on, the RRE but 
are unable to function once bound. These mutant 
Rev proteins are therefore capable of blocking the 
interaction of functional Rev protein with the RRE 
and, hence, the replication of HIV-1. 
In collaboration with the laboratory of Dr. Gary 
Nabel (HHMI, University of Michigan) , Dr. Cullen's 
laboratory has now demonstrated that stable expres- 
sion of such a trans-dominant negative Rev protein 
in human T cells can render these cells refractory to 
productive infection by HIV-1. Importantly, these 
protected T cells displayed a normal growth pattern 
and retained the ability to elaborate cytokines in re- 
sponse to stimulation. These observations suggest 
that trans-dominant Rev mutants can protect T cells 
against HIV-1 without exerting any deleterious ef- 
fect on the expressing cell. This strategy may there- 
fore represent a promising gene therapy approach to 
the treatment of HIV-1 -infected persons. The gene 
therapy project described above was supported by a 
grant from the National Institute of Allergy and In- 
fectious Diseases. 
Dr. Cullen is also Associate Professor in the Sec- 
tion of Genetics and the Department of Microbiol- 
ogy and Associate Medical Research Professor in 
the Department of Medicine at Duke University 
Medical Center. 
Books and Chapters of Books 
Malim, M.H., McCarn, D.F., Tiley, L.S., and Cul- 
len, B.R. 1991. Domain structure of the HIV-1 
Rev protein. In Genetic Structure and Regula- 
tion o////K(Haseltine, W.A., and Wong-Staal, F., 
Eds.). New York: Raven, pp 369-376. 
Articles 
Chen, H , Boyle, T.J., Malim, M.H., Cullen, B.R., 
and Lyerly, H.K. 1992. Derivation of a biologi- 
cally contained replication system for human im- 
munodeficiency virus type 1 . Proc Natl Acad Sci 
USA 89:7678-7682. 
Cullen, B.R. 1991. Regulation of gene expression 
in the human immunodeficiency virus type 1. 
Adv Virus Res 40:1-17. 
Cullen, B.R. 1991. Regulation of human immuno- 
deficiency virus replication. Annu Rev Microbiol 
45:219-250. 
Cullen, B.R., and Garrett, E.D. 1992. A compari- 
son of regulatory features in primate lentiviruses. 
AIDS Res Hum Retroviruses 8:387-393. 
Cullen, B.R., and Malim, M.H. 1991 The HIV-1 
Rev protein: prototype of a novel class of eukaryo- 
tic post-transcriptional regulators. Trends Bio- 
chem Sci 16:346-350. 
Garcia-Blanco, M.A., and Cullen, B.R. 1991 . Molec- 
ular basis of latency in pathogenic human viruses. 
Science 254:815-820. 
Garrett, E.D., and Cullen, B.R. 1992. Comparative 
analysis of Rev function in human immunodefi- 
ciency virus types 1 and 2. / Virol 66:4288- 
4294. 
Hwang, S.S., Boyle, T.J., Lyerly, H.K., and Cullen, 
B.R. 1992. Identification of envelope V3 loop as 
the major determinant of CD4 neutralization sen- 
sitivity of HIV-1 . Science 257:535-537. 
Keller, A., Garrett, E.D., and Cullen, B.R. 1992. 
The Bel- 1 protein of human foamy virus activates 
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