108
AIDS/HIV, Molecular and Cell Biology
hijacked this budding mechanism for an
external budding process and uses the
same cellular factors to facilitate this. The
complete array of proteins involved is not
yet elucidated.
After or during the process of budding,
the protease component of the Gag/Pol
polyprotein becomes activated. This en-
zyme is inactive in the Gag/Pol monomer
and functions as a homodimeric molecule.
An as yet unknown process appears to ap-
proximate two protease monomers leading
to autolytic cleavage of the Frst protease en-
zyme, following which cleavage of further
Gag/Pol molecules will lead to release of
further protease subunits and a cascade of
proteolytic cleavage of Gag and Gag/Pol
can occur. This cleavage is accompanied
by a morphological change in which the
particle changes from a spherical one con-
taining a ‘‘doughnut’’ ring of structural
proteins into a typical retrovirus particle
with matrix protein underlying the enve-
lope and an apparent space between this
and the pyramidal core, which is composed
of capsid proteins.
2.3
Additional Accessory Proteins
These can be divided into those that are or
are not incorporated into the viral particle.
2.3.1
Virion Associated Proteins
As noted previously, the Vpr protein is
involved in the preintegration complex tar-
geting the nucleus of the newly infected
cell. There is evidence that Vpr binds to
the nucleoporin hCG1. Vpr also appears
to have other functions. It may be a tran-
scriptional transactivator in its own right
through binding to p300/CBP coactivators.
It has also been implicated in G2 phase
cell cycle arrest. This is suggested to be the
phase of the cell cycle at which Tat trans-
activation is most efFcient. Vpr may also
have a role in pathogenesis of AIDS since it
has clearly been associated with apoptosis
in a number of different cell types includ-
ing neurons. It appears to gain entry to the
virus by binding to the p6 region of Gag.
In HIV-2 and SIV, a gene duplication
appears to have occurred to produce
a second regulatory protein, Vpx, with
homology to Vpr. There is evidence that
in these viruses, Vpx may have subsumed
the speciFc nuclear entry role of Vpr.
Vif is another small accessory protein
that is incorporated into the virus particle.
It has been clear for many years that Vif
is an essential protein for viral replication
in some cell lines but not others. The Vif
phenotype depends on virion associated
Vif since expression of Vif in a target
cell does not appear to allow replication
of an incoming Vif negative virus. Recent
work suggests that Vif may be interacting
with an inhibitory cellular protein that
has sequence homology to proteins of
the cytidine deaminase family and it may
be that the actions of this nucleotide-
modifying enzyme must be neutralized
for successful reverse transcription and
integration to occur.
2.3.2
Nonvirion Associated Proteins
Vpu is a small protein found only in HIV-1
and SIV
cpz
. It has a number of roles that
enhance the efFciency of budding of the
virus. The envelope glycoprotein, gp120,
which on the virion particle interacts
with the CD4 protein, is synthesized and
exported in the infected cell through the
same pathway as the cell’s own CD4.
Complexing of these two molecules in the
ER has been documented. Vpu appears to
facilitate disaggregation of these two by
binding to and degrading CD4, enhancing
the export of the gp120 SU protein.
previous page 108 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online next page 110 Encyclopedia of Molecular Cell Biology and Molecular Medicine read online Home Toggle text on/off