AIDS/HIV, Molecular and Cell Biology
109
Vpu
also
appears
to
have
additional
envelope-independent effect, enhancing
virus export.
The Nef protein is found throughout the
primate lentiviruses. It is a multifunctional
molecule. It has been documented as
being capable of downmodulating cell sur-
face expression of certain cellular proteins
including CD4 and the MHC proteins.
Recent evidence suggests that Nef may be
involved in recruiting lymphocytes to HIV-
infected macrophage/monocytes. SpeciFc
effects on migration inhibition of lympho-
cytes have been documented and these
properties seem to be a powerful func-
tional argument for Nef having important
effects on virus spread and infectivity. This
is further supported by the observation
that Nef-deleted or Nef-mutated viruses
have been shown to be associated with a
severely attenuated pathogenicity. Recipi-
ents of HIV-infected blood from a single
donor in Australia remained well for many
years and the virus was identiFed as having
a defective Nef protein. In SIV infection,
Nef mutant viruses show an attenuated
phenotype and reversion of the Nef muta-
tion to wild type is associated with a regain
of virulence.
2.4
Envelope Variants
The envelope gene of HIV-1 encodes a
polyprotein comprising the two compo-
nents of the external viral receptor ligand.
A
tt
h
eN
-
t
e
rm
in
u
si
st
h
es
u
r
f
a
c
e(
SU
)
or gp120 protein. At the C-terminal, the
TM is found. This latter sequence con-
tains a hydrophobic stretch of amino acids,
which comprise the membrane anchor and
a second hydrophobic region involved in
binding to the target cell membrane and
fusing it with the virus envelope. The SU
region is divided into Fve constant (C1-5)
and Fve variable (V1-5) regions. The SU
protein of HIV is responsible for binding
to target cells. The V3 loop region of SU
has attracted much attention because of
its critical importance in receptor binding.
The CD4 protein found on lymphocytes
and cells of the monocyte/macrophage
series was identiFed early in the AIDS
epidemic as being a major receptor for
the virus. At the same time, it was clear
that binding to CD4 was necessary but
not sufFcient for infection. Observations
that activated lymphocytes released sub-
stances that block infection by HIV and the
identiFcation of these as chemokines and
their receptors as belonging to the family
of 7-transmembrane spanning chemokine
receptors revealed the existence of a family
of coreceptor molecules, which are re-
quired for successful entry and infection.
The two major families of these are the
so-called
CC chemokine receptors
and the
CXC receptors
. Two of these are the prin-
cipal HIV receptors. The CC chemokine
receptor CCR5 responds to the cytokines
MIP1
α
,M
IP1
β
, and RANTES. The CXC
chemokine receptor CXCR4 is bound by
SD±1. There are a number of other re-
ceptors that have been identiFed as being
involved in binding of HIV-1, HIV-2, and
SIV. The identiFcation of these recep-
tors neatly mapped on the long-standing
observation that there were at least two
types of tropism identiFable in HIV. Some
viruses appeared to be able to infect cells
of the monocyte/macrophage series very
efFciently but were very poor at infect-
ing T lymphocytes. Others appear to be
extremely efFcient at infecting T lym-
phocyte cell lines
in vitro
but were very
poor at infecting macrophages. These were
broadly divided into ‘‘macrophage tropic’’
and ‘‘lymphocyte tropic’’ viruses (although
this is a simpliFcation). The chemokine re-
ceptor data link these tropisms with the
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