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HIV and AIDS CCR-5 Virus
HIV Entry Inhibitors and the Possibility of Resistance
a report by
Rolf Kaiser and Saleta Sierra-Aragón
Institute of Virology, University of Cologne
Two decades of research into HIV and AIDS has yielded an excellent immunodeficiency viruses in vivo. Research by Maddon et al. using mouse
armamentarium of antiretroviral therapies (ARTs). By 2003, this research cells engineered to express CD4 revealed that CD4 alone is not sufficient
had resulted in several classes of drugs that inhibit intracellular HIV for fusion.
2
Chemokine co-receptors stabilise the initial gp120–CD4
replication processes: protease inhibitors (PIs), nucleoside reverse interaction: gp120–CD4 binding causes gp41 to undergo conformational
transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors changes, exposing hydrophobic regions that embed in the lipid bi-layer of
(NtRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). the host cell. Once this is achieved, the viral membrane fuses to the host
However, the disease was and still is a major health threat as the virus can membrane and the nucleocapsid containing its RNA genome enters the
evolve to elude all of the ARTs, thus more are always needed. This article cytoplasm of the cell. Once inside, the viral RNA undergoes reverse
reviews the new class of entry inhibitor drugs and the likelihood that HIV transcription to DNA and is integrated into the host’s genome, where it
will remain susceptible to them. takes advantage of the normal replication mechanism. As already noted,
until now these intracellular processes were one of the main targets for
HIV Entry anti-HIV therapies, together with the inhibition of virion maturation by
In order to infect a host, HIV must first fuse with the host’s membrane the PIs, but recently attention has diverted to the earlier processes of virus
and then inject its core into the cell. The initial step is attachment of binding and fusion.
the virion to the target cell surface, a process that is mediated by the
interaction between glycoproteins on the viral surface and the host cell Chemokine Receptors and HIV Tropism
surface receptors. The HIV envelope (Env) glycoprotein gp160 is a In vitro research has identified a number of chemokine receptors that can
precursor protein that, when post-translationally cleaved, forms the act as HIV co-receptors.
3,4
However, only two chemokine receptors are
receptor binding subunit gp120 and the membrane-anchored fusion recognised to have biological relevance for HIV-1 in vivo: CC chemokine
protein gp41, which associate into non-covalently linked trimers in the receptor 5 (CCR-5) and CXC chemokine receptor 4 (CXCR-4). The
viral membrane.
1
Gp120 and gp41 remain associated until the process co-receptor used by HIV defines its tropism: CCR-5-tropic (R5) or
of viral entry into the cell begins. CXCR-4-tropic (X4). CCR-5 is the major co-receptor used by HIV-1 during
the early years of infection.
5
As the infection progresses, the virus evolves
Virus attachment involves the interaction of gp120 with the CD4 and the co-receptor usage switches to CXCR-4 in 10–20% of therapy-
receptor. CD4 is expressed on the surface of T lymphocytes, monocytes, naïve patients and 30–60% of severely immunodeficient highly active
dendritic cells and brain microglia, the main target cells for primate antiretroviral therapy (HAART)-experienced patients.
6,7
HIV-1 tropism can be determined by phenotypic recombinant virus assays
Rolf Kaiser is Head of the Research Group on HIV and
hepatitis B virus (HBV) resistance at the Institute of
or predicted by bioinformatics tools. Among the former, Trofile
Virology at the University of Cologne, where he is also in
(Monogram Biosciences) and Phenoscript (VIRalliance) are single-cycle
charge of molecular diagnostics. He is a member of the
assays that are able to determine co-receptor tropism without
Scientific Board of the European HIV Drug Resistance
Workshop and a Co-Founder of GenaFor, with co-cultivation of HIV particles in cell culture.
8
Trofile has been automated
responsibility for the organisation of the annual
for high-throughput use; it can be used to identify patients most likely to
AREVIR–GenaFor meeting on technical, bioinformatic,
virological and clinical aspects of drug resistance in
benefit from treatment regimens that include a co-receptor inhibitor and
HIV and HBV. Throughout his career, Dr Kaiser has been involved in virus research and to monitor patients on treatment for the emergence of resistant virus
diagnostics; prior to taking up his position at the University of Cologne, he was a group
populations that switch co-receptor tropism. The detection of minority
leader in the Institute of Medical Microbiology at the University of Bonn. He obtained his
PhD in human genetics at the University of Bonn in 1990.
variants is a limitation of all population-based assays and varies between
0.3 and 10%, depending on the assay used.
9,10
E:
rolf.kaiser@uk-koeln.de
Saleta Sierra-Aragón is a Post-doctoral Researcher at the
XtrackC/PhenX-R (inPheno) and a platform developed by Virco are two tests
Institute of Virology at the University of Cologne, where she
is engaged in research into HIV co-receptors. She completed
that combine genotypic and phenotypic assays to detect tropism. Although
her PhD on the variability of RNA virus quasispecies and the
all assays are validated for the assessment of co-receptor tropism in different
application of error catastrophe as a new antiviral strategy at
the Autonomous University of Madrid in 2001. Dr Sierra-
HIV-1 subtypes, Trofile is the one used in most cases for acquisition of clinical
Aragón graduated in pharmacy at the University of Granada measurements. There is still a need for further evaluations for all of these
in 1995 and in 1996 completed an MSc in microbiology,
tests, as detection of X4 minority species is challenging and is affected by
analysing nitrogen fixation by soil micro-organisms.
many factors, including sample quality, input volume, viral load, the
detection limits and polymerase chain reaction variations.
68 © TOUCH BRIEFINGS 2008
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