Chemistry Reference
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a consequence, the desire to identify novel classes of drugs with antiviral
activity continues to be strong.
9.2 HIV Infection and the Choice to Target CCR5
Antagonism
The HIV virus enters the host cell through a cascade of events that result in
fusion of viral and host cellular membranes. The process is believed to be
initiated by binding of viral surface protein (gp120) to host cell CD4, resulting
in conformational changes that enable interaction with a co-receptor (CCR5 or
CXCR4); this exposes a second viral protein (gp41), which mediates host/virus
membrane fusion.
6
It is generally only following interaction with the co-
receptor that infection by primary HIV-1 strains can take place. Viral strains
that are transmitted and establish new infections tend to require the presence of
CCR5 (these are termed R5-tropic strains). Viral entry via CXCR4 (X4-tropic
strains) is typically seen in later stages of disease progression and has been
associated with rapid CD4 T-lymphocyte decline.
There are many potential points to intervene in the viral life-cycle (Figure
9.1)
7-9
and the majority of these steps have been targeted as potential inter-
vention points against the HIV virus. The choice to block a host receptor to
prevent viral infection is at first sight an unusual one, since the pharmacological
consequences of intervention of host cellular function would normally preclude
this option. The risks become even higher when one considers that an effective
antiviral agent would require chronic dosing at levels to ensure permanent and
complete blockade of CCR5. In this case, however, such safety concerns were
neatly addressed by key data that also demonstrated the importance of CCR5
for viral infection. Approximately 1% of north European Caucasians
i
carry a
homozygous 32 base-pair deletion in the gene encoding CCR5 (CCR5-D32),
resulting in the lack of functional CCR5. These individuals are highly resistant
to HIV-1 infection. Heterozygotes for this allele show low cell-surface expres-
sions of CCR5 receptors and exhibit delayed disease progression. The vast
majority of individuals
12
either homo- or heterozygous for CCR5-D32 are
healthy.
ii
This then suggests that CCR5 is a redundant receptor and that
blockade by an antagonist to prevent cellular infection by HIV-1 will be safe
during chronic treatment. Interestingly, CCR5 agonists have also been pro-
posed as potential antiviral agents, as they could both directly block the
receptor and accelerate its clearance from the cell surface by triggering receptor
internalization mechanisms.
14
However,
to be pharmacologically benign,
i
The emergence of a significant population of north European Caucasians carrying CCR5-D32 is
believed to be a result of selective pressure from a long-term and widespread epidemic. Population
modelling suggests that this could be the result of endemic smallpox which infected the vast
majority of children for around 700 years in Europe. This had a fatality rate of
B
30% and could
have resulted in the levels of CCR5 -/- observed today.
10,11
ii
It has been reported that individuals expressing homozygous CCR5-D32 have reduced resistance
to West Nile virus.
13
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