Transcript Viral tropism - UK-CAB

Viral tropism
VIRAL TROPISM
UK CAB 22 13 July 2007
Matt Williams
Viral tropism
Tropic = shape response. [from Middle
English tropik, Old French tropique, Latin
tropicus, Greek tropikos, turn]
Viral tropism = the way the virus responds to
external stimulus in order to attach to and
infect cells
Viral tropism
Viral tropism
Viral tropism
Scientists studying HIV-1 discovered by the
1990s that different forms of HIV use different
coreceptors to attach to cells.
Viral tropism
The most commonly-transmitted strains of HIV
use the CCR5 coreceptor - strains that develop
in (contribute to?) late-stage infection often use
CXCR4
Viral tropism
R5 = HIV strains which use the CCR5
coreceptor
X4 = HIV strains which use the CXCR4
coreceptor
Viral tropism
During the early stages of infection HIV
mainly targets macrophages using the
CCR5 coreceptor (called M-tropic)
Viral tropism
During later stages of infection HIV
isolates are T-cell tropic and use the
CXCR4 coreceptor (T-tropic)
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There are also R5X4 strains of HIV which
can use either of these receptors.
Viral tropism
Balance of an HIV infection can be mixed
between X4 and R5 and change over time
Viral tropism
Viral tropism is important for a new class
of drugs called CCR5 agonists. These are
a kind of entry inhibitor (like T-20) and
stop HIV binding to cells by blocking the
CCR5 coreceptor.
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Viral tropism can be tested for.
The tropism test that you need to take before
using a CCR5 inhibitor only works if your viral
load is over 500 copies/mL.
1 routine test – more in development
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Viral tropism
Viral tropism
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Viral tropism
HIV carries on its surface "spikes" which are the
glycoprotein known as gp120.
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HIV virus connects with a CD4+ marker sticking
out of a cell and a coreceptor - like two pieces of
jigsaw joining together
Once HIV attaches to a cell in this way it can
merge with the cell.
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There are other types of cell which carry CD4 on
their surface besides T-cells eg macrophages
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CD4 is part of the immunolgobulin superfamily
immnoglobulin = general term for antibodies
which bind onto invading organisms
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Viral tropism
HIV will not successfully complete the
binding/fusion stages unless a coreceptor is
present on the cell surface in addition to the CD4
immunoglobulin marker.
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...coreceptor...
T-cells – X4 or R5
Macrophages - R5
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X4 and R5 are chemokines - chemical
messengers that signal to white blood cells to
mobilise and activate
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Syncytia formation
Syncytia = large groups of cells
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Syncytia formation
When an infected cell starts producing HIV
proteins, the HIV env proteins migrate to the cell
membrane and (maybe) poke out of the cell this means that the infected cell can now bind to
other cells with the CD4 protein on their
surface...
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Syncytia formation
...so an infected CD4+ cell can join with a
healthy CD4+ cell and merge. The membranes
fuse and become one. This repeats, and
eventually you have one large HIV-infected
CD4+ cell with many nuclei - as many as 500.
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Viral tropism
Syncytia = clinical undesirable (inevitable?) =
advanced disease
Autopsies have often found syncytia in the
brains of HIV-positive people who had serious
neurological complications
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Syncytia formation seems to relate to X4-using
HIV
X4 and R5-using HIV seems to be in competition
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Studies
Harrigan - retrospective evaluation of samples
and records from 806 participants in a cohort of
treatment naive-adults in British Columbia
Moyle – evaluation of data and coreceptor
phenotype in a collection of 169 stored samples
from treatment-naive individuals
Viral tropism
Studies
Harrigan
Detection of R5/X4 or X4 phenotype increased
from 6% in people with CD4 counts above 500
3
cells/mm to over 50% in those with CD4 counts
3
below 25 cells/mm . One exclusively X4
phenotype sample in the cohort.
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Studies
Harrigan
Odds of having X4-using virus increased by
about 1.5-fold in people with CD4 counts
between 200 and 500 compared to those above
500
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Studies
Harrigan PR, et al. Prevalence, predictors and
clinical impact of baseline HIV co-receptor
usage in a large cohort of antiretroviral naive
individuals starting HAART.
Abstract MoPeB3117. 2004 IAC, Bangkok
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Studies
Moyle
Detection of the R5/X4 phenotype ranged from
about 7% in samples with CD4 counts above
300 to 46% in those with CD4 counts below 100.
No exclusively X4 phenotype. Mean CD4 count
for R5 samples was 307 versus 117 for R5/X4.
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Studies
Moyle GJ, et al. Prevalence and predictive
factors for CCR5 and CXCR4 co-receptor usage
in a large cohort of HIV-1 positive individuals.
Abstract WePeB5725. 2004 IAC, Bangkok
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Studies
In neither study was viral load a significant
predictor of co-receptor usage phenotype
Harrigan - injection drug use was not correlated
with having R5 or X4 HIV
Moyle - no difference between B and non-B HIV
subtypes
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CCR5 resistance
env gene and V3 (not routine test yet)
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CCR5 and resistance - articles
Mutations Outside V3 Loop May Further Resistance to CCR5
Drugs
http://www.natap.org/2007/ResisWksp/ResisWksp_15.htm
Treatment failure and tropism changes in maraviroc trial related
to previously undetected CXCR4, rather than a mutational shift
from CCR5
http://www.i-base.info/htb/v8/htb8-6-7/Treatment.html
Mechanisms of failure to CCR5 inhibitors is not explained by
mutation in the V3 loop, cross-resistance between CCR5
inhibitors is likely
http://www.i-base.info/htb/v8/htb8-6-7/Mechanisms.html
Viral tropism
Viral tropism and treatment - articles
HIV resistance mutations common but CXCR4 rare among
untreated US gay men
http://www.aidsmap.com/en/news/
821F9F52-A44A-4D7F-B6D8-9A281D4B4CCC.asp
CXCR4, dual or mixed tropic HIV does not reduce response to
HAART
http://www.aidsmap.com/en/news/
5FFD235B-6D39-42A7-88D6-731BE5B7E24F.asp
HIV may use different coreceptors in blood and brain
http://www.i-base.info/htb/v7/htb7-10/hiv.html
Viral tropism
Viral tropism and treatment – articles
Maraviroc results in R5/X4 mixed/dual tropic patients:
unexpected safety data shows possible immunological effect
http://www.i-base.info/htb/v7/htb7-9/Maraviroc.html
Patients treated with maraviroc with X4-tropic virus had increases
in CD4 cell count consistent with the overall maraviroc-treated
population at treatment failure
Mayer H, van der Ryst E, Saag M et al. Safety and efficacy of
maraviroc, a novel CCR5 antagonist, when used in combination
with optimised background therapy for the treatment of
antiretroviral-experienced subjects infected with dual/mixedtropic HIV-1: 24-week results of a phase 2b exploratory trial. IAS
Toronto, 2006. Abstract late breaker THLB0215
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Molecules of HIV
Dan Stowell
http://www.mcld.co.uk/hiv