Viral tropism

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Viral tropism

• VIRAL TROPISM
• UK CAB 22 13 July 2007
• Matt Williams

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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

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Viral tropism
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Viral tropism
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Viral tropism

• Scientists studying HIV-1 discovered by the 1990s
  that different forms of HIV use different
  coreceptors to attach to cells.

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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

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Viral tropism

• R5 HIV strains which use the CCR5 coreceptor
• X4 HIV strains which use the CXCR4 coreceptor

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Viral tropism

• During the early stages of infection HIV mainly
  targets macrophages using the CCR5 coreceptor
  (called M-tropic)

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Viral tropism

• During later stages of infection HIV isolates are
  T-cell tropic and use the CXCR4 coreceptor
  (T-tropic)

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Viral tropism

• There are also R5X4 strains of HIV which can use
  either of these receptors.

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Viral tropism

• Balance of an HIV infection can be mixed between
  X4 and R5 and change over time

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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

• 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
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Viral tropism
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Viral tropism
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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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Viral tropism

• 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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Viral tropism

• There are other types of cell which carry CD4 on
  their surface besides T-cells eg macrophages

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Viral tropism

• CD4 is part of the immunolgobulin superfamily
• immnoglobulin general term for antibodies which
  bind onto invading organisms

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Viral tropism
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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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Viral tropism

• ...coreceptor...
• T-cells X4 or R5
• Macrophages - R5

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Viral tropism

• X4 and R5 are chemokines - chemical messengers
  that signal to white blood cells to mobilise and
  activate

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Viral tropism

• Syncytia formation
• Syncytia large groups of cells

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Viral tropism

• 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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Viral tropism

• 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
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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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Viral tropism

• Syncytia formation seems to relate to X4-using
  HIV
• X4 and R5-using HIV seems to be in competition

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Viral tropism

• 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

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Viral tropism

• Studies
• Harrigan
• Detection of R5/X4 or X4 phenotype increased
  from 6 in people with CD4 counts above 500
  cells/mm3 to over 50 in those with CD4 counts
  below 25 cells/mm3. One exclusively X4 phenotype
  sample in the cohort.

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Viral tropism

• 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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Viral tropism

• 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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Viral tropism

• 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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Viral tropism

• 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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Viral tropism

• 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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Viral tropism

• CCR5 resistance
• env gene and V3 (not routine test yet)

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Viral tropism

• CCR5 and resistance - articles
• Mutations Outside V3 Loop May Further Resistance
  to CCR5 Drugs
• http//www.natap.org/2007/ResisWksp/ResisWksp_15.h
  tm
• 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.h
  tml
• 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

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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

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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.htm
  l
• 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/mixed-tropic HIV-1 24-week results of a
  phase 2b exploratory trial. IAS Toronto, 2006.
  Abstract late breaker THLB0215

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Viral tropism

• Molecules of HIV
• Dan Stowell
• http//www.mcld.co.uk/hiv