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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.

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Viral tropism

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  1. VIRAL TROPISM UK CAB 22 13 July 2007 Matt Williams Viral tropism

  2. 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

  3. Viral tropism

  4. Viral tropism

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

  6. 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

  7. R5 = HIV strains which use the CCR5 coreceptor X4 = HIV strains which use the CXCR4 coreceptor Viral tropism

  8. During the early stages of infection HIV mainly targets macrophages using the CCR5 coreceptor (called M-tropic) Viral tropism

  9. During later stages of infection HIV isolates are T-cell tropic and use the CXCR4 coreceptor (T-tropic) Viral tropism

  10. There are also R5X4 strains of HIV which can use either of these receptors. Viral tropism

  11. Balance of an HIV infection can be mixed between X4 and R5 and change over time Viral tropism

  12. 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. Viral tropism

  13. 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 Viral tropism

  14. Viral tropism

  15. Viral tropism

  16. Viral tropism

  17. Viral tropism

  18. HIV carries on its surface "spikes" which are the glycoprotein known as gp120. Viral tropism

  19. 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. Viral tropism

  20. There are other types of cell which carry CD4 on their surface besides T-cells eg macrophages Viral tropism

  21. CD4 is part of the immunolgobulin superfamily immnoglobulin = general term for antibodies which bind onto invading organisms Viral tropism

  22. Viral tropism

  23. 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. Viral tropism

  24. ...coreceptor... T-cells – X4 or R5 Macrophages - R5 Viral tropism

  25. X4 and R5 are chemokines - chemical messengers that signal to white blood cells to mobilise and activate Viral tropism

  26. Syncytia formation Syncytia = large groups of cells Viral tropism

  27. 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... Viral tropism

  28. 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. Viral tropism

  29. Viral tropism

  30. Syncytia = clinical undesirable (inevitable?) = advanced disease Autopsies have often found syncytia in the brains of HIV-positive people who had serious neurological complications Viral tropism

  31. Syncytia formation seems to relate to X4-using HIV X4 and R5-using HIV seems to be in competition Viral tropism

  32. 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

  33. 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. Viral tropism

  34. 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 Viral tropism

  35. 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 Viral tropism

  36. 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. Viral tropism

  37. 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 Viral tropism

  38. 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 Viral tropism

  39. CCR5 resistance env gene and V3 (not routine test yet) Viral tropism

  40. 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

  41. 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

  42. 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/mixed-tropic HIV-1: 24-week results of a phase 2b exploratory trial. IAS Toronto, 2006. Abstract late breaker THLB0215 Viral tropism

  43. Molecules of HIV Dan Stowell http://www.mcld.co.uk/hiv Viral tropism

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