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)

Viral tropism

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.

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

Viral tropism

Viral tropism

Viral tropism

Viral tropism

Viral tropism

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

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.

Viral tropism

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

Viral tropism

CD4 is part of the immunolgobulin superfamily

immnoglobulin = general term for antibodies which bind onto invading organisms

Viral tropism

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.

Viral tropism

...coreceptor...

T-cells – X4 or R5

Macrophages - R5

Viral tropism

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

Viral tropism

Syncytia formation

Syncytia = large groups of cells

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...

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.

Viral tropism

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

Viral tropism

Syncytia formation seems to relate to X4-using HIV

X4 and R5-using HIV seems to be in competition

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

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.

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

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

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.

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

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

Viral tropism

CCR5 resistance

env gene and V3 (not routine test yet)

Viral tropism

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 CCR5http://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 likelyhttp://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 HAARThttp://www.aidsmap.com/en/news/5FFD235B-6D39-42A7-88D6-731BE5B7E24F.asp

HIV may use different coreceptors in blood and brainhttp://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/mixed-tropic HIV-1: 24-week results of a phase 2b exploratory trial. IAS Toronto, 2006. Abstract late breaker THLB0215

Viral tropism

Molecules of HIVDan Stowell

http://www.mcld.co.uk/hiv