The role of CMV in the long term outcome for older Australians, renal transplant recipients and HIV patients

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1 The role of in the long term outcome for older Australians, renal transplant recipients and HIV Some well known facts is a herpes virus so it is has a DNA genome It replicates in fibroblasts, monocytes and endothelial cells It can become latent and persist for a lifetime A subset of its genes are expressed in latently infected cells 8% of people in this room are seropositive Some trickier facts has over 2 open reading frames but most are not needed for growth in cultured cells Many of these non-essential genes are homologues (copies) of cellular genes including chemokines and NK receptors. These are implicated in the ability of to avoid being cleared by the immune system Another tricky fact.. causes a lot of inflammation for a small amount of virus Other mammals have their own versions of which have been separate from human throughout mammalian evolution. Since each has picked up similar genes from their host, they must confer a survival advantage. This is from a patient with myocarditis pathology varies with the immunological capacity of the host This example is the lung of a mouse receiving cyclosporin with pneumonitis and a nude mouse with no T-cells has more persistent inflammation, necrosis and more infected cells. Epidemiological evidence associating with diseases of aging is gathering Eg: Seropositivity and higher IgG antibody levels against associated with all-cause mortality and ischemic heart disease in the population based EPIC-Norfolk cohort. Clin. Inf. Dis : Q1. Is associated with all diseases of aging? Price & Olver. Clin Immunol Immunopath :

2 Ab Titre for example do older people with pulmonary disease associated with non-tuberculous mycobacteria have high levels of antibodies? IgG reactive with whole viral lysate, glycoprotein B (gb) or Immediate Early-1 (IE-1) were measured by ELISA in plasmas from 112 NTM & 117 controls. 1 1 lysate p<.1 1 gb 1 p<.1 1 IE-1 1 p<.1 Is it valid to use antibody as a measure of the lifetime burden of? particularly in HIV p-values determined by Mann-Whitney Test YES! p =.4 p =.1 p =.2 p =.28 p =.69 p =.868 antibody levels are high in all HIV but particularly high in Indonesian HIV where they rise in the first year on ART and EBV antibody titres rise on ART and then decline slowly but stay above healthy controls Does this reflect changes in immune activation on ART? V V1 V2 V3 V6 V9 V12 Indonesian Ctls Perth HIV+ Perth Ctls The rise and fall of antibody did not follow plasma markers of monocyte or B-cell activation Monocyte activation: stnfr & scd14 so if Ab levels are not a simple mirror of immune activation.then perhaps has a distinct immunological footprint lets look at long term ART B-cell activation: Total Ig & sbaff with nadirs <2 CD4 T-cells/ml, a median of 14 years on ART and no identifiable disease..have high titres of reactive antibody n Age (years) 62 (7-68) a 6 (7-62) (3-9) lysate : IgG (AU/ml) 94 (6-24) 2 (1-3).9 (.6-1.) gb : IgG (AU/ml) 127(9-172) 4 (27-) 1.9 ( ) IE-1 : IgG (AU/ml) 49 (21-166) 8 (4.3-18) 2.6 (2.-3.7) lysate : IFNg from d CD4 T-cells 227(16-7) 17(13-617) (-.) 2

3 No of IFNg NLV spots/2, PBMC No of IFNg VLE spots/2, PBMC No of IFNg Whole spots/2, PBMC CD8 T-cell senescence correlates with antibody and age in Senescence vs. Age Senescence vs. Ab So if antibody is a measure of, then perhaps it is not protective??? When we measured IFNg responses by T-cells after 8 years on ART NLV peptide CD8 T-cells P= Whole CD4 T-cells P= VLE.CD8 T-cells 136 P= VLE is an IE peptide seropositivity and controlled HIV disease (~14 yrs on ART) increase T-cell differentiation towards an exhausted phenotype NK cells are also important in the control of NK cells CD3 - CD6 + CD6 lo CD7 + CD6 + IFNg + CD6 + CD17a + HIV infection decreases NK cell function even after ~14 years on ART Controlled HIV disease (median 14 years on ART) decreases NK numbers & function and increases NK expression of CD7 LIR-1 expression is increased by not by HIV + + controls controls NK cells (%) 12 (8.3-18) 17 (11-2) 17 (12-22) IFNg + )lymphocytes) (%NK cells) + K62.8 (.3-1.1) 1.7 (1.-2.6) 1. (.6-2.7) LIR-1 MFI (NK cells) 4 (419-76) 24 (31-774) 31 (27-734) CD7 + (%NK cells) 77 (9-83) 64 (4-66) 63 (9-6) IFNγ CD17a This may impair clearance of reactivated CD7 LIR-1 may is an mark inhibitory "memory" receptor NK cells for NK expanded cells in response to infection, as CD7+ NK cells are expanded by seropositivity in young adults, but not by EBV Binds to HLA-G on a healthy cells to say DON T KILL ME! accelerates age-related increases in CD7 expression, but Binds levels to plateau protein by 6-7 UL18 years with of 1 age. times higher affinity than HLA-G In LIR1 expression the plateau on NK cells is higher is increased and perhaps in transplant reached sooner. after disease 3

4 Framingham Score % OF CD27-CD4RA+ MEDIAN OF LIR-1 (CD6DIM) Antibody titre Can we look at another group of with a high lifetime burden of? renal transplant recipients We recruited and 4 age-matched controls. All had been stable on therapy for >2 years Renal transplant recipients also have high levels of antibody reactive with Lysate gb p <.1 p <.1 IE Lysate p.2 gb IE Lysate Mixture of antigens gb Fusion protein required for infection IE Immediate Early protein secreted first during replication % of CD27-CD4RA+ CD4 T-cells CD8 T-cells 8 p=.22 p< SEROPOSITIVE SERONEGATIVE SEROPOSITIVE SERONEGATIVE Levels of LIR-1 on NK cells are high in and proportional to levels of gb antibody and DNA 1 p= <.1 1 RTP CONTROLS Correlating NK markers with gb antibody in Marker R value P value NKG2C.3.3 LIR-1 (gb).41.3 Perforin (gb) Correlating NK markers with DNA in LIR-1 (gb).37.7 seropositive have more senescent T-cells So blocks the cells that are supposed to control it in! So does influence cardiovascular disease? antibodies correlate with increased risk of cardiovascular disease in..based on a study by Dr Lucette Cysique in Sydney p=.6 p=.77* is this clearer in and/or? p=.9** Spearman R=.317 Framingham score (CVD risk) p= No component of Framingham score (gender, lipids, use of hypertensives, smoking, diabetes) associated with antibody - with the exception of age -2, 2,-4, 4,-6, antibody titre 6,-8, Whilst we cant correlate this with real measurements of CVD in, we do have data from renal transplantation 4

5 Both seropositivity and renal transplantation decrease arterial elasticity n In the lab In the clinic Male:Female 39:3 3:6 39:3 13:1 Age (years) 7(31-76) 3(33-62) (21-86) 43(31-69) Dr Silvia Lee Dr Jacquita Affandi HIV Dr David Nolan Prof Martyn French BMI 26(17-8) 3(2-4) 26(18-4) 27(2-38) lysate antibody AU/L Arterial elasticity %FMD [((B-A)/A) x 1] Thickness of arterial wall Left cimt 79(6-7611).(-3.2) 299(6-1496).9(-6.6) 3.(-16).9(2.3-13) 7.6(1.4-14) 9.(4-18).66(.4-1.3).6(.-1).6(.4-.9).6(.4-.9) Samantha Brunt Dr Christine Bundell Fathiah Amran Nandini Makwana HIV NTM Dr Lucette Cysique Prof Bruce Brew Dr Rachel Thomson Prof Grant Waterer Dr Ashley Irish Prof Gerald Watts