The outcome and prognosis of chronic infectious diseases often involves genetic and immunological mechanisms which may predict susceptibility to the underlying infection or affect the consequences of infection. Here I focus my investigations on tuberculosis immune restoration disease (TB-IRD) and cytomegalovirus (CMV) disease in patients with human immunodeficiency virus (HIV) disease. Non-tuberculous mycobacterial (NTM) disease is clinically and radiographically indistinguishable from TB diagnosis and often overlooked. NTM disease diagnosis is rising worldwide due to better laboratory identification, hence I explored genetic markers as another approach to distinguish from TB or if similar genetic observations will be reproduced.
Carriage of the variant allele in TNFA-1031*C and SLC11A1 D543N*G were associated with susceptibility to developing immune restoration disease (IRD) in Cambodian HIV patients co-infected with TB. However these effects were not reflected in Indian HIVTB patients, where the associations with susceptibility to an IRD event were increased with carriage of IL18-607*G and VDR FokI (F/f)*T. In the Appendix to Chapter 3, TB-IRD was not associated with plasma levels of Vitamin D and the VDR Fok I (F/f) allele did not predict susceptibility to succumbing to an IRD event in TB patients in Cambodia, India nor South Africa.
Caucasian NTM patients carrying IL28B-rs8099917*TG, TNFA-1031*TT, IL10-1082*AA, and IL1A+4845*AA were significantly associated with NTM disease. IL10-1082 warrants further investigation because high production of IL-10 by peripheral blood mononuclear cells (PBMC) from NTM patients has been observed previously.
Genetic polymorphisms associated with (a) susceptibility to CMV end-organ disease, and (b) predisposing low nadir CD4 T cell counts in CMV seropositive HIV-infected patients. In part (a), IL12B 3’UTR*AA and SLC11A1 D543N*AG in African Americans and Caucasian Americans carrying IL10-1082*AG and LILRB1 I142T*TT were associated with increased risk of developing CMV end-organ disease. In part (b), African Americans patients who carried DARC T-46C*AA and variant allele in CD14 C(-159)T, associated with low nadir CD4 T cell counts. In Caucasian patients, however, associations with low nadir CD4 T cell counts were observed with carriage of TNFA-1031*TT, TNFA-308*A, IL2-330*G, CCL2- 2518*GG, LILRB1 I142T*C, IL10-1082*GG and IL12B3’UTR*AC.
Immunological markers of the effects of CMV driving immune activation and inflammation were explored in a cohort of HIV patients who had been on ART for more than 12 years with good viral suppression. CMV antibody titres (reactive with lysate, gB or IE1) remain high in HIV patients who have been on ART for more than 12 years, compared to healthy CMV seropositive controls. Levels of soluble B cell activating factor (sBAFF) were higher in patients and correlated with levels of CMV antibodies, but this relationship was unclear in healthy CMV seropositive controls. In HIV patients, their CD8 T cell IFNγ responses against VLE peptide of the CMV IE1 protein persisted. Age was a strong factor correlated with CD57+CD45RA+CD27- expression on CD8 T-cells. This senescent phenotype also exhibited associations with antibodies against the CMV IE1 protein and CD4 T cell IFNγ response to CMV lysate. These results point towards an “accelerated” immune ageing effect which similar to the normal ageing process, with increased immune activation and increased levels of inflammation potentiated by periodic CMV reactivation. These observations show that CMV leaves a long-lasting effect on the immune system of HIV patients even after 12 years on ART. Extending this study in a cohort including CMV-seronegative HIV patients, CMV-DNA viral assessments and evaluation of phenotype and function of CMV-specific CD8 T cells can further elucidate how CMV reactivation promotes accelerated ageing of the immune system.
In sum, carriage of TNFA-1031*T, IL10-1082 and SLC11A1 D543N stood out the most as potential genetic markers of susceptibility in mycobacterial and CMV disease. Genetic haplotype studies looking into inflammatory markers such as tumour necrosis factor, IL10 and SLC11A1 SNPs should be further investigated in larger cohorts. Subsequent studies should investigate patterns of linkage disequilibrium to determine whether the associations observed here reflect ethnic differences in the haplotypic structure across critical genes. Functional studies investigating the effects of these SNPs may evolve into successful therapeutics for these diseases.
|Qualification||Doctor of Philosophy|
|Publication status||Unpublished - 2014|