Immune dysregulation in HIV patients following successful ART Dino Tan, Yean Kong Yong, Hong Yien Tan, Adeeba Kamarulzaman, Lian Huat Tan, Andrew Lim,

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Immune dysregulation in HIV patients following successful ART Dino Tan, Yean Kong Yong, Hong Yien Tan, Adeeba Kamarulzaman, Lian Huat Tan, Andrew Lim, Martyn French, Patricia Price Hypothesis: Immune restoration disease (IRD) in ART-treated HIV patients is caused by immune dysregulation which may involve: - Excessive antigen-specific IFNγ responses - High proportions of activated CD4+ T-cells - Deficiency of regulatory CD4+ T-cells (T-regs) Objectives: To investigate the immunological characteristics of IRD from a cohort of HIV patients (n=47) commencing ART at the Infectious Disease Outpatient Clinics in University Malaya Medical Centre, Kuala Lumpur, Malaysia

Study design 2 Cryptococcal IRD & 3 TB IRD patients 8 Non-IRD patients 17 HIV-negative Healthy controls Matched by ethnicity (Chinese), gender (male) and age All HIV patients selected: Started ART with <100 CD4+ T-cells/μl Suppressed viral replication & recovered CD4+ T-cells on ART PBMC were collected at 0, 6, 12, 24 and 48 weeks ELISpot IFNγ responses to Cryptococcus neoformans PPD, ESAT-6 & CMV Flow cytometry Activated (HLA-DRhi) CD4+ T-cells (CD25+CD127lo) CD4+ T-regs (CTLA-4+) CD4+ T-regs

Increased IFNγ responses & proportions of activated CD4+ T-cells during IRD are not associated with reduced CD4+ T-regs IFNγ response peaks during IRD IFNγ response peaks at IRD Activated CD4+ T-cells high during IRD Activated CD4+ T-cells increased during IRD Cryptocoocus neoformans specific IFNγ producing cells (% of CD4+ T-cells) HLA-DRhi Weeks on ART Weeks on ART CTLA-4+ (% of CD4+ T-cells) CD25+CD127lo (% of CD4+ T-cells) CD4+ T-regs high during IRD Weeks on ART Cryptococcal IRD patients Non-IRD patients Healthy controls (median) Healthy controls (interquartile range)