Active and Persistent Cytomegalovirus Infections Affect T Cells in Young Adult HIV Patients Commencing Antiretroviral Therapy

Abstract

Altered T cell profiles have been linked with metrics of persistent cytomegalovirus (CMV) infections in healthy aging and older HIV patients stable on antiretroviral therapy (ART). In this study, we use CMV DNA to identify active infections, and levels of CMV-reactive antibody to assess the persistent burden of CMV in a longitudinal study of 78 young adult patients beginning ART in Jakarta, Indonesia, with <200 CD4 T cells/μL. CMV antibodies, inflammatory markers (C-reactive protein [CRP], soluble interferon-α/β receptor) and T cell phenotypes were assessed before ART (V0) and after 1, 3, 6, and 12 months (V1-V12). CMV DNA was detected in 41 patients (52%) at V0, irrespective of CD4 T cell counts, gender, age, or plasma HIV RNA. CMV DNA+ patients had higher levels of antibody reactive with CMV Immediate Early 1 (IE-1) at V0 and V12 (p = 0.04), and with CMV lysate at V12 (p = 0.01). Detectable CMV DNA did not align with inflammatory markers, but associated with lower CD4/CD8 ratios until V3. CMV antibody levels correlated inversely with proportions of naive CD4 and CD8 T cells, and directly with proportions of CD57 and activated memory T cells (CD3 CD45RA) after 3-12 months on ART. Overall, active CMV replication is common in HIV patients beginning ART in Indonesia and associates with low CD4/CD8 ratios. Elevated levels of CMV-reactive antibody measured on ART also mark a depletion of naive T cells, accumulation of memory T cells, and may be a stable metric of the burden of CMV.

Sequencing Directly from Clinical Specimens Reveals Genetic Variations in HCMV-Encoded Chemokine Receptor US28 That May Influence Antibody Levels and Interactions with Human Chemokines

“…This may reflect the high levels of HCMV replication in the source population, HIV patients beginning ART. Fifty-two percent were HCMV DNA positive when assessed with a simple qPCR detecting UL54 ( 35 ). This assay was optimized in our Australian laboratory, but the frequency of detection in Australian RTR was notably lower (13%) ( 36 ).…”

“…The JakCCANDO project is a comprehensive survey of clinical and immunological responses to ART undertaken in Cipto Mangunkusumo Hospital’s outpatient clinic (Jakarta, Indonesia) ( 35 ). Eighty-two ART-naive HIV patients were enrolled during 2013 to 2014 with <200 CD4 T cells/μl.…”

“…Results are presented as arbitrary units (AU)/ml based on a standard plasma pool, allowing comparisons between people but not between antigens ( 27 , 45 ). Soluble receptors for interferon-α/β were assessed in plasma using human IFNAR2 ELISA kits (generously provided by PBL Assay Science, Piscataway, NJ) ( 35 ).…”

Cytomegalovirus may influence vascular endothelial health in Indonesian HIV-infected patients after 5 years on ART

“…JakCCANDO was a comprehensive survey of clinical and immunological responses in 75 HIV-infected patients who began ART with < 200 CD4 T-cells/µl in the HIV outpatient clinic of a tertiary hospital (Cipto Mangunkusumo Hospital, Jakarta, Indonesia) [ 5 , 6 , 11 ]. Here we describe a subset of 32 patients who attended a 5-year follow up ( V isit 60 ).…”

“…FMD was independently predicted by high levels of antibodies reactive with cytomegalovirus (CMV) in renal transplant recipients [ 4 ]. CMV is addressed here in Indonesian HIV patients (the JakCCANDO study) with a very high CMV burden [ 5 , 6 ]. In this population, changes to cIMT and cardiac parameters were small in the first year on ART [ 5 ].…”