The Use of Humoral Responses as a Marker of CMV Burden in HIV Patients on ART Requires Consideration of T-Cell Recovery and Persistent B-Cell Activation

Abstract

Objectives. Elevated humoral responses to cytomegalovirus (CMV) associate with increased risk of cardiovascular disease (CVD) in HIV patients on antiretroviral therapy (ART). To better understand the persistence of CMV humoral responses in relation to CVD, we determined trends in CMV antibody levels over the first 10 years on ART. Design. We describe longitudinal analyses of plasma from 13 HIV patients commencing ART with <210 CD4 T-cells/µL and 27 controls. Antibodies reactive with CMV (fibroblast lysate, gB and IE-1 antigens), EBV-VCA, and HIVgp41 were quantitated. B-cell activation was assessed via total IgG and sBAFF. Inflammation was assessed via sTNF-RI and sCD14. Results. Amongst CMV seropositive HIV patients, levels of antibody reactive with CMV (P = 0.03) and EBV-VCA (P = 0.02) peaked after 1 year on ART. Levels of total IgG, sCD14, and sTNF-RI declined to approximate those in controls after 10 years, but sBAFF (P = 0.0002), EBV-VCA (P = 0.001), and CMV (P = 0.0004) antibodies remained elevated. A strong correlation between sBAFF and CMVgB antibody was seen at 10 years (R = 0.93, P = 0.0009) and verified in a second cohort. Conclusions. CMV antibody titres peak on ART and remain high. A correlation between CMV antibody and sBAFF suggests a role for HIV-induced B-cell pathology that may affect its use as a marker of CMV burden.

Elevated cytomegalovirus IgG antibody levels are associated with HIV-1 disease progression and immune activation

“…Similarly, among women on ART for a median of 4-5 months, we noted that elevated post-ART CMV IgG antibody levels were associated with higher plasma immune activation markers. There is considerable variability between studies in precisely which immune activation markers are associated with post-ART CMV IgG levels [11, 13, 26, 44-47] , but our findings are consistent with the model suggesting that CMV has a role in driving persistent immune activation during suppressive ART [25] . The durability of these associations require confirmation during long-term ART use.…”

The Association of Human Cytomegalovirus with Biomarkers of Inflammation and Immune Activation in HIV-1-Infected Women

“…There have been reports that HIV infection affects B cell function leading to nonspecific hypergammaglobulinemia. 18,46 Brunt et al 18 reported elevated levels of CMV and Epstein-Barr virus (EBV) antibodies over a period of 10 years after initiation of cART in a small group of nine CMV-seropositive patients. sCD14 levels were not associated with CMV antibody over this time period.…”

“…All of these biomarkers have been associated with a greater risk of cardiovascular disease and all-cause mortality as reported in several studies. 5,[12][13][14][15][16][17][18][19][20][21] Thus, it appears that the inflammatory response to CMV reactivation and replication could be linked to endothelial cell damage that in turn could lead to subclinical vascular changes and atherosclerosis. 6,8,[22][23][24] Although there have been multiple studies of CMV coinfection in HIV-infected patients, the results have not always been consistent, which may be attributed in part to differences in study populations and types of specimens analyzed.…”

Levels of CMV-reactive antibodies correlate with the induction of CD28null T cells and systemic inflammation in chronic obstructive pulmonary disease (COPD)

“…Levels of IgG and IgM reactive with a lysate of CMV-infected fibroblasts (CMV-lysate), CMV glycoprotein-B (CMV-gB) and CMV immediate early-1 antigen (CMV-IE-1) in plasma were measured by in-house ELISAs. 9 Three antigen preparations of CMV were used in our assay because CMV-lysate contains several CMV antigens, while antibodies to CMV-IE-1 arise during early CMV infection and antibodies against CMV-gB denotes previous infection. Plasma levels of soluble tumour necrosis factor receptor-1 (sTNFR1), a marker of systemic inflammation, were measured using a commercial ELISA kit (R&D Systems, Minneapolis, MN, USA).…”