The high frequency of autoantibodies in HIV patients declines on antiretroviral therapy.

Autoantibodies have been described in samples from HIV positive patients, but the effects of antiretroviral therapy (ART) remain unclear. In a retrospective longitudinal study, we applied clinical assays for autoantibodies to sera collected from 13 HIV positive patients as they began ART with <210 CD4 T-cells/µL and over 2 years on treatment. Twelve of the 13 patients had at least one autoantibody. The frequency peaked before ART (21 from 156 assays) and declined to 8/143 positive reactions after 2 years. As anti-smooth muscle (ASM) antibodies remained common, these assays were applied to HIV patients (n = 67) who had <50 copies HIV RNA/mL plasma after 13 (2-17) years on ART, and healthy controls (n = 55). The frequency of ASM was high in these patients and correlated with levels of total IgG. Hence the high frequency of autoantibodies before ART declined, but did not disappear, with successful therapy. Autoantibody levels may reflect B-cell hyperactivity in patients stable on ART.

Short Communication: Do Cytomegalovirus Antibody Levels Associate with Age-Related Syndromes in HIV Patients Stable on Antiretroviral Therapy?

HIV(+) persons stable on antiretroviral therapy (ART) face early onset of age-related diseases. This may arise from a high burden of cytomegalovirus (CMV). To address the role of CMV, we investigated univariate and multivariate associations between markers of systemic and endothelial inflammation, vascular damage, insulin resistance (IR), neurocognitive decline, and antibodies reactive with CMV. In this study, HIV(+) participants (n = 91) aged >45 years with <50 copies HIV RNA/ml plasma after >2 years on ART were assessed for cardiovascular risk (the D:A:D algorithm), type II diabetes (the HOMA-IR index), and neurocognitive performance. Blood samples were assayed for lipids, T cells, insulin, glucose, C-reactive protein, CX3CL1, sTNF-R1, total immunoglobulin G (IgG), and antibodies reactive with CMV lysate, glycoprotein B, or immediate-early-1. Levels of antibodies detected with the three antigens were tightly correlated. Levels of CMV lysate antibody were higher in patients than in age-matched healthy controls and reflected their nadir CD4 T-cell count (p = .001), total IgG (p = .02), and age (p = .08). Levels of CMV lysate antibody correlated with D:A:D score (p = .04), neurocognitive performance (p = .045), and fasting insulin (p = .02). In multivariable analyses, some associations reflected the effect of age, but CMV lysate antibody and CD8 T-cell counts were significant predictors of the HOMA-IR index (R(2) = 0.09, p = .01) independent of age. We conclude that associations between levels of CMV antibodies, cardiovascular risk, and neurocognitive health in HIV(+) patients stable on ART are moderated by age-associated increases in response to CMV, while CMV antibodies may be independently linked with IR.

The immunological footprint of CMV in HIV-1 patients stable on long-term ART.

BACKGROUND: Most HIV-infected persons are cytomegalovirus (CMV) seropositive and retain latent virus that can be reactivated by immune activation. Their T cell populations express markers reflecting a late stage of differentiation, but the contributions of HIV and CMV to this profile are unclear. We investigated the immunological "footprint" of CMV in HIV patients who had a history of extreme immunodeficiency but were now stable on antiretroviral therapy (ART). RESULTS: Twenty CMV seropositive HIV patients >50 years old with nadir CD4 T-cell counts <200 cells/µl were studied after >12 years on ART. 16 CMV seropositive and 9 CMV seronegative healthy controls were included. CMV antibody titres were higher in HIV patients than controls (P < 0.001-0.003). Levels of soluble B-cell activating factor (sBAFF) were elevated in patients (P = 0.002) and correlated with levels of CMV antibodies (P = 0.03-0.002), with no clear relationship in controls. CD8 T-cell IFNγ responses to the IE1 peptide (VLE) remained elevated in HIV patients (P = 0.005). The CD57(+)CD45RA(+)CD27(-) phenotype of CD8 T-cells correlated with age (r = 0.60, P = 0.006), antibodies against CMV IE1 protein (r = 0.44, P = 0.06) and CD4 T-cell IFNγ response to CMV lysate (r = 0.45, P = 0.05). CONCLUSIONS: Humoral and T-cell responses to CMV remained elevated in HIV patients after >12 years on ART. Age and presence of CMV disease influenced CD8 T-cell phenotypes. Elevated levels of sBAFF may be a consequence of HIV disease and contribute to high titres of CMV antibody.

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.

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.