Systemic Immune Activation Profiles of HIV-1 Subtype C-Infected Children and Their Mothers

Abstract

Little is known about immune activation profiles of children infected with HIV-1 subtype C. The current study compared levels of selected circulating biomarkers of immune activation in HIV-1 subtype C-infected untreated mothers and their children with those of healthy controls. Multiplex bead array, ELISA, and immunonephelometric procedures were used to measure soluble CD14 (sCD14), beta-2 microglobulin (β2M), CRP, MIG, IP-10, and transforming growth factor beta 1 (TGF-β1). Levels of all 6 biomarkers were significantly elevated in the HIV-infected mothers and, with the exception of MIG, in their children (P < 0.01–P < 0.0001). The effects of antiretroviral therapy (ART) and maternal smoking on these biomarkers were also assessed. With the exception of TGF-β1, which was unchanged in the children 12 months after therapy, initiation of ART was accompanied by decreases in the other biomarkers. Regression analysis revealed that although most biomarkers were apparently unaffected by smoking, exposure of children to maternal smoking was associated with a significant increase in IP-10. These findings demonstrate that biomarkers of immune activation are elevated in HIV-infected children pre-ART and decline, with the exception of TGF-β1, after therapy. Although preliminary, elevation of IP-10 in smoke-exposed infants is consistent with a higher level of immune activation in this group.

The Role of Transforming Growth Factor Beta-1 in the Progression of HIV/AIDS and Development of Non-AIDS-Defining Fibrotic Disorders

“…Worryingly, however, several studies have reported that even in the face of administration of virally suppressive HAART for periods of 6–12 months, circulating levels of both Tregs and TGF-β1 remained elevated. This appears to be consistent with ongoing chronic immune activation and its associated risks of persistent, albeit of lesser magnitude, immunosuppression, and development of HIV-associated, non-AIDS-defining conditions ( 6 , 7 , 51 – 53 ).…”

“…As mentioned above, increases in the concentrations of TGF-β1 in the circulation of HIV-1 infected patients have been reported in several studies, and, in one of these, were found to be highly correlated with increased numbers of circulating Tregs ( r = 0.921, p = 0.001) ( 52 ), indicating that the cytokine is likely to originate predominantly from Tregs. This contention is supported by findings that elevated numbers of circulating Tregs and concentrations of TGF-β1 correlate with increased levels of circulating biomarkers of chronic immune activation (monocyte- and lymphocyte-derived activation markers) and bacterial translocation ( 51 – 53 ). As mentioned earlier, these are considered to be major drivers of immunosuppression and progression to AIDS ( 3 – 5 , 62 ).…”

“…Possibly the first article documenting increases of plasma/serum TGF-β in treatment naive male patients with AIDS was published by Allen et al ( 47 ). Several later reports also documented increased concentrations of this cytokine in the blood, lymphoid tissues and cerebrospinal fluid of HIV-infected individuals ( 6 , 48 – 53 ). In addition, two other earlier studies reported that isolated peripheral blood mononuclear cells (PBMCs) from HIV-infected persons spontaneously released high levels of TGF-β, which was associated with selective upregulation of the TGF-β1 isoform ( 54 , 55 ).…”

Effects of Tobacco Usage and Antiretroviral Therapy on Biomarkers of Systemic Immune Activation in HIV-Infected Participants

“…According to the findings of two studies, South African HIV-infected participants, particularly males, like their European and North American counterparts, have high rates of cigarette smoking with frequencies of 52–71% recorded in males and 13–28% in females [34, 37, 53], with somewhat lower rates recorded in another study which was undertaken at the same HIV clinic as the current study [54].…”

“…The selection of biomarkers used in this study was based on previous findings with the inclusion of several additional markers [33, 34].…”