Immune activation and cigarette smoke exposure as potential determinants of failure of haart in the setting of mother-to- child transmission

Abstract

Persistent immune activation, even in the setting of virologically-suppressive HAART, is a hallmark of chronic immunodeficiency virus type (HIV-1) infection and a major force driving HIV-1 replication and progression to AIDS. Little is known about immune activation profiles and the effect of therapy in children infected with HIV-1 subtype C. The objectives of this study were to i) investigate and compare levels of circulating biomarkers of immune activation in a cohort of mothers (n=46) infected with HIV-1 subtype C relative to those of 20 healthy controls; ii) compare the biomarkers of immune activation between mothers and their HIV-infected children (n=46); iii) monitor the effects of virologically suppressive and non-suppressive HAART immune activation profiles in a subgroup of children (n=28) and iv) determine the effects of active smoking as well as maternal smoking on the biomarkers of immune activation in the mothers and their children, respectively. Multiplex bead array, ELISA and immunonephelometric procedures were used to measure plasma levels of the following biomarkers of immune activation: soluble CD14 (sCD14), beta 2 microglobulin (β2M), C-reactive protein (CRP), interferon gamma (IFNγ), monokine induced IFNγ, IFNγ-inducible protein 10 (IP10), tumour necrosis factor α (TNFα), macrophage inflammatory protein α and β (MIP-1α and β), transforming growth factor β (TGFβ), interleukin-1 receptor antagonist (IL-2 Ra), granulocyte- and granulocyte macrophage colony stimulating factors (G-CSF and GM-CSF), and several interleukins including IL-2, IL-4, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, and IL-17. Relative to the healthy control subjects, almost all of the circulating biomarkers of immune activation, including sCD14, β2M, CRP, MIG, IP10, IFNγ, TNFα,TGFβ and several of the interleukins and colony stimulating factors, were elevated in the HIV-infected mothers (P=0.0346-P<0.0001). The biomarker levels of the children were generally lower than those of the mothers with the exception of β2M which was significantly higher (P=0.001). Virologically suppressive HAART caused decreases in sCD14, β2M and MIG in a subgroup of the children (P=0.0286-P<0.0001) while sCD14 and MIG were increased in the treatment failure groups relative to the suppressed groups (P=0.0407-0.0002). An unexpectedly high number of mothers were smokers (21.7%); however no significant differences were observed between the non-smokers and smokers. In children exposed to maternal smoking, TGFβ levels were higher (P=0.0288). In conclusion, although somewhat lower than those of their mothers, HIV-infected children were found to have high levels of a range of circulating biomarkers of immune activation in the setting of higher viral loads. Successful HAART with virological suppression and increased levels of CD4+ T lymphocytes, was associated with significant decreases in some of the biomarkers, notably sCD14, beta 2 microglobulin and MIG, in children. Maternal smoking was associated with a significant increase in the concentration of immunosuppressive TGFβ in children, however further studies in larger groups are necessary.