Inflammation and Immune Activation in HIV infection

Abstract

Although widespread availability of antiretroviral therapy (ART) has markedly enhanced survival in HIV-1 infected individuals, its long-term use and cessation has been linked to an increase in non-AIDS morbidity and mortality. The pathogenesis of these complications is thought to reflect excessive immune activation and inflammation. The SMART trial showed that in chronic HIV-1 infection, inflammatory and coagulation biomarkers were predictive of all cause mortality, and that stopping ART lead to a rise in these biomarkers. The impact of interrupting ART started in primary HIV-1 infection (PHI) on these biomarkers is unknown. This thesis examines the effect of different stages of HIV-1 infection on markers of inflammation, coagulation and immune activation, and focuses on the effects of short-course ART in participants enrolled in the SPARTAC trial; a blinded RCT investigating the role of short-course ART versus no therapy in PHI. Baseline parameters associated with biomarkers of inflammation, coagulation, immune activation, endothelial activation and microbial translocation, and the effect of starting and stopping ART on IL-6 and D-dimer levels, were examined in SPARTAC participants. Viral dynamics on treatment discontinuation were compared in PHI (SPARTAC) to chronic infection (SMART). The majority of biomarkers were raised in HIV-1 infected individuals compared to healthy controls and highly correlated with HIV RNA levels. Viral and host factors, including age, HLA type and viral tropism, determined levels of T-cell activation. IL-6 and D-dimer fell significantly on commencing ART but rebounded to baseline levels within 4 weeks of stopping. Viral rebound after stopping ART initiated in PHI was lower than that observed in chronic infection. This work highlights factors associated with immune activation and inflammation in PHI, which could potentially be used to identify individuals at high risk of disease progression. Immune activation and inflammation are influenced by direct effects of the virus, ART and other variables. The clinical impact of these findings warrants further investigation.