Biomarkers of immune dysfunction following combination antiretroviral therapy for HIV infection

A large number of biomarkers have been evaluated in HIV-infected patients and have largely been used to predict clinical outcome, including AIDS and death. Given the widespread availability of combination antiretroviral therapy (cART) and the ability of cART to reduce morbidity and mortality, this article primarily focuses on biomarkers of interest in HIV-infected patients receiving cART, with an emphasis on the effect of microbial translocation and immune activation. Following cART, many patients continue to demonstrate ongoing immune abnormalities and patients are at an increased risk of non-AIDS events including cardiovascular disease (CVD) and malignancy. Some of these biomarkers are in early clinical development while others have been evaluated in larger clinical trials and cohorts to determine whether they can predict adverse clinical outcomes in patients on cART. Most of these biomarkers are not yet used in routine clinical practice but are currently being evaluated to understand the pathogenesis of immune dysfunction in patients on cART, identify patients at highest risk of immune dysfunction and non-AIDS events, such as CVD and malignancy, and develop novel immunotherapeutic approaches that could be used in addition to cART.

HIV pathogenesis & response to cART

The physiological hallmark of HIV infection is the destruction of CD4⁺ T cells and persistent immune activation. HIV predominantly infects activated CD4⁺ T cells, resulting in productive viral infection [1], and a rapid and profound depletion of GI tract-associated CD4⁺ T cells, leading to loss of integrity of the intestinal mucosa [2,3]. The depletion of GI tract CD4⁺ T cells has been associated with increased translocation of microbial products from the intestinal lumen into the blood stream, which can trigger the innate immune system to produce proinflammatory cytokines and chronic immune activation [3]. However, the pathogenesis of immune activation is complex and multifactorial. In addition to the translocation of microbial products, immune activation is believed to be driven by direct infection of CD4 ⁺ T cells and release of cytokines, a combination of innate and adaptive immune responses against viral antigens and/or secondary infections, and an imbalance in the immune response caused by the loss of T regulatory and central memory T cells (reviewed in [4]).

Combination antiretroviral therapy has led to a dramatic reduction in mortality and morbidity in...