An NIAID study suggests that the increased frequency of an immune cell called CD14++CD16- monocyte is a strong indicator that a patient with HIV and tuberculosis (TB) may develop complications from anti-HIV drugs. For unclear reasons, a subset of people with both HIV and TB experience worsening of their TB symptoms after starting antiretroviral therapy (ART) to treat HIV. The study, which appears in the October 2, 2014, issue of PLOS Pathogens, offers a better understanding of why this may occur.
According to the World Health Organization, there were an estimated 35 million HIV-infected people in 2013. For this population, TB is the most common life-threatening infection. In most cases, antiretroviral therapy (ART) used to treat HIV also will improve TB. However, a subset of patients who begin ART will experience a worsening of TB, a disorder called immune reconstitution inflammatory syndrome (IRIS).
Scientists are unsure why ART triggers IRIS in some patients. They know that the disease is not directly caused by infectious microbes, but rather, by an overactive immune response. Previous studies have examined CD4+ T cells, which are immune cells restored to healthy levels by ART. However, no single cell type has been implicated in IRIS. Researchers also have looked at blood biomarkers -- substances that indicate a disorder is forthcoming or has occured -- to understand differences between patients.
Results of Study
NIAID researcher Irini Sereti, M.D., chief of the HIV Pathogenesis Unit in the Laboratory of Immunoregulation, and Bruno Andrade, M.D., Ph.D., from the Laboratory of Parasitic Diseases, led a study examining cells called monocytes, which are involved in innate immunity, or the first line of immune defense against pathogens. Monocytes are known to produce several IRIS biomarkers, but these cells had not been profiled in IRIS patients.
Collaborating with the National Institute for Research in Tuberculosis in Chennai, India, and the Institute of Infectious Disease and Molecular Medicine in Cape Town, South Africa, the team examined samples taken from two groups of coinfected patients. They found that CD14++CD16- monocytes were elevated, both before and after ART, in patients who later developed IRIS. For patients who did not develop IRIS, the frequency of this cell was lower after ART.
The researchers speculate that CD14++CD16- monocytes cause IRIS when overstimulated by CD4+ T cells -- the targets of HIV infection. When ART brings these cells to healthy levels, a patient with high levels of CD14++CD16- monocytes may be predisoposed to develop IRIS. To test this hypothesis, the team used blood samples from a group of patients from North America who only had HIV. When these patients' cells were exposed to TB bacteria, the CD14++CD16- monocytes produced the majority of IRIS-associated biomarkers, implying a role for these cells in the development of the disease.
The study is the first to link a an innate immune cell, CD14++CD16- monocyte, to the development of IRIS. If these results hold firm in additional patients, monocytes may be used to identify patients at-risk for the disease. In addition, CD14++CD16- monocytes may be studied further as potential therapeutic targets for IRIS treatment and prevention.
NIAID researchers are enrolling HIV patients in a clinical trial at the NIH Clinical Center to expand upon this study. They aim to assess what cell types are present in the tissues of HIV patients before they begin ART, and how these cells may contribute to IRIS. For more information, visit www.clinicaltrials.gov and use the trial identifier NCT02147405.
Andrade BB, Singh A, Narendran G, Schechter ME, Nayak K, Subramanian S, Anbalagan S, Jensen SMR, Porter BO, Antonelli LR, Wilkinson KA, Wilkinson RJ, Meintjes G, Van der Plas H, Follmann D, Barber DL, Swaminathan S, Sher A, Sereti I. Mycobacterial antigen driven activation of CD14++CD16- monocytes is a predictor of tuberculosis-associated immune reconstitution inflammatory syndrome. Plos Pathogens (2014)
Dr. Sereti's Laboratory