Abstract:
There is increasing awareness of an association between the uptake of the HIV integrase inhibitor,
dolutegravir, in first-line antiretroviral regimens with unusual weight gain and development
of the metabolic syndrome, particularly in African women. Although seemingly unexplored, the development
of systemic inflammation linked to the putative pro-inflammatory activity of dolutegravir
represents a plausible pathophysiological mechanism of this unusual weight gain. This possibility
was explored in the current study undertaken to investigate the effects of dolutegravir (2.5–20 g/mL)
on several pro-inflammatory activities of neutrophils isolated from the blood of healthy, adult humans.
These activities included the generation of reactive oxygen species (ROS), degranulation (elastase
release) and alterations in the concentrations of cytosolic Ca2+ using chemiluminescence, spectrophotometric
and fluorimetric procedures, respectively. Exposure of neutrophils to dolutegravir alone
resulted in the abrupt, dose-related, and significant (p < 0.0039–p < 0.0022) generation of ROS that
was attenuated by the inclusion of the Ca2+-chelating agent, EGTA, or inhibitors of NADPH oxidase
(diphenyleneiodonium chloride, DPI), phospholipase C (U733122), myeloperoxidase (sodium azide)
and phosphoinositol-3-kinase (wortmannin). In addition, exposure to dolutegravir augmented the
release of elastase by stimulus-activated neutrophils. These pro-inflammatory effects of dolutegravir
on neutrophils were associated with significant, rapid, and sustained increases in the concentrations
of cytosolic Ca2+ that appeared to originate from the extracellular compartment, seemingly consistent
with an ionophore-like property of dolutegravir. These findings are preliminary and necessitate
verification in the clinical setting of HIV infection. Nevertheless, given the complex link between
inflammation and obesity, these pro-inflammatory interactions of dolutegravir with neutrophils may
contribute to unexplained weight gain, possibly via the development of insulin resistance.
