Oxygen Levels Affect Macrophage HIV-1 Gene Expression and Delay Resolution of Inflammation in HIV-Tg Mice

Abstract

While antiretroviral therapy increases the longevity of people living with HIV (PLWH), about 30% of this population suffers from three or more concurrent comorbidities, whose mechanisms are not well understood. Chronic activation and dysfunction of the immune system could be one potential cause of these comorbidities. We recently demonstrated reduced macrophage infiltration and delayed resolution of inflammation in the lungs of HIV-transgenic mice. Additionally, trans-endothelial migration of HIV-positive macrophages was reduced in vitro. Here, we analyze macrophages' response to LPS challenge in the kidney and peritoneum of HIV-Tg mice. In contrast to the lung infiltration, renal and peritoneal macrophage infiltrations were similar in WT and HIV-Tg mice. Higher levels of HIV-1 gene expression were detected in lung macrophages compared to peritoneal macrophages. In peritoneal macrophages, HIV-1 gene expression was increased when they were cultured at 21% O 2 compared to 5% O 2 , inversely correlating with reduced trans-endothelial migration at higher oxygen levels in vitro. The resolution of macrophage infiltration was reduced in both the lung and the peritoneal cavity of HIV-Tg mice. Taken together, our study described the organ-specific alteration of macrophage dynamics in HIV-Tg mice. The delayed resolution of macrophage infiltration might constitute a risk factor for the development of multiple comorbidities in PLWH.

Human iPSC-derived neurons reveal NMDAR-independent dysfunction following HIV-associated insults

“…We were then curious whether the resistance to neurotoxicity observed across a variety of HIV supernatant paradigms in i 3 neurons was a general resistance to the activated myeloid cell secretome, or specific to HIV. Previous studies have used bacterial lipopolysaccharide (LPS) to activate myeloid cells and induce neurotoxicity, especially in the context of HIV infection ( Jiang et al, 2001 ; Gajanayaka et al, 2017 ; Jerebtsova et al, 2020 ). Beyond its usefulness as a known immune activator, LPS is clinically relevant in the context of HIV infection, where gut microbial translocation leads to increased levels of plasma LPS ( Nottet et al, 1996 ; Kumar et al, 2016 ).…”

Targeting Tat–TAR RNA Interaction for HIV-1 Inhibition

“…Thus, the early steps of HIV-1 infection including entry, binding and reverse transcription are not likely to be affected by the compounds. The utility of HIV-1 transcription inhibitors is highlighted by our recent study in which the activation of HIV-1 in macrophages was the major contributing factor to lung inflammation in HIV-1 transgenic (HIV-Tg) mice [25,26]. Treatment of HIV-Tg mice with 1E7-03, an HIV-1 transcription inhibitor, ameliorated LPS-induced lung inflammation and prevented mice death [26].…”

Targeting Tat-TAR RNA Interaction for HIV-1 Inhibition

“…Thus, the early steps of HIV-1 infection including, entry, binding and reverse transcription are not likely to be affected by the compounds. Utility of HIV-1 transcription inhibitors is highlighted by our recent study in which activation of HIV-1 in macrophages was the major contributing factor to lung inflammation in HIV-1 transgenic (HIV-Tg) mice [15,16].…”