HIV-derived ssRNA binds to TLR8 to induce inflammation-driven macrophage foam cell formation

Area of Science:

• Immunology
• Cardiovascular Research
• Virology

Background:

• Combined anti-retroviral therapy (cART) improves survival for HIV+ patients but increases non-infectious complications like cardiovascular disease (CVD).
• Persistent inflammation and chronic immune activation are linked to increased CVD risk in individuals with HIV.
• HIV-derived single-stranded RNAs (ssRNAs) may contribute to this inflammatory process.

Purpose of the Study:

• To investigate if HIV ssRNAs induce TNFα release and foam cell formation in macrophages via Toll-like receptor 8 (TLR8) activation.
• To elucidate the mechanism of HIV ssRNA-induced inflammation and foam cell formation.
• To identify potential therapeutic targets for reducing CVD risk in HIV+ patients.

Main Methods:

• HIV ssRNAs were used to induce foam cell formation in monocyte-derived macrophages (MDMs).
• Endocytosis and endosomal acidification inhibitors (dynasore, chloroquine) were used to assess cellular uptake and processing.
• Flow cytometry FRET assay confirmed ssRNA binding to TLR8 in HEK cells and MDMs.
• TLR8 and MYD88 gene silencing and anti-TNFα neutralizing antibody were employed to investigate signaling pathways.

Main Results:

• HIV ssRNAs induced dose-dependent foam cell formation in MDMs.
• Inhibition of endocytosis and endosomal acidification reduced this response.
• ssRNAs were shown to bind TLR8, triggering a TLR8-mediated inflammatory response and TNFα release, leading to foam cell formation.
• Silencing TLR8/MYD88 and blocking TNFα significantly reduced foam cell formation.

Conclusions:

• HIV ssRNAs are internalized, bind TLR8 within endosomes, and trigger TNFα release, ultimately causing foam cell formation in MDMs.
• This pathway contributes to chronic inflammation and immune activation associated with CVD risk in HIV+ individuals.
• Targeting HIV ssRNA-driven TLR8 activation presents a potential therapeutic strategy to mitigate CVD in HIV+ patients.