Gues show that the HIV Nef also disrupts cholesterol trafficking machinery

To see irrespective of whether Nef may possibly affect efflux impairment, the authors infected macrophages with HIV strains carrying either a functional or mutated Nef gene (recognized to influence cholesterol binding and delivery). Cholesterol efflux to Title Loaded From File ApoA-I was "substantially reduced" in cells infected with functional Nef. In contrast, cholesterol efflux in cells infected with Nef-deficient strains was similar to that observed in uninfected cells--allowing the authors to conclude that HIV needs Nef to block cholesterol efflux.Cholesterol is removed from macrophages by proteins named ATPbinding cassette (ABC) transporters, which hand off their cargo to distinctive molecules. Getting shown that Nef hinders efflux to apoA-I, the authors reasoned that Nef does so by targeting apoA-I's donor--ABCA1. By stopping the normal efflux of cholesterol from macrophages, Nef ensures that nascent virions have access to a steady provide of cholesterol. Unfortunately, what's excellent for the virus causes a lot more trouble for any individual infected with HIV: reduced cholesterol efflux from macrophages may possibly clarify why patients with HIV face enhanced risk of atherosclerosis and coronary artery illness. Ordinarily, excess cholesterol is exported to molecules within the extracellular space. The authors located that cholesterol efflux to anPLoS Biology | www.plosbiology.orgDOI: 10.1371/journal.pbio.0040400.gHIV-infected monocyte-derived macrophages show lipid accumulation (lipids are stained red) in HIV-infected cells. (Image: Zahedi Mujawar)extracellular molecule called apoAI was impaired in HIV-infected macrophages. Reduce levels of efflux correlated with higher levels of viral replication. To find out whether Nef may possibly impact efflux impairment, the authors infected macrophages with HIV strains carrying either a functional or mutated Nef gene (recognized to have an effect on cholesterol binding and delivery). Cholesterol efflux to apoA-I was "substantially reduced" in cells infected with functional Nef. In contrast, cholesterol efflux in cells infected with Nef-deficient strains was related to that seen in uninfected cells--allowing the authors to conclude that HIV demands Nef to block cholesterol efflux.Cholesterol is removed from macrophages by proteins known as ATPbinding cassette (ABC) transporters, which hand off their cargo to diverse molecules. Having shown that Nef hinders efflux to apoA-I, the authors reasoned that Nef does so by targeting apoA-I's donor--ABCA1. This conclusion is supported by two lines of proof: stimulating expression of ABCA1 in infected cells substantially decreased Nef-mediated impairment of efflux to ApoA-I, but efflux was unaffected when ABCA1 levels were quite low. Nef mediates these effects, the authors show, by especially downregulating ABCA1 just after transcription and limiting its abundance, and by maintaining ABCA1 sequestered at the membrane. Regardless of whether these mechanisms function in tandem or operate independently is actually a question for future study. HIV-infected macrophages that expressed Nef not simply contained far more lipid-containing vacuoles than uninfected cells or cells infected with Nef-deficient HIV, they also synthesized molecules linked with cholesterol accumulation and cholesterol-laden "foam cells." And when the authors analyzed atherosclerotic plaque sections taken from patients with HIV who had been treated with antiretroviral therapy (HAART), they found HIV-infected, cholesterol-laden macrophages in the atherosclerotic plaque--suggesting that these cells contribute to arterial disease. Altogether, the results show that HIV inhibits cholesterol efflux via Nef, major to cholesterol accumulation and foam cell formation.