HIV-1 Nef mobilizes lipid rafts in macrophages through a pathway that competes with ABCA1-dependent cholesterol efflux

Abstract

This article is available online at http://www.jlr.org Supplementary key words cholesterol metabolism • cholesterol traffi cking • ATP binding cassette transporter A1 • human immunodeficiency virus Impairment of cholesterol metabolism plays a key role in pathogenesis of many disorders, most importantly cardiovascular and neurodegenerative diseases. Many infectious agents, from prions to parasites, affect cholesterol metabolism of the host. Microorganisms modify host cholesterol metabolism for two main reasons: to satisfy their own requirements for cholesterol at different stages of their life cycle, and to weaken the immune response of the host. These modifi cations may cause "unintended" consequences, triggering development of diseases that are not directly related to infection. This situation is exemplifi ed by the increased risk of atherosclerosis coincident with HIV infection. Targeting cholesterol metabolism for antimicrobial intervention, while at the same time correcting metabolic consequences of the infection, is a tempting possibility limited by the lack of knowledge about mechanisms of interaction between microorganisms and pathways of cholesterol metabolism in host cells.

HIV-1 Protein Nef Inhibits Activity of ATP-binding Cassette Transporter A1 by Targeting Endoplasmic Reticulum Chaperone Calnexin

“…As a result, Env maturation may be optimized while that of ABCA1 is impaired, leading to retention of ABCA1 in the ER and its subsequent degradation. Nef may also stimulate internalization and lysosomal degradation of cell surface ABCA1 (7). The proposed model is in part speculative, as not all of its elements have been proven; however, it is consistent with our findings and those of others.…”

“…2C, panels b, d, and e), indicating ER association, whereas in Nefnegative cells ABCA1 was well represented on the periphery of the cells. Reduction of cell surface ABCA1 is likely due both to prevention of ABCA1 delivery from ER to the plasma membrane and internalization and degradation of ABCA1 that had been delivered (7). Histograms showing frequency distribution of mean fluorescence intensities (MFI) in 271 Nef-positive and 257 Nef-negative randomly selected cells are shown in Fig.…”

Stimulation of Liver X Receptor Has Potent Anti-HIV Effects in a Humanized Mouse Model of HIV Infection

“…This is most likely due to very low levels of ABCA1 expression in T cells. In addition, a small increase of ABCA1 observed in T0901317-stimulated PBLs from some donors (Cui et al, 2012) was very short-lived. Whereas we cannot rule out other possible reasons for the differences between PBLs and MDM in response to LXR agonist, we believe that different level of ABCA1 expression is the most likely explanation.…”

“…Because the main mechanism behind the suppressive effect of LXR agonists on HIV replication is reduction of lipid raft abundance (Morrow et al, 2010;Cui et al, 2012), we analyzed lipid raft content in T0901317-pretreated cells at various times after washing away the LXR agonist. As shown in Fig.…”

“…Reversion of this impairment by drugs stimulating ABCA1 expression, such as liver X receptor (LXR) agonists, inhibits HIV replication by reducing viral production and infectivity (Morrow et al, 2010). Importantly, the mechanism of anti-HIV activity of LXR agonists involves reduction of lipid rafts, the sites of HIV assembly (Cui et al, 2012), and reduction of cholesterol in the viral membrane required for effective fusion (Morrow et al, 2010), making it very difficult for the virus to acquire resistance to these agents. In this study, we tested whether LXR agonists can be used to treat and prevent HIV infection in humanized mice.…”