New clues to understanding HIV nonprogressors: low cholesterol blocks HIV trans infection

Abstract

A small percentage of HIV-infected subjects (2 to 15%) are able to control disease progression for many years without antiretroviral therapy. Years of intense studies of virologic and immunologic mechanisms of disease control in such individuals yielded a number of possible host genes that could be responsible for the preservation of immune functions, from immune surveillance genes, chemokines, or their receptors to anti-HIV restriction factors. A recent mBio paper by Rappocciolo et al. (G. Rappocciolo, M. Jais, P. Piazza, T. A. Reinhart, S. J. Berendam, L. Garcia-Exposito, P. Gupta, and C. R. Rinaldo, mBio 5:e01031-13, 2014) describes another potential factor controlling disease progression: cholesterol levels in antigen-presenting cells. In this commentary, we provide a brief background of the role of cholesterol in HIV infection, discuss the results of the study by Rappocciolo et al., and present the implications of their findings.

FIG 1

Schematic depicting the role of ABCA1 expression levels in APCs during HIV-1 trans infection. Individuals with genetically determined high levels of ABCA1 gene expression have lower cholesterol levels than normal subjects in cells expressing ABCA1, such as DCs, whereas the cholesterol levels in cells where ABCA1 is not expressed, such as T cells, are similar in these two groups. The paper by Rappocciolo et al. suggests that HIV disease in individuals with high ABCA1 expression progresses more slowly than in normal individuals. They demonstrate an absence of trans infection of CD4⁺ T cells by DCs and B cells derived from NPs (individuals with high ABCA1 expression levels). Cholesterol depletion has been shown to inhibit HIV uptake by DCs. Therefore, high ABCA1 expression is expected to reduce HIV uptake and consequently trans infection. Trans infection proceeds through a virological synapse, which is formed with the participation of lipid rafts. Lipid rafts are reduced when ABCA1 expression increases. See text for details.