Cholesterol Metabolism in Antigen-Presenting Cells and HIV-1 Trans-Infection of CD4+ T Cells

Abstract

Antiretroviral therapy (ART) provides an effective method for managing HIV-1 infection and preventing the onset of AIDS; however, it is ineffective against the reservoir of latent HIV-1 that persists predominantly in resting CD4⁺ T cells. Understanding the mechanisms that facilitate the persistence of the latent reservoir is key to developing an effective cure for HIV-1. Of particular importance in the establishment and maintenance of the latent viral reservoir is the intercellular transfer of HIV-1 from professional antigen-presenting cells (APCs-monocytes/macrophages, myeloid dendritic cells, and B lymphocytes) to CD4⁺ T cells, termed trans-infection. Whereas virus-to-cell HIV-1 cis infection is sensitive to ART, trans-infection is impervious to antiviral therapy. APCs from HIV-1-positive non-progressors (NPs) who control their HIV-1 infection in the absence of ART do not trans-infect CD4⁺ T cells. In this review, we focus on this unique property of NPs that we propose is driven by a genetically inherited, altered cholesterol metabolism in their APCs. We focus on cellular cholesterol homeostasis and the role of cholesterol metabolism in HIV-1 trans-infection, and notably, the link between cholesterol efflux and HIV-1 trans-infection in NPs.

Keywords: HIV-1; antigen-presenting cells; antiretroviral therapy; cholesterol metabolism; immunometabolism; latent reservoir; non-progressor; trans-infection.

Figure 1

A schematic representation of the cis-infection and trans-infection models of HIV-1. (1) During cis-infection, cell-free viruses are transmitted via a site of infection, e.g., mucosal, and then infect activated CD4⁺ T cells by specific binding of the viral gp120 glycoprotein to cellular receptor CD4 in the presence of chemokine receptors such as CCR5. (2) In trans-infection, cell-free viruses are taken up by professional APCs (monocytes/macrophages, B lymphocytes, and myeloid dendritic cells) via DC-SIGN and Siglec-1. Upon virus uptake, the virus is internalized in multivesicular bodies and then transferred by the trafficking of these multivesicular bodies to the virological synapse formed during APC-CD4⁺ T cell interactions.

Figure 2

Cholesterol metabolism pathway illustrating the transcriptional control of cholesterol biosynthesis and reverse cholesterol transport by SREBP and LXR/RXR, respectively. Steps A–E and A*–D** describe the process of cholesterol biosynthesis during low cellular cholesterol levels and are regulated by SREBP. This involves the synthesis of new cholesterol by HMG-CoA reductase (steps A*–C**) or influx of cholesterol/LDL particles via the LDL receptor (steps A–E and B*–C*). Steps I–VI describe reverse cholesterol transport, which is regulated by LXR/RXR during high cellular cholesterol levels, signaled by the presence of oxysterol. The binding of oxysterols to LXR/PPARγ leads to their activation and subsequent upregulation in cholesterol efflux genes such as ABCA1 and ABCG1 and the upregulation of CD36 which further modulates cholesterol efflux.

Figure 3

A schematic representation of trans-infection via the formation of a virological synapse through the interaction between cellular receptors and integrins. (A) Uptake of cell-free virus by APCs using DC-SIGN or Siglec-1. (B) Internalization of HIV-1 in the cholesterol-rich multivesicular body. (C,D) Trafficking of the virus to the plasma membrane for transfer via the virological synapse.