Dual role of autophagy in HIV-1 replication and pathogenesis

Abstract

Autophagy, the major mechanism for degrading long-lived intracellular proteins and organelles, is essential for eukaryotic cell homeostasis. Autophagy also defends the cell against invasion by microorganisms and has important roles in innate and adaptive immunity. Increasingly evident is that HIV-1 replication is dependent on select components of autophagy. Fittingly, HIV-1 proteins are able to modulate autophagy to maximize virus production. At the same time, HIV-1 proteins appear to disrupt autophagy in uninfected cells, thereby contributing to CD4+ cell death and HIV-1 pathogenesis. These observations allow for new approaches for the treatment and possibly the prevention of HIV-1 infection. This review focuses on the relationship between autophagy and HIV-1 infection. Discussed is how autophagy plays dual roles in HIV-1 replication and HIV-1 disease progression.

Figure 1

The 3 stages of autophagy. Illustrated are distinct stages in the process of autophagy.i) Autophagy is initiated by pathways that inactivate mTOR. ii) Autophagosome synthesis involves the coupling of LC3-II to the autophagosome membrane and the formation of double membrane vesicles that sequester cytoplasmic material. iii) The final stage of autophagy, proteolysis, entails the fusion of mature autophagosomes with lysosomes and the release of breakdown products into the cytoplasm.

Figure 2

Example of an autophagosome in an HIV-infected cell. Shown is a transmission electron micrograph of an HIV-1_SF33-infected monocyte-derived macrophage (L Ackerman and MS Killian, unpublished data). At higher magnification, the HIV-1 particles (roughly 0.1 μm in diameter) are clearly visible within the autophagosomal structure (inset). Abbreviations: nucleus, N; autophagosome, AP; rough endoplasmic reticulum, RER. Arrows point to the multiple membranes surrounding the autophagosome.

Figure 3

Autophagy in HIV-1 infection. Left) HIV-1 replication requires early autophagic events for its replication [39], perhaps because the autophagosomal membrane provides a scaffold for virion assembly. Incomplete, or fully formed virions that enter the cell via endocytosis [40], could be degraded by the autophagy (xenophagy) pathway. However, HIV-1 can inhibit the late stage of autophagy to avoid the digestion of virions within autolysosomes. Right) Autophagy is a crucial component of innate and adaptive immune responses to HIV-1 infection. Autophagy is required for the TLR7-mediated signaling of interferon-alpha (IFN-α) production by plasmacytoid dendritic cells (innate immunity) in response to HIV [41]. Autophagy also contributes to proteolytic processing for the presentation of HIV-1 peptides in the context of MHC class II (adaptive immunity).