Research on the Role of Cellular Autophagy in Anti-HIV-1 Infection

Effect of HIV-1 Infection on Autophagy

• Effect of HIV-1 on Autophagy in Early Infection

The early stage of HIV-1 infection includes viral adsorption and penetration and reverse transcription and integration. Among them, the viral envelope glycoprotein (encoded by the structural gene env, containing two subunits, gp120 and gp41) plays an important role in the process of viral adsorption and penetration and viral assembly and budding. When HIV-1 interacts with the main receptor CD4 and the auxiliary receptor CCR5/CXCR4 in the target cell, it mediates the entry and early infection of HIV-1. From HIV-1 infection to the development of AIDS, the core factor is the depletion of uninfected CD4 cells, and Env expressed on the surface of infected cells plays a key role in this process. Therefore, the effect of HIV-1Env on autophagy in the early stage is of great significance. Studies have shown that autophagy is inhibited in CD4 cells infected with X4 or R5 HIV-1, and autophagy is induced in monocytes/macrophages infected with X4 or R5 HIV-1. R5Env and X4Env expressed by infected cells trigger autophagy and cell death in uninfected CD4 cells but not in uninfected monocytes/macrophages, indicating that Env-triggered autophagy is cell type dependent and mediated by gp41-triggered membrane fusion, independent of co-receptors. Weaker autophagy and enhanced viral replication were observed in monocytic-differentiated macrophages (MDMs) infected with R5 HIV-1 compared with those infected with X4 HIV-1, suggesting that R5 HIV-1 is more infectious in MDMs. Recent studies have also shown that Env-mediated autophagy acts on peroxisomes to induce oxidative stress, leading to cell death in uninfected CD4 cells. Therefore, autophagy is an important antiviral process triggered by Env membrane fusion when HIV-1 infects and enters CD4 cells. Subsequently, studies have found that HIV-1Vpr also negatively regulates autophagy in the early stages of HIV-1Env infection of CD4 cells, so that autophagy is quickly controlled after HIV-1 enters the cells. In addition, HIV-1Env needs to activate ARF6-related autophagy factors to produce effective infection in CD4 cells. Since dendritic cells (DCs) are early targets of HIV-1 infection, studies have found that HIV-1Env-mediated mTOR pathway activation can inhibit autophagy in DCs, which can lead to an increase in HIV-1 in DCs and promote DC-mediated HIV-1 transfer to CD4 cells. Therefore, HIV-1 infection can activate the mTOR pathway and promote viral integration and viral replication by inhibiting autophagy.

• Effects of HIV-1 on Autophagy during the Infection and Replication Cycle

The late stages of HIV-1 infection and replication include transcription and translation and assembly and maturation until viral release. Two regulatory genes of HIV-1 (tat transactivator and rev virion protein expression regulator) play a regulatory role in the early stages of the viral replication cycle, and four auxiliary genes (nef negative regulator, vpr viral protein r, vpu viral protein u and vif viral infection factor) play an important role in the production of the virus. Previous studies have shown the effects of viral proteins on autophagy during infection, such as transactivator (Tat) can block interferon gamma (INF-γ)-mediated autophagy in monocytes and macrophages; activation of the SRC-Akt signaling pathway inhibits autophagy in uninfected monocytes and macrophages. Negative regulator (Nef) prevents the maturation of autophagosomes in macrophages and astrocytes and hinders autophagy-mediated degradation of HIV-1; and prevents the nuclear translocation of the pro-autophagy transcription factor TFEB in macrophages. Viral infection factor (Vif) inhibits autophagy at the late stage of viral replication in CD4 cells and promotes HIV-1 replication. Viral protein r (Vpr) impedes early autophagic steps to prevent macrophage apoptosis. Viral protein u (Vpu) promotes BST2 displacement from the viral budding site through LC3-related phagocytosis. In recent years, related studies have been continuously deepened. For example, Tat also activates microglia by increasing mitochondrial damage through defective mitochondrial autophagy, while microglia exposed to Tat impair lysosomal function, leading to autophagy dysregulation and activation of NLRP3 inflammasome signaling. Tat can also induce autophagy through PELI1/K63-linked BECN1 ubiquitination, reduce ZO-1 in brain endothelial cells, and disrupt the blood-brain barrier. Tat upregulates PKM2 to activate the AKT/mTOR pathway and inhibit the AMPK pathway, thereby inhibiting autophagy and causing Tat-mediated HIV-1 transcriptional activation. Tat increases BAG3 through NF-κB signaling and induces autophagy in HIV-related neurocognitive disorder disease models. Nef can prevent the degradation of HIV-1Gag promoted by autophagy through ubiquitination through parkin/PRKN-mediated BCL2 ubiquitination and promote apoptosis. For viruses lacking Nef, continuous activation of autophagy by degradation of HIV-1Gag can effectively inhibit HIV-1 replication. ATG9A can also interact with Nef, but ATG9A promotes HIV-1 infection in a manner independent of interaction with Nef. Vpu uses the LC3C-related pathway to antagonize the antiviral ability of BST2, during which ATG5 acts as a signal bridge. In addition, under starvation conditions, HIVp17 interacts with Obg-like ATPase 1 (OLA1), destroys the OLA1-glycogen synthase kinase-3β (GSK3β) complex, leading to GSK3β hyperactivation, thereby inhibiting autophagy and ultimately enhancing the proliferation of HIV-1-infected CD4 cells.