From Entry to Egress: Strategic Exploitation of the Cellular Processes by HIV-1

Abstract

HIV-1 employs a rich arsenal of viral factors throughout its life cycle and co-opts intracellular trafficking pathways. This exquisitely coordinated process requires precise manipulation of the host microenvironment, most often within defined subcellular compartments. The virus capitalizes on the host by modulating cell-surface proteins and cleverly exploiting nuclear import pathways for post entry events, among other key processes. Successful virus-cell interactions are indeed crucial in determining the extent of infection. By evolving defenses against host restriction factors, while simultaneously exploiting host dependency factors, the life cycle of HIV-1 presents a fascinating montage of an ongoing host-virus arms race. Herein, we provide an overview of how HIV-1 exploits native functions of the host cell and discuss recent findings that fundamentally change our understanding of the post-entry replication events.

Keywords: HIV-1 infection; capsid uncoating; cell organelles; host-virus interactions; restriction factors.

FIGURE 1

The HIV lifecycle. The infection begins when the envelope glycoprotein attaches to the receptor CD4 and the membrane-spanning co-receptors (CXCR4/CCR5) (step 1), facilitating the entry and fusion of the viral particle into the target cell (step 2). Following core delivery (step 3), reverse transcription begins in the cytoplasm (step 4), and the core is imported into the nucleus (step 5). Following the nuclear import, uncoating and reverse transcription completes (step 6) and viral integrase facilitate viral genome integration into the host chromosome (step 7). Proviral transcription (step 8) yields viral RNAs that are exported to the cytoplasm for viral protein production (step 9). Genome-length viral RNA and viral proteins are assembled to package into virions for budding (steps 10 and 11). Ensuing budding, the virus progeny releases and matures to become an infectious virion (step 12).

FIGURE 2

Alteration of host signaling pathways by HIV-1. (A) The binding of HIV-1 to its receptor and co-receptor triggers the activation of P2Y2 by releasing ATP from host cytosol through pannexin-1 (PNX-1). The activated P2Y2 promotes the ubiquitin-mediated degradation of NLRP3, facilitating the phosphorylation and activation of PYK-2, which subsequently enables the F-actin polymerization required for the fusion and entry of HIV-1 into the host cell (not shown). (B) Nef activates NFAT and NF-κB via PAK2, which triggers the expression of cytoskeletal remodeling genes. (C) Binding of the virus also activates the lipid-associated Lck protein by myristoylation at p56. Lck activates the PLC-γ that breaks PIP3 into IP3 and DAG. IP3 triggers the opening of calcium channels in the ER and increases the concentration of Ca²⁺ in the cytosol. Increased Ca²⁺ activates the NFAT signaling. The virally encoded Vpr can also trigger the NFAT signaling through Ca²⁺ efflux and interferes with cGSK3β kinase for NFAT export (not shown). On the other hand, DAG via PKC activates the MAPK pathway. The NFAT and MAPK then promote the transcription of genes required for cytokine production and T-cell proliferation and activation. (D) The gp120-CD4 and CXCR4/CCR5 interaction upregulates the apoptotic receptor and ligand, Fas/FasL expression, which in turn activates the caspase 8 and caspase 3 for apoptosis of the infected cell via FADD/TRADD. (E) Additionally, the released viral Tat and Nef in the cytoplasm can also upregulate the Fas expression in the plasma membrane and can directly act on the caspase 8, promoting apoptosis.

FIGURE 3

Insights into the counteraction of host defense by viral protease and Vpu. (A) Inhibition of antiviral signaling by viral protease: The host RIG-I senses viral ssRNA to promote the antiviral signaling through MAVS and activates the IκB kinases (IKKs). The IKKε phosphorylates IRF3, which then translocates into the nucleus to trigger the IFN-I production. On the other hand, IKK-α/β phosphorylates and degrades IκB, reliving NF-κB to go into the nucleus for transcription of proinflammatory cytokine genes. The viral protease (PR) promotes the degradtaion of RIG-I in the cytosol. (B) Suppression of peroxisome biogenesis by Vpu: in the absence of HIV-1 infection, the adapter protein βTrCP binds to β-catenin and promotes its degradation via ubiquitin-mediated proteasomal pathway. Upon HIV-1 infection, the Vpu stabilizes the β-catenin by sequestering βTrCP. Subsequently, β-catenin enters into the nucleus and activates the transcription factor TCF-4, which is required to drive the expression of indicated microRNAs. These microRNAs were found to regulate the expression of peroxisome biogenesis factors for peroxisome synthesis. However, the peroxisomal MAVS triggers the rapid induction of type III IFNs downstream ISGs that acts as antiviral factors. The direct/indirect counteraction of peroxisomal MAVS signaling by HIV-1 remains to be elucidated.