Figure 23–17 Receptor and co-receptors for HIV. All strains of HIV require the CD4 protein as a primary receptor. Early in an infection, most of the viruses use CCR5 as a co-receptor, allowing them to infect macrophages and their precursors, monocytes. As the infection progresses, mutant variants arise that now use CXCR4 as a co-receptor, enabling them to infect helper T cells efficiently. The natural ligand for the chemokine receptors (Sdf1 for CXCR4; Rantes, Mip1α, or Mip1β for CCR5) blocks co-receptor function and prevents viral invasion.
Viruses Enter Host Cells by Membrane Fusion, Pore Formation, or Membrane Disruption
After recognition and attachment to the host cell surface, the virus must enter the cell to replicate. Some enveloped viruses enter the host cell by fusing their envelope membrane with the plasma membrane. Most viruses, whether enveloped or nonenveloped, activate signaling pathways in the cell that induce endocytosis, commonly via clathrin-coated pits (see Figure 13–7), leading to internalization into endosomes. Large viruses that do not fit into clathrin-coated vesicles, such as poxviruses, often enter cells by macropinocytosis, a process by which membrane ruffles fold over and entrap fluid into macropinosomes (see Figure 13–50). Once inside endosomes, fusion of the viral envelope occurs from the lumenal side of the endosome membrane. The mechanism of membrane fusion mediated by viral spike glycoproteins has similarities with SNARE-mediated membrane fusion during normal vesicular trafficking (discussed in Chapter 13).
Enveloped viruses regulate fusion both to ensure that they fuse only with the appropriate host cell membrane and to prevent fusion with one another. For viruses such as HIV-1 that fuse at neutral pH with the plasma membrane (Figure 23–18A), binding to receptors or co-receptors usually triggers a conformational change in a viral envelope protein that exposes a normally buried fusion peptide (see Figure 13–21). Other enveloped viruses, such as influenza A virus, only fuse with a host cell membrane after endocytosis (Figure 23–18B); in this case, it is frequently the acid environment in the late endosome that triggers the conformational change in a viral surface protein that exposes the fusion peptide. The H+ (B) acidifcation, fusion, uncoating fusion with membrane after endocytosis endosomal membrane disruption pore formation(C) (D) endocytosis endocytosis early endosome lysis uncoating, pore formation DNA enters nucleus
Figure 23–18 Four virus entry strategies.
(A) Some enveloped viruses, such as HIV, fuse directly with the host-cell plasma membrane to release their RNA genome (blue) and capsid proteins (brown) into the cytosol. (B) Other enveloped viruses, such as influenza virus, first bind to cell-surface receptors, triggering receptor-mediated endocytosis; when the endosome acidifies, the virus envelope fuses with the endosomal membrane, releasing the viral RNA genome (blue) and capsid proteins (brown) into the cytosol. (C) Poliovirus, a nonenveloped virus, induces receptor-mediated endocytosis, and then forms a pore in the endosomal membrane to extrude its RNA genome (blue) into the cytosol. (D) Adenovirus, another nonenveloped virus, uses a more complicated strategy: it induces receptor-mediated endocytosis and then disrupts the endosomal membrane, releasing the capsid and its DNA genome into the cytosol; the trimmed-down virus eventually docks onto a nuclear pore and releases its DNA (red) directly into the nucleus (Movie 23.5).