D. Goosney et al., Annu. Rev. Cell Dev.  Biol. 16:173–189, 2000. With permission from Annual Reviews.) machinery for their reproduction. This lifestyle, however, requires that the pathogen have mechanisms for entering host cells, for finding a suitable subcellular niche where it can replicate, and for exiting from the infected cell to spread the infection. Below we consider some of the myriad ways that individual intracellular pathogens exploit and modify host cell biology to satisfy these requirements.
Viruses Bind to Virus Receptors at the Host Cell Surface
The first step for any intracellular pathogen is to bind to the surface of the host target cell. Viruses accomplish this by the binding of viral surface proteins to virus receptors displayed on the host cell. The first virus receptor identified was an
E. coli surface protein that is recognized by the bacteriophage lambda; the protein normally functions to transport the sugar maltose from outside the bacterium to the inside where it is used as an energy source. Receptors need not be proteins, however: an envelope protein of herpes simplex virus, for example, binds to heparan sulfate proteoglycans (discussed in Chapter 19) on the surface of certain vertebrate host cells, and simian virus 40 (SV40) binds to a glycolipid. The specificity of virus-receptor interactions often serves as a barrier preventing the spread of a virus from one species to another. Acquiring the ability to bind to a new receptor often requires multiple changes in a virus, but it can be crucial in allowing the cross-species transmission that can result in new disease outbreaks.
Viruses that infect animal cells generally exploit cell-surface receptor molecules that are either ubiquitous (such as the sialic-acid-containing oligosaccharides used by the influenza virus) or found uniquely on those cell types in which the virus replicates (such as the neuron-specific proteins used by rabies virus). Although a virus usually uses a single type of host-cell receptor, some viruses use more than one type. An important example is HIV-1, which requires two types of receptors to enter a host cell. Its primary receptor is CD4, a cell-surface protein on helper T cells and macrophages that is involved in immune recognition (discussed in Chapter 24). It also requires a co-receptor, which is either CCR5 (a receptor for β-chemokines) or CXCR4 (a receptor for α-chemokines), depending on the particular variant of the virus; macrophages are susceptible only to HIV variants that use CCR5 for entry, whereas helper T cells are most efficiently infected by variants that use CXCR4 (Figure 23–17). The viruses that are found within the first few months after HIV infection almost invariably use CCR5, which explains why individuals that carry a defective CCR5 gene are less susceptible to HIV infection. In the later stages of infection, viruses often either switch to use CXCR4 or adapt to use both co-receptors through the accumulation of mutations; in this way, the virus can change the cell types it infects as the disease progresses. It may seem paradoxical that viruses would infect immune cells, as we might expect that virus binding would trigger an immune response; but invasion of an immune cell can be a useful way for a virus to weaken the immune response and travel around the body to infect other immune cells.
°-chemokine ˜-chemokine (Sdf1) (Rantes, Mip1°, or Mip1˜)