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Coffin JM, Hughes SH, Varmus HE, editors. Retroviruses. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 1997.

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Effect of Infection on Cell Division and Differentiation

Given the dependence of viral infection on the cell cycle and differentiation state, it is reasonable to expect that retroviruses would have evolved mechanisms to alter these processes for their benefit, and a number of examples are known. Among simple retroviruses, some MLV strains can exert a mitogenic affect on T cell or erythrocyte precursors, a consequence of interaction of certain modified Env proteins with cytokine receptors, including those for erythropoietin and interleukin-2 (IL-2). Such altered env genes can originate during the recombination events that give rise to oncogenic MLVs in some strains of mice and are thought to contribute both to the ability of the virus to replicate efficiently in the target tissue and to transform a small fraction of the infected cells. This effect is apparently amplified by the env deletions that give rise to rapidly oncogenic spleen-focus-forming virus. An analogous activity may be encoded by the variant Gag protein of the MAIDS virus, but the mechanism of action of this viral protein is unclear. HTLV-1 can also stimulate cells to enter into cycle, both through stimulation of the transcription of cellular genes such as IL-2 and its receptor by the Tax trans-activator, and by the oncogene-like activity of a small gene product from the X region.

The MMTV sag gene is a special example of stimulation of the host cell cycle by a viral protein. Infected B cells expressing sag are strongly stimulated to divide by interacting with, and activating, certain T cells, inducing them to release stimulatory factors. In this case, as in the others discussed here, the principal importance to the virus is presumably to promote viral replication by promoting replication of infected, provirus-containing cells, although in some cases, factors released by infected cells may stimulate neighboring cells to enter the cell cycle, making them more suitable as targets for infection. The cyclin-related genes recently discovered in the genome of a fish retrovirus may play a similar role.

The clearest examples of viruses that can affect the cycling and differentiation state of the infected cells are those simple viruses that have acquired oncogenes from the cell. These viruses have been of great importance in the development of modern cancer research, but most likely represent evolutionary dead ends. Although the rapid overgrowth of cells infected with oncogene-containing viruses provides a strong selective pressure in the host in which the viruses arise, the fact that these viruses are almost all defective for replication, combined with their rapid lethality, makes them poorly adapted for efficient host-to-host transmission. Unless given a good home in the laboratory, these viruses probably die along with the animal in which they arise.

A rather different case in which retroviral infection affects the host cell cycle is the Vpr protein of primate lentiviruses. Instead of promoting transit of the infected cell through the division cycle, Vpr arrests dividing cells in G2. Since most HIV- and SIV-infected cells in vivo die within a few days of infection, this block does not seriously affect the number of infected cells. Rather, it appears to leave the cells in a state in which they are better suited for efficient viral production. Since some of the early HIV isolates were maintained in chronically infected cell lines, whose replication would be inhibited by Vpr, this gene is often inactivated by mutation in common laboratory strains of virus.

Viral infection can also affect the host by direct effects on expression of cellular genes. Insertion of the viral DNA into the genome of the host, if not perfectly random with respect to the target sites, can certainly occur at any of a very large number of available sites, with important consequences for both the virus and the host. Although we do not yet understand the underlying mechanisms in detail, we do know that not all sites in the host genome are equally favorable for the expression of the provirus, suggesting that signals in flanking cellular DNA can affect the transcriptional efficiency of the provirus. Conversely, proviral gene expression signals—enhancers and promoters—can affect the expression of nearby host genes in either a positive or a negative sense. Although it is a rare event for a provirus to be inserted in an individual cell near a gene whose expression is critical for the control of division and/or differentiation, and to thereby stimulate the cell to divide inappropriately, such events are not rare when retroviruses infect multicellular hosts.

Copyright © 1997, Cold Spring Harbor Laboratory Press.
Bookshelf ID: NBK19425


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