Chapter 16 : Retrovirus Variation and Evolution

Polymorphism among endogenous murine leukemia viruses. The provirus maps show linked sequence differences useful for distinguishing the four groups. These include sequences in env and the long terminal repeat that generate useful oligonucleotide probes, restriction site polymorphisms, receptor utilization differences, and an insertion of a small transposable element into the long terminal repeat ( 81 ). emv, ecotropic murine virus; pmv, polytropic murine virus; mpmv, modified polytropic murine virus; xmv, xenotropic murine virus.

Mapping of endogenous murine leukemia viruses. All polytropic, modified polytropic, and xenotropic proviruses were mapped onto the mouse genome by using the proviral DNA distribution in recombinant inbred and intercross mice. The proviruses are shown on the left side of each chromosome, and standard markers are shown on the right side ( 39 – 41 ).

Distribution of some endogenous proviruses among common inbred strains of mice. The chart on the right depicts the relationships of some strains inferred from the historical record ( 64 ).

Phylogeny of inbred strains. (Left) Tree derived from the endogenous provirus distribution by using PAUP ( 86 ); (right) relationships of inbred strains derived by analysis of biochemical polymorphisms ( 6 ). Branches depicted by heavy lines are consistent with the historical record.

Phylogeny of retroviruses. The figure shows a phylogenetic tree based on comparison of reverse transcriptases and relating the presently defined genera ( 32 ) (listed on the left). Heavy curved arrows indicate probable recombination events. Retrovirus genera with endogenous members are shown in boldface. MLV, murine leukemia virus; ALV, avian leukemia virus; HSRV, human spuma-retrovirus; HERV-C, human endogenous retrovirus C; EIAV, equine infectious anemia virus; SMRV, squirrel monkey retrovirus; IAP, intracisternal A particle; RSV, Rous sarcoma virus; BLV, bovine leukemia virus; HTLV, human T-lymphotropic leukemia virus.

Protocol for in vitro rapid passage of Rous sarcoma virus. A biologically cloned sample of the Prague strain of Rous sarcoma virus (subgroup B) was subjected to undiluted passage in cultures of chicken embryo fibroblasts (CEF) every 3 to 4 days. At selected passages, a sample was taken for analysis, initially by quantitative RNase T1 fingerprinting (30) and later by PCR amplification, cloning, and sequencing of a selected region on env ( 26 ).

Selected changes in the Rous sarcoma virus genome as a function of passage. (Top) Biological properties: transformation (measured by focus assay) and cytopathicity (measured by plaque assay); (bottom) genome changes measured by quantitative fingerprinting, including loss of the src gene, overgrowth of a highly defective variant, and appearance of selected point mutations in the SU portion of env ( 30 ).

Selected point mutations in the Rous sarcoma virus env gene. The region of the SU portion of env shown in the top lines was amplified, cloned, and sequenced from selected passages of the experiment shown in Fig. 6 and 7 . The two most prominent selected changes are indicated in the nucleotide and amino acid sequences shown at the bottom, and the same region from a number of avian leukemia virus isolates of chickens and pheasants is shown for comparison. RAV-1, Rous-associated virus-1; Pr-C, Prague strain RSV, subgroup C; SR-D, Schmidt-Ruppin RSV, subgroup D; RPV-F, ring-necked pheasant virus, subgroup F.

Genetic change as a function of time in Rous sarcoma virus passaged in vitro and SIV growing in vivo. The genetic distance of the passaged virus from the experiment shown in Fig. 6 was calculated from the sequences of at least 50 clones from each selected passage (closed circles). For comparison, the data of Burns and Desrosiers ( 15 ) for molecularly cloned SIV growing in monkeys are shown by open circles.

Effect of mutation and selection on a virus population. The curves were obtained by a simple computer simulation in which the frequency of a given mutation was incremented by the effects of forward mutation (μ) and selective advantage (5 if positive), and decremented by reverse mutation (assumed to be equal to μ) and .v (if negative). (A) Effect of varying μ from 10–3 to 10–5 while holding .5 constant at 10–2; (B and C) effects of varying positive (B) and negative (C) s while holding μ constant at 10–4 ( 21 , 25 ).

Kinetics of HIV infection after inhibitor treatment in vivo. Shown is a compilation of data from a number of studies ( 49 , 71 , 76 , 102 ) in which the concentration of virus (as genome RNA) and the CD4 cell number were monitored after administration of one of a number of (nucleoside or nonnucleoside) reverse transcriptase or protease inhibitors ( 25 ). wt, wild type.

Types of HIV-infected cells in vivo. At steady state, the rate of creation of each cell type by infection matches its rate of death, and the overall rate of replenishment matches the death rates of all types combined. The horizontal axis is labeled “time” to indicate that at steady state, the number of cells in each state (nonproducing or virus producing) is proportional to the time spent in that state ( 25 ).