Viral Replication

Many retroviruses replicate only in dividing cells. Most mammalian and avian retroviruses are not cytocidal and do not dramatically alter the metabolism of the cells that they infect, but this is not the case with the lentiviruses.

Virions adsorb to specific cell receptors via one of the two envelope gly-

Viral Replication Steps

Fig. 35-1 Retroviridae. Murine leukemia virus, a typical type C retrovirus (A) Budding of virions from a cultured mouse embryo cell (B) Virions negatively stained with uranyl acetate, showing peplomers on the surface. (C) Virion somewhat damaged and penetrated by uranyl acetate, so that the concentric arrangement of core, shell, and nucleoid becomes visible (D) Cores isolated by ether treatment of virions, freeze-dried and shadow-cast The hexagonal arrangement of the subumts of the shell around the core is recogni/.able. Bars, 100 nm. (Courtesy Drs H. Frank and W Schafer.)

Fig. 35-1 Retroviridae. Murine leukemia virus, a typical type C retrovirus (A) Budding of virions from a cultured mouse embryo cell (B) Virions negatively stained with uranyl acetate, showing peplomers on the surface. (C) Virion somewhat damaged and penetrated by uranyl acetate, so that the concentric arrangement of core, shell, and nucleoid becomes visible (D) Cores isolated by ether treatment of virions, freeze-dried and shadow-cast The hexagonal arrangement of the subumts of the shell around the core is recogni/.able. Bars, 100 nm. (Courtesy Drs H. Frank and W Schafer.)

coproteins. Entry occurs either by receptor-mediated endocytosis or by direct fusion with plasma membrane, for different retroviruses. Uncoating releases the nucleoprotein complex into the cytoplasm. Using the genome-associated tRNA as a primer, the reverse transcriptase transcribes a minus sense cDNA from the viral genome (see Fig. 11-2B). Concomitantly, the viral RNA template

Table 35-1

Properties of Retroviruses

Spherical enveloped virion, 80-100 nm diameter

Ribonucleoprotem in central nucleoid (concentric m type C viruses, truncated cone in lenti-

viruses) within icosahedral capsid; surrounded by envelope with glycoprotein peplomers Two copies of linear plus sense ssRNA genome, each 7-10 kb, covalently linked; pot, env genes, some also contain regulatory genes; some carry an oncogene Reverse transcriptase transcribes DNA from virion RNA, following formation of long terminal repeats, dsDNA is integrated into cellular chromosomes as provirus Full-length RNA transcripts encode core and capsid proteins, protease, reverse transcriptase/ RNase FÎ, integtase, shorter spliced transcripts encode envelope glycoproteins and regulatory proteins

In productive infections, virions assemble at and bud from plasma membrane Infection may be cytocidal, noncytocidal, or transforming; oncogenic retroviruses may be leplication-competent or defective, and induce malignancy by transduction, as-activahon, or fnms-activation is digested by a second domain of the reverse transcriptase molecule, which carries RNase H enzymatic activity. Oligonucleotides resulting from this hydrolysis then serve as primers for the synthesis of plus sense cDNA using the newly made minus sense cDNA as template. The resulting linear double-stranded DNA contains long terminal repeats (LTRs) composed of sequences duplicated from the 3' (U3) and 5' (U5) ends of the viral RNA, so that each end of the provirus contains an LTR consisting of a U3, R, and U5 region; within the LTR are to be found the regulatory sequences, including an enhancer/promoter region with binding sites for viral and/or cellular regulatory proteins. The dsDNA moves to the nucleus, and several such molecules become integrated as provirus at random sites in the cell DNA. Integration requires the viral integrase and involves removal of two nucleotides from the ends of the viral DNA and generation of a short duplication of cell sequences at the integration site, enabling joining of the ends of the viral DNA to the cell DNA.

Integration is a prerequisite for virus replication. The integrated provirus is transcribed by cellular RNA polymerase II. The complete RNA transcript is identical to the original genomic RNA and serves as mRNA for translation into the Gag (core) polyprolein and, after frameshifts, the protease and the Pol polyprotein A second, shorter mRNA,"spliced from the full-length RNA, is translated, again in a different reading frame, to yield the Env precursor. In

Table 35-2

Human Retroviruses

Table 35-2

Human Retroviruses

Genus

Virus

Disease

BLV-H1LV retrovirus

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