Hfv

Spumavirus

Figure 12—1. Phylogram showing the genetic relationship of the pol genes of the seven geni of exogenous retroviruses. The branch lengths are shown to scale and unique gene products are as indicated. MMTV, mouse mammary tumor virus; MPMV, Mason-Pfizer monkey virus; RSV, Rous sarcoma virus; Mo-MLV, Moloney murine leukemia virus; HFV, human foamy virus; SIVagm, simian immunodeficiency virus African green. The lentiviruses, PTLV/BLV, and spumaviruses are complex retroviruses because of the noted additional regulatory proteins encoded in their genomes. The other viruses are referred to as simple viruses because they lack such genes. Both the lentiviruses and the spumaviruses are cytopathic to the host cell, while all of the other geni transform the host cell.

By the 1970s it had been well established that retroviruses were a common cause of malignancies among animals. Their distinct life cycle (Figure 12-2), which had been shown to depend on a unique RNA-dependent DNA polymerase termed reverse transcriptase (Figure 12-3), had also been fully dissected. Early work in animal retroviruses had revealed that most cells were latently infected but, when induced into the cell cycle, the viral DNA became transcriptionally active. These observations led to an intense effort at the Laboratory of Tumor Cell Biology of the National Cancer Institute (NCI) to identify growth factors capable of sustaining hematopoietic cellular proliferation and to screen such cell cultures for the presence of retroviral reverse transcriptase activity. In 1978 those efforts bore fruit when it was demonstrated that the neoplastic cells from patients with T-lymphocyte malignancies could be induced to grow in the presence of the cytokine interleukin-2 (IL-2) and that some of these cultures expressed retrovirus particles (Figure 12-4) containing a unique reverse transcriptase activity.1-3 The subsequent purification and characterization of the virions in these cultures and epidemiologic studies verified that HTLV-1 was a unique

Figure 12-2. Drawing of the life cycle of a retrovirus. The virus binds to a specific cell surface receptor and enters the cell via direct fusion or endocytosis. Its single-stranded RNA is copied into an RNA/DNA hybrid via reverse transcription. The RNA is degraded by Rnase-H and the reverse transcriptase copies the single-stranded DNA into a double-stranded species that ultimately integrates into the host genome as proviral DNA. It can also exist as a circularized nonintegrated episomal form. The proviral DNA replicates with host genomic DNA during cell division. It can remain latent for prolonged periods of time or be transcribed into RNA resulting in the production of viral proteins and genomic RNA that assemble at the cell surface, and bud out of the cell as virions, which "mature" extracellularly to complete the life cycle.

Figure 12-2. Drawing of the life cycle of a retrovirus. The virus binds to a specific cell surface receptor and enters the cell via direct fusion or endocytosis. Its single-stranded RNA is copied into an RNA/DNA hybrid via reverse transcription. The RNA is degraded by Rnase-H and the reverse transcriptase copies the single-stranded DNA into a double-stranded species that ultimately integrates into the host genome as proviral DNA. It can also exist as a circularized nonintegrated episomal form. The proviral DNA replicates with host genomic DNA during cell division. It can remain latent for prolonged periods of time or be transcribed into RNA resulting in the production of viral proteins and genomic RNA that assemble at the cell surface, and bud out of the cell as virions, which "mature" extracellularly to complete the life cycle.

Figure 12-3. Schematic of reverse transcription of retroviral RNA into double-stranded DNA. RNA sequences are shown in small letters and DNA as capital letters. The (+) strand viral genomic RNA contains repetitive sequences (r) at its termini. These are internally flanked by regulatory sequences U5 and U3 at the 5' and 3' ends, respectively. These regions are in turn flanked by sequences termed the primer binding site (pbs), which is annealed to a cellular transfer RNA (tRNA) and a polypurine tract (ppt). Initial reverse transcription of (—) strand DNA is primed by the tRNA, proceeds to the 5' terminus of the genomic RNA, and stops. After Rnase-H degradation of its complementary RNA, this small piece of (—) strand "strong stop" DNA "jumps" to anneal its R sequences to the complementary r sequence of the 3' terminus of the genomic RNA. First strand (—) DNA synthesis is then primed by this translocated "strong stop" DNA and terminates at the complementary pbs. Studies in our laboratory indicate that the HIVs and HTLVs synthesize "strong stop" DNA at approximately the same efficiency, but that the HIV produces first-strand DNA about 1000-fold greater than HTLV. This difference could explain the marked disparity between both their in vitro and in vivo replication rates. Rnase-H degradation next proceeds (3' to 5') up the ppt of the (+) strand RNA. The residual (+) strand RNA then primes initial (+) strand "strong stop" DNA synthesis, which involves copying the still attached tRNA annealing sequences. The remaining (+) strand genomic RNA and the tRNA are then degraded by Rnase-H and the (+) strand "strong stop" DNA "jumps" to anneal to the complementary pbs sequences on the previously synthesized first (—) strand DNA. DNA synthesis then proceeds on both strands to their respective termini. As can be seen, this sequence (of RNA- and DNA-dependent DNA synthesis, RNA degradation of RNA/DNA hybrids, and intramolecular "jumps") results in the production of a larger double-stranded DNA that contains repetitive U3-R-U5 sequences (long terminal repeats or LTR) at both ends. The LTR sequences are important for directing proviral DNA integration and for regulating viral RNA transcription and processing.

human retrovirus.2-8 The subsequent association of HTLV-1 with a subset of mature CD4+ T-cell malignancies, which were especially prevalent in Southern Japan and the Caribbean, established the fact that HTLV-1 was pathogenic in humans.9,10

A few years later, the related virus HTLV-2 was isolated from the cultured T cells of another patient who in retrospect suffered from both hairy cell B-cell leukemia and CD8+ large granular lymphocytic (LGL) leukemia.11 Parenthetically it should be

Figure 12-4. Electron micrograph of a cultured neoplastic ATL cell and HTLV-I virions (arrows) (E). Virions are 100 nm in diameter. (A, B): Early and late budding virions, respectively; (C, D): Immature and mature extracellular virions, respectively. Mature virions shown an electron-dense core surrounded by an outer envelope. Accompanying schematic (F) illustrates the various viral components within the virion. MA, matrix; CA, capsid; NC, nucleocapsid; PR, protease; IN, integrase; RT, reverse transcriptase; SU, surface; TM, transmembrane.

Figure 12-4. Electron micrograph of a cultured neoplastic ATL cell and HTLV-I virions (arrows) (E). Virions are 100 nm in diameter. (A, B): Early and late budding virions, respectively; (C, D): Immature and mature extracellular virions, respectively. Mature virions shown an electron-dense core surrounded by an outer envelope. Accompanying schematic (F) illustrates the various viral components within the virion. MA, matrix; CA, capsid; NC, nucleocapsid; PR, protease; IN, integrase; RT, reverse transcriptase; SU, surface; TM, transmembrane.

host-cell membrane proteins genomic RNAs lipid bilayer envelope genomic RNAs lipid bilayer envelope

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