Herpes simplex virus type 1 latency-associated transcript (LAT) promoter deletion mutants can express a 2-kilobase transcript mapping to the LAT region

Nicosia, Monica; Deshmane, Satish L.; Zabolotny, Janice M.; Vályi-Nagy, Tibor; Fraser, N W

doi:10.1128/jvi.67.12.7276-7283.1993

Cited by 46 publications

(28 citation statements)

References 48 publications

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“…The transcription present during latency consists of two, more abundant latency-associated transcripts (LAT) 2.0 and 1.5 kb in size, and transcripts that are present in smaller amounts, about 8.4 kb in size, termed the minor LAT (mLAT). Two promoters of this gene (latency-active promoters; LAP), LAP-1 and LAP-2, have been mapped (Nicosia et al 1993, Goins et al 1994, Chen et al 1995. While LAP-1 is more active during latent in vivo infection and LAP-2 is more active during viral replication in cells in culture, both are probably required for effective latent infection.…”

Section: The Molecular and Cellular Phenomenology Of Hsv-1 Latent Infmentioning

confidence: 99%

Human Herpes Viruses Latent Infection in the Nervous System

Steiner

1996

Immunological Reviews

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The neurotropic herpes viruses, HSV-1, HSV-2 and VZV, colonize and establish latent infection in human peripheral sensory ganglia. Recurrent diseases due to reactivation of these viral pathogens can take place despite an effective immune response. Molecular, cellular, physiological and immune mechanisms work in concert to enable the establishment of latency, the maintenance of the latent state for the entire life of the host, and the reactivation infection. Although all three viruses belong to the same family and establish latent infection in the same tissue, the clinical pattern of their reactivation is quite different. This review covers current knowledge of the basis of these infections, and offers a theory explaining the basis of HSV-1 latent infection and the differences of the disorders caused by HSV-1 and VZV reactivation in humans.

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Section: The Molecular and Cellular Phenomenology Of Hsv-1 Latent Infmentioning

confidence: 99%

Human Herpes Viruses Latent Infection in the Nervous System

Steiner

1996

Immunological Reviews

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“…Recent studies suggest that LAP1 and LAP2 may function differentially during lytic versus latent infections (6). Accumulation of the 2-kb LAT during lytic infection depends on LAP2 and is independent of LAP1 sequences, while during latency the reverse is true (6,35).…”

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confidence: 99%

cis-acting elements involved in transcriptional regulation of the herpes simplex virus type 1 latency-associated promoter 1 (LAP1) in vitro and in vivo

Soares

Hwang

Ramakrishnan

et al. 1996

J Virol

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Latency-associated promoter 1 (LAP1) of herpes simplex virus type 1 is required to generate a series of latency-associated transcripts (LATs) in sensory neurons of latently infected animals. Sequence analysis and DNA binding studies have suggested the existence of several cis-acting elements within LAP1 that are potentially important for promoter function, although their role in LAT gene expression during latency is largely unexplored. In this report, we present evidence that the LAP1 TATA box is essential for transcription initiation in vitro. A reduction in LAT synthesis measured by in situ hybridization and reverse transcription-PCR (RT-PCR) of rat brain tissue latently infected with a LAP1 TATA substitution virus demonstrated that this sequence was required for full LAP1 activity in vivo. Analysis of additional site-directed and 5-deletion mutants of LAP1 by in vitro transcription-primer extension assays showed that upstream elements including the USF and cyclic AMP response element (CRE) site specifically contributed to LAP1 function and that sequences beginning at position ؊620 relative to the transcription start site were essential for full promoter activity. The combination of deleting USF, CRE, and TATA completely abolished LAT expression in the brain, identifying these as essential elements for the neuron-specific functioning of LAP1 during latency. Mutation of the transcription start site did not abolish transcription, suggesting the absence of an initiator element. However, one of the most exciting findings from this study is that the region downstream of the TATA box appears to contain a true enhancer that is not only essential for transcription, but also functional when positioned 1.6 kb downstream of the start site of transcription. It was concluded that (i) the TATA box was essential for full transcriptional activity from LAP1 both in vitro and in vivo, (ii) the USF element and CRE contribute to LAP1 function during latency in combination with the TATA element, (iii) multiple trans-acting factors besides the USF-and CRE-binding proteins were required for full promoter activity in vitro, and (iv) sequences downstream of the TATA box enhanced promoter activity in vitro.

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“…The most compelling evidence for the role of LAP1 in LAT expression during latency has come from in vivo studies with a viral mutant, KOS/29, in which the sequences for LAP1 and the putative start site of the 8.5-kb LAT have been deleted (10). This mutant establishes latency but does not produce LAT as detected by in situ hybridization (10) or by Northern (RNA) blot (30). This finding is consistent with the hypothesis that the 2-kb LAT is processed from a larger precursor, perhaps the 8.5-kb polyadenylated LAT (8,10).…”

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confidence: 99%

Two herpes simplex virus type 1 latency-active promoters differ in their contributions to latency-associated transcript expression during lytic and latent infections

Chen

Schmidt

Goins

et al. 1995

J Virol

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Herpes simplex virus type 1 (HSV-1) establishes latency in human sensory ganglia, during which time the viral genome is transcriptionally silent with the exception of the latency-associated transcripts (LATs). The most abundant LAT is a 2-kb RNA whose biosynthesis is poorly characterized. The 2-kb LAT may be a primary transcript, or its synthesis may involve splicing and/or other forms of processing. Two potential RNA polymerase II promoters (LAP1 and LAP2) upstream of the 2-kb LAT 5 end have been identified. To investigate the role played by LAP1 and LAP2 in the synthesis of the 2-kb LAT under lytic and latent conditions, we analyzed HSV-1 mutants which contain deletions of one or both of these promoters. During lytic infection in cell culture, the cis elements critical for the normal accumulation of the 2-kb LAT were mapped to LAP2, while LAP1 sequences were largely dispensable. The 5 ends of the major 2-kb LATs produced by the wild-type and LAP deletion viruses were examined by primer extension analysis and were all found to be identical (؎2 bp). The accumulation of the 2-kb LAT during latent infections of murine trigeminal ganglia was examined by Northern (RNA) blot and by reverse transcription-PCR. In contrast to the results found in lytic infections, the critical cis elements needed for 2-kb LAT accumulation during latency were mapped to LAP1. Deletion of LAP1 resulted in a 500-fold reduction in 2-kb LAT accumulation, whereas deletion of LAP2 resulted in only a 2-to 3-fold reduction. Deletion of both LAP1 and LAP2 resulted in undetectable levels of the 2-kb LAT. Our results indicate that both LAP1 and LAP2 are critical for 2-kb LAT expression but under different conditions. LAP1 is essential for LAT expression during latency, while LAP2 is primarily responsible for LAT expression in lytic infections in cell culture. LAP1 and LAP2 may prove to be functionally independent promoter elements that control 2-kb LAT expression during different stages of HSV-1 infections.

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Herpes simplex virus type 1 latency-associated transcript (LAT) promoter deletion mutants can express a 2-kilobase transcript mapping to the LAT region

Cited by 46 publications

References 48 publications

Human Herpes Viruses Latent Infection in the Nervous System

Human Herpes Viruses Latent Infection in the Nervous System

cis-acting elements involved in transcriptional regulation of the herpes simplex virus type 1 latency-associated promoter 1 (LAP1) in vitro and in vivo

Two herpes simplex virus type 1 latency-active promoters differ in their contributions to latency-associated transcript expression during lytic and latent infections

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