Bimodal Temporal Distribution of Herpes Explains Resistant Cases to Oral Antiviral Agents

Herpes Simplex Virus (HSV) is a double-stranded virus that affects the skin and mucous membranes. There has been a long-standing dogma stating that the virus remains dormant and is reactivated from the dorsal root ganglia. However, more recent studies have established that there is a secondary mode of viral reactivation from the epidermis itself. These two distinct reactivation patterns help explain why prophylactic antivirals do not consistently prevent herpes outbreaks.

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Herpes Simplex Virus Type 2 (HSV-2) Establishes Latent Infection in a Different Population of Ganglionic Neurons than HSV-1: Role of Latency-Associated Transcripts

Journal of Virology ◽

10.1128/jvi.02110-06 ◽

2006 ◽

Vol 81 (4) ◽

pp. 1872-1878 ◽

Cited By ~ 68

Author(s):

Todd P. Margolis ◽

Yumi Imai ◽

Li Yang ◽

Vicky Vallas ◽

Philip R. Krause

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Virus Type ◽

Dorsal Root Ganglia ◽

Herpes Simplex Virus Type ◽

Dorsal Root ◽

Acute Infection ◽

Viral Reactivation ◽

Simplex Virus ◽

Hsv 1

ABSTRACTHerpes simplex virus type 1 (HSV-1) and HSV-2 cause very similar acute infections but differ in their abilities to reactivate from trigeminal and dorsal root ganglia. To investigate differences in patterns of viral infection, we colabeled murine sensory ganglia for evidence of HSV infection and for the sensory neuron marker A5 or KH10. During acute infection, 7 to 10% of HSV-1 or HSV-2 antigen-positive neurons were A5 positive and 13 to 16% were KH10 positive, suggesting that both viruses reach each type of neuron in a manner proportional to their representation in uninfected ganglia. In murine trigeminal ganglia harvested during HSV latency, 25% of HSV-1 latency-associated transcript (LAT)- and 4% of HSV-2 LAT-expressing neurons were A5 positive, while 12% of HSV-1 LAT- and 42% of HSV-2 LAT-expressing neurons were KH10 positive. A similar difference was observed in murine dorsal root ganglia. These differences could not be attributed to differences in LAT expression levels in A5- versus KH10-positive neurons. Thus, HSV-1 demonstrated a preference for the establishment of latency in A5-positive neurons, while HSV-2 demonstrated a preference for the establishment of latency in KH10-positive neurons. A chimeric HSV-2 mutant that expresses the HSV-1 LAT exhibited an HSV-1 phenotype, preferentially establishing latency in A5-positive neurons. These data imply that the HSV-1 and HSV-2 LAT regions influence the ability of virus to establish latency in different neuronal subtypes. That the same chimeric virus has a characteristic HSV-1 reactivation phenotype further suggests that LAT-influenced establishment of latency in specific neuronal subtypes could be an important part of the mechanism by which LAT influences viral reactivation phenotypes.

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Reactivation of latent herpes simplex virus from explanted dorsal root ganglia

Journal of General Virology ◽

10.1099/0022-1317-75-8-2017 ◽

1994 ◽

Vol 75 (8) ◽

pp. 2017-2028 ◽

Cited By ~ 9

Author(s):

M. Ecob-Prince ◽

K. Hassan

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Dorsal Root Ganglia ◽

Dorsal Root ◽

Simplex Virus

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Evidence for a Bidirectional Element Located Downstream from the Herpes Simplex Virus Type 1 Latency-Associated Promoter That Increases Its Activity during Latency

Journal of Virology ◽

10.1128/jvi.74.8.3613-3622.2000 ◽

2000 ◽

Vol 74 (8) ◽

pp. 3613-3622 ◽

Cited By ~ 32

Author(s):

Herve Berthomme ◽

James Lokensgard ◽

Li Yang ◽

Todd Margolis ◽

Lawrence T. Feldman

Keyword(s):

Herpes Simplex Virus ◽

Herpes Simplex ◽

Thymidine Kinase ◽

Dorsal Root Ganglia ◽

Herpes Simplex Virus Type ◽

Dorsal Root ◽

Dna Fragment ◽

Simplex Virus

ABSTRACT Herpes simplex virus type 1 (HSV-1) latent infection in vivo is characterized by the constitutive expression of the latency-associated transcripts (LAT), which originate from the LAT promoter (LAP). In an attempt to determine the functional parts of LAP, we previously demonstrated that viruses harboring a DNA fragment 3′ of the LAT promoter itself were able to maintain detectable promoter expression throughout latency whereas viruses not containing this element could not (J. R. Lokensgard, H. Berthomme, and L. T. Feldman, J. Virol. 71:6714–6719, 1997). This element was therefore called a long-term expression element (LTE). To further study the role of the LTE, we constructed plasmids containing a DNA fragment encompassing the LTE inserted into a synthetic intron between the reporterlacZ gene and either the LAT or the HSV-1 thymidine kinase promoter. Transient-expression experiments with both neuronal and nonneuronal cell lines showed that the LTE locus has an enhancer activity that does not activate the cytomegalovirus enhancer but does activate the promoters such as the LAT promoter and the thymidine kinase promoter. The enhancement of these two promoters occurs in both neuronal and nonneuronal cell lines. Recombinant viruses containing enhancer constructs were constructed, and these demonstrated that the enhancer functioned when present in the context of the viral DNA, both for in vitro infections of cells in culture and for in vivo infections of neurons in mouse dorsal root ganglia. In the infections of mouse dorsal root ganglia, there was a very high level of promoter activity in neurons infected with viruses bearing the LAT promoter-enhancer, but this decreased after the first 2 or 3 weeks. By 18 days postinfection, neurons harboring latent virus without the enhancer showed no β-galactosidase (β-gal) staining whereas those harboring latent virus containing the enhancer continued to show β-gal staining for long periods, extending to at least 6 months postinfection, the longest time examined.

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