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Review
. 2013 Apr 9:6:1-16.
doi: 10.4137/JCD.S10803. eCollection 2013.

Bovine Herpes Virus 1 (BHV-1) and Herpes Simplex Virus Type 1 (HSV-1) Promote Survival of Latently Infected Sensory Neurons, in Part by Inhibiting Apoptosis

Clinton Jones  1
Affiliations
Review

Bovine Herpes Virus 1 (BHV-1) and Herpes Simplex Virus Type 1 (HSV-1) Promote Survival of Latently Infected Sensory Neurons, in Part by Inhibiting Apoptosis

Clinton Jones. J Cell Death. .

Abstract

α-Herpesvirinae subfamily members, including herpes simplex virus type 1 (HSV-1) and bovine herpes virus 1 (BHV-1), initiate infection in mucosal surfaces. BHV-1 and HSV-1 enter sensory neurons by cell-cell spread where a burst of viral gene expression occurs. When compared to non-neuronal cells, viral gene expression is quickly extinguished in sensory neurons resulting in neuronal survival and latency. The HSV-1 latency associated transcript (LAT), which is abundantly expressed in latently infected neurons, inhibits apoptosis, viral transcription, and productive infection, and directly or indirectly enhances reactivation from latency in small animal models. Three anti-apoptosis genes can be substituted for LAT, which will restore wild type levels of reactivation from latency to a LAT null mutant virus. Two small non-coding RNAs encoded by LAT possess anti-apoptosis functions in transfected cells. The BHV-1 latency related RNA (LR-RNA), like LAT, is abundantly expressed during latency. The LR-RNA encodes a protein (ORF2) and two microRNAs that are expressed in certain latently infected neurons. Wild-type expression of LR gene products is required for stress-induced reactivation from latency in cattle. ORF2 has anti-apoptosis functions and interacts with certain cellular transcription factors that stimulate viral transcription and productive infection. ORF2 is predicted to promote survival of infected neurons by inhibiting apoptosis and sequestering cellular transcription factors which stimulate productive infection. In addition, the LR encoded microRNAs inhibit viral transcription and apoptosis. In summary, the ability of BHV-1 and HSV-1 to interfere with apoptosis and productive infection in sensory neurons is crucial for the life-long latency-reactivation cycle in their respective hosts.

Keywords: alpha-herpesviruses; apoptosis; latency in sensory neurons; non-coding RNAs.

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Figures

Figure 1
Figure 1
Location of genes within the HSV-1 repeats. (Panel A) UL and U denote the unique sequences of the long (L) and short (S) components of the genome. The boxes depict repeat sequences. (Panel B) Transcription map of the repeat region. Location and orientation of LAT,, ICP0, α134.5,, ORFP, L/STs are indicated by solid lines. Note: Partially mapped transcripts (αX and αX) are denoted by dashed arrows.,
Figure 2
Figure 2
Schematic of putative factors encoded within the LAT locus. (Panel A) Schematic of genes within the long repeats that contain the LAT locus. The large arrow indicates the primary LAT transcript. The solid rectangle represents the sTable 2 kb LAT intron. Initiation of LAT transcription is denoted by the arrow at +1 (genomic nucleotide 118801). Several restriction enzyme sites and the relative locations of the ICP0 and ICP34.5 transcripts are shown for reference. The location of the 6 microRNAs (miR-H1-6) that is located within the 8.5 kb LAT are shown. (Panel B) Partial restriction map of LAT and position of LAT open reading frames (L1-8) within the first 1.5 Kb of strain McKrae LAT coding sequences, which were based on previous studies. The numbering system of the ORFs was consistent with a previous study. Only the ORFs with at least 30 amino acids are shown (the number of amino acids in each ORF is denoted by the numbers in brackets). Open circles denote the position of two LAT small RNAs that are encoded within the first 1.5 kb LAT coding sequences. Positions of UOL transcript, AL transcript, and ORFs located on the opposite strand of LAT (AL2 and AL3) are shown. The number of amino acids of AL2 and AL3 are in brackets. Nucleotide positions relative to the start of LAT transcription are not shown in parenthesis.
Figure 3
Figure 3
Schematic of the BHV-1 LR gene and surrounding genes. (Panel A) The start sites for LR transcription during latency and productive infection were previously described., (Panel B) Organization of LR ORFs and 3′ terminus of bICP0. ORF-1 and ORF-2 are located in the LR gene and have the potential to encode a 40 or 25 kd protein respectively. Notes: Reading Frames B (RF-B) and C (RF-C) are open reading frames that lack an initiating Met. The (*) denotes the position of stop codons that are in frame with the respective ORF. The positions of ORF-E and bICP0, which are antisense to LR-RNA, are also shown.
Figure 4
Figure 4
Putative steps that occur during the latency-reactivation cycle. Note: For details, see text.
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