Novel Approach to Herpesvirus Infections

Stop Herpes Now

You'll discover: What foods are bad for you, encouraging outbreaks. What foods are good for discouraging outbreaks. The connection between genital herpes and stress. What herbs actually suppress the herpes virus. How to heal your body naturally and safely. How to manage stress in your life.

Stop Herpes Now Summary


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Author: Dr. David Hogg
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Inhibition of Viruses by RNAi

The first demonstration of RNAi-mediated inhibition of a human pathogenic virus was reported by Bitko and Barik in 2001 (Bitko and Barik 2001). These authors reported a tenfold inhibition of human respiratory syncytial virus (HRSV) replication in vitro using nanomolar concentrations of synthetic siR-NAs that targeted the viral polymerase subunit P and the fusion protein F. Currently, many other studies have described RNAi-mediated inhibition of a large variety of viruses. RNAi-mediated inhibition of HIV-1 has received much attention (see below, Tables 1 and 2). In addition, 17 different RNA viruses, and 10 different DNA viruses have been efficiently targeted by RNAi (Tables 3 and 4). These include important human pathogens such as hepatitis C virus (HCV), dengue (DEN) virus, severe acute respiratory syndrome (SARS) coronavirus, poliovirus, influenza A virus, hepatitis D virus (HDV), human rhinovirus-16 (HRV-16), hepatitis B virus (HBV), herpes simplex virus type-1 (HSV-1), human...

Selecting Functional Ribozymes

A related strategy, based on the selection of'external guide sequences' (EGS) has been applied by Kilani et al. (2000). To inhibit expression of herpes simplex virus (HSV)-1 and human cytomegalovirus (HCMV) mRNA in vivo, they used the M1 ribozyme, derived from the catalytic RNA subunit of RNase P (Trang et al. 2000). The M1 ribozyme cleaves an RNA helix that resembles its natural transfer (t)RNA substrate. When covalently linked to an EGS, M1 RNA can be engineered into a sequence-specific endonuclease, the M1GS RNA, which cleaves any target RNA that can form base pairs with the guide sequence. To date only selection strategies to find guide sequences for RNase P or M1GS RNA variants with high catalytic activity have been applied, but its potential utility for mapping accessible target sites was already proposed (Raj and Liu 2003, 2004).

Viruses Utilize RNAi in Their Replication Strategy

Alternatively, viruses could exploit RNA silencing to control the expression of genes of viral or host origin. The first example was recently provided for EBV, a large DNA virus of the herpes family that preferentially infects human B cells (Pfeffer et al. 2004). When the small RNAs from a latently EBV-infected Burkitt's lymphoma cell line were cloned, 4 of them originated from two regions of the EBV genome. A computational method was used to identify potential targets of these EBV-encoded miRNAs. Among the predicted targets were regulators of cell proliferation, apoptosis, transcriptional regulators and components of signal transduction pathways. Although these targets should be verified experimentally, it is striking that several of these genes have more than one binding site for a particular EBV-miRNA. Degradation of a cellular DNA polymerase was demonstrated experimentally (Pfeffer et al. 2004). Furthermore, the expression of the EBV-miRNAs was shown to differ in the lytic versus...

Clinical Applications

Couraging results in laboratory experiments and have been evaluated in the clinic. One of them, Vitravene, developed by Isis Pharmaceuticals, has been approved by the US Food and Drug Administration (FDA) in 1998. Vitravene (sodium fomivirsen) is used to treat an inflammatory viral infection of the eye, caused by cytomegalovirus (CMV) in immunocompromised patients and in patients with acquired immunodeficiency syndrome (AIDS) (Opalinska and Gewirtz 2002). Another representative of antiviral agents is ISIS 14803 a phos-phorothioated ODN directed against the hepatitis C virus (HCV). The results of phase I clinical trials have been reported (Soler et al. 2004). The study was performed on 24 patients with chronic hepatitis C. Two of the patients showed significant viral load reduction and nine of them minor viral load reduction. AS-ONs have also been used in combating inflammation, cardiovascular diseases, and cancer. Oligonucleotides could also play a role in immunotherapy, because of...

Application in Disease Treatment

Although the first publication about using As-ODNs in cells appeared more than two decades ago (Zamecnik and Stephenson 1978), antisense technology has not achieved the initially anticipated breakthrough as a therapeutic tool. To date only one antisense drug, Vitravene (Isis Pharmaceuticals, Carlsbad, CA, USA), which targets the cytomegalovirus IE2 mRNA, has been approved by the Food and Drug Administration (FDA), and approximately 20 are in clinical trials (Crooke 2004). In addition to difficulties accessing the target RNA, problems with delivery, stability and toxicity have been hampering the development of antisense drugs. Recent progress to overcome these problems has been made by chemical modification of antisense agents. Chemical modifications were often used as part of a strategy to increase the stability of the antisense agent, thereby lowering its effective concentration and reducing its toxicity for in vivo applications (Kurreck 2003). For instance, Jakobsen et al. (M.R....

Stable Intracellular Expression of Short Hairpin RNA

The addition of chemically or enzymatically synthesized siRNA to cells is the most convenient way to induce RNAi in the laboratory setting, but stable intracellular expression may be required for several therapeutic applications. The first vectors for the expression of functional siRNA mostly short hairpin (sh)RNA were described in 2002 (Brummelkamp et al. 2002 Paddison et al. 2002). Several improvements have been reported, but much optimization is still to be expected. RNA polymerase III (Pol III) promoters have been widely used to express shRNA for silencing a variety of target genes (Brummelkamp et al. 2002), and several modifications of this system were recently published. It was reported that the enhancer from the cytomegalovirus immediate-early promoter (a Pol II unit) can enhance the synthesis of siRNA from a Pol III unit (Xia et al. 2003).

Viral reproduction Dna Rna or retro

Different viruses use different nucleic acids (DNA or RNA) as the genetic material. Some, like herpes, use DNA. Some, like the flu, use RNA. And some (like HIV) use both, alternating back and forth. This third type of virus is called a retrovirus. Retroviruses use the enzyme reverse-transcriptase to make RNA from DNA (refer to Figure 18-1).

Arbovirus and Gene Therapy

Cheng et al. also indicated that the VP22, a herpes simplex virus type 1 (HSV-1) tegument protein, strategy applied in the context of Sindbis virus replicon particles might enhance the generation of a highly effective vaccine for widespread immunization 45 . Zhnag et al. reasoned that Sindbis-virus-based vectors might be good for gibbon ape leukemia virus envelope glycoprotein (GALV.fus) gene transfer because high-titer stocks can easily be caused in hamster cells and Sindbis virus efficiently infects human tumor cells through the high-affinity 67 kDa laminin receptor 46 . They reported that Sindbis vectors expressing GALV.fus could be packaged into contagious viral particles to high titer, exhibited potent bystander cytopathic activity and were active against U87 glioma xenografts 28 . They concluded that Sindbis-virus-based replicons was efficient vector systems for delivery and expression of fusogenic membrane glycoproteins 46 . In 1998, Swai and Meruelo explored the...

Conservation Implications

Et al., 2003) and 20 ring-tailed lemurs at Beza Mahafaly using PCR analysis (Miller et al., in press) have been negative. At the first ring-tailed lemur site, which is an isolated reserve with reduced human contact, it is unlikely that domestic or feral cats are common. At the second site, the reserve is intact but the surrounding areas have had considerable human impact. Nearby villages do contain domestic cats in low numbers, and a preliminary screening of several cats found that 50 of the sample (3 of 6) exhibited positive titers to toxoplasmosis (Mills, Conrad, and Lappin, personal communication). A potentially greater threat comes from the more numerous Ampaha (feral cats), which have been seen stalking ring-tailed lemurs in areas outside of the reserve (Sauther, personal observation). It remains to be seen if the Ampaha exhibit positive titers, but if so they could provide an avenue for transmission to the lemurs. Similarly, old and new world primate species are susceptible to...


Another approach proposed for delivery of nucleic acid molecules employs viral vectors, in which genes essential for virus replications have been replaced with sequences of interest (Hoeller et al. 2002 Thomas et al. 2003). The main classes of viral vectors that have been utilized include retroviruses, ade-noviruses, lentiviruses, adeno-associated viruses, and herpes simplex viruses. Although the retroviral strategy appears to be very effective, there are some safety issues that need to be dealt with (Kalota et al. 2004).


The expression of non-host RNA in a cell must also be considered, given that cells have evolved elaborate mechanisms for detecting and eliminating foreign RNA and DNA, for example, from viruses. The measures evolved by viruses to ensure the uptake and expression of their own genetic material perhaps highlight the need to be sophisticated in attempts to transfer genetic material to human cells. There has been a relatively high degree of success using constitutive and inducible expression systems in human cells. A wide variety of promoters have been used to constitutively express genes including ribozymes and small hairpin (sh)RNAs that are Pol II- and Pol III-dependent (Brummelkamp et al. 2002). It is not just expression per se a key issue appears to be the intracellular location, in that investigators have demonstrated the need to co-localise the target and therapeutic RNA (Kuwabara et al. 2001 Bertrand et al. 2001). This is particularly true for ribozymes that do not utilise a host...


Bmdc Culture

Tracing of BMDC in the kidney using reporter genes relies on the expression of the reporter gene (i.e. the transgene) by the BMDC. Expression of the reporter gene at all times can only be accomplished if the gene is driven by a promoter of a ubiquitously expressed gene, such as mouse metallothionein 18 19 , P-actin from human 20 , rat 21 and chicken 22 , ubiquitin 23 , simian virus 40 24 , cytomegalovirus immediate-early 25 or ROSA 26 26 . Green fluorescent protein (GFP) is responsible for the green bioluminescence of the jellyfish Aequorea Victoria. Using this protein, transgenic mouse lines were generated, in which all tissues emitted green light under excitation. However, the first generation GFP transgenic mice proved to be unsuitable for use in experimental renal disease models, since GFP was, in the healthy animal, not expressed in all renal components 7 37 . If, in the setting of GFP+ bone marrow transplantation, BMDC regulate GFP in a similar way as kidney cells and BMDC...

Imiquimod [

Imiquimod is a new famous immunomodulative drug. Imiquimod is a new product recently introduced to physicians. Imiquimod, an imidazoquinoline amine, is a new immune response modifier agent recently approved for the local application in treatment of treatment of external genital and perianal warts 15-24 . Compared with the other routine therapeutic options for genital and perianal warts, imiquimod is less complicated to use and can be self-administrated by affected patients. Imiquimod poses no direct antiviral or antiproliferative activity when tested in a number of cell culture systems. Its activity for anti-herpes virus activity was accepted. One of the first analogs in the series, S -25059 was tested in the early 1980's and due to its slight toxicity, caused some reduction of pathology from herpes infection in cell cultures 15-17 . The dosage form of imiquimod is cream, generally known as ALDARA.(5) The chemical name of imiquimod is 1-(2-methylproply)-1 H-imidazol 4,5-c quinolin - 4...