Alphaherpesviruses

Fast Shingles Cure

How To Cure Shingles In 3 Days

Get Instant Access

Human Alphaherpesvirus Members and Associated Diseases

Three human herpesviruses belong to the alphaherpesvirus subfamily: HSV-1, HSV-2, and VZV. HSV-1 and HSV-2 belong to the genus simplexvirus, are very closely related at genetic and nucleic acid levels, and produce similar diseases (reviewed by Whitley and Gnann (13)). Clinically, both HSV-1 and HSV-2 cause a variety of syndromes ranging from inapparent infections and self-limiting cutaneous lesions to fatal encephalitis. In addition, both viruses establish and maintain a latent state in nerve cells from which recurrent HSV infections arise.

In a primary infection, HSV enters the body through a mucosal membrane or abraded skin and establishes infection locally in epithelial cells. Viral replication in the epithelial cells results in the amplification of virus, the formation of a virus-filled blister, and the elicitation of both cellular and humoral immune responses. The virus then spreads from the site of primary infection by retrograde transport to the nuclei of sensory neurons that innervate the site of the local infection (14). Studies using animal models have indicated that a limited viral replication occurs within these neurons followed by the establishment of latency. A latent HSV infection is characterized by the presence of viral genomes in the nuclei of sensory ganglia neurons and the absence of viral replication or protein production (reviewed by Hill [15]).

A latent HSV infection is maintained for the life of the host, but the virus (in some individuals) can be reactivated periodically to produce infectious virus resulting in asymptomatic shedding or recurrent disease. During reactivation, viral replication occurs within the reactivated neuron, and the virus is transported back down the axon, where it can establish an infection in the epithelia of the skin. Studies using both animal models and human subjects have shown that viral reactivation can be triggered by a variety of stressful or stress-related stimuli including heat, ultraviolet light, fever, hormonal changes, menses and surgical trauma to the neuron (16-19). Although the virus appears to be latent most of the time, HSV infection probably is best characterized as reoccurring reactivations divided by periods of latency.

VZV belongs to the genus varicellavirus and is related genetically at the amino acid sequence level to both HSV-1 and HSV-2 (20). VZV gets its name from the two dis eases it causes: the childhood disease varicella (more commonly known as chickenpox) and the adult disease herpes zoster (commonly known as shingles). Varicella is the clinical outcome of a primary VZV infection, while herpes zoster is the result of the reactivation of latent VZV. Although HSV can reactivate frequently, VZV generally reactivates only once during the host's lifetime (21).

VZV is considered to be endemic among most populations (22). The majority of varicella cases occur in children younger than 10 of age and can be epidemic among cloistered children, such as schools, nurseries, etc. A VZV infection begins as a result of direct contact with viral lesions or inhalation of airborne droplets. A primary viremia develops that results in the spread of virus to multiple organs, including the spleen and liver (23). A secondary viremia, mediated by lymphocytes, results in the spread of virus to cutaneous epithelial cells and the development of characteristic "chicken pox" lesions. VZV is communicable at least 1-2 d prior to the onset of a rash and during the presence of the virus-infected lesions.

Epidemiology of Alphaherpesvirus Infections

Epidemiologic studies of HSV-1 and HSV-2 based on clinical symptoms alone are inadequate due to the fact that many primary infections are asymptomatic (13). Primary HSV-1 infections occur most often in young children and present clinically as gingivostomatitis. Primary infection is associated with socioeconomic factors such that individuals in lower socioeconomic classes seroconvert at an earlier age when compared to members of higher socioeconimic classes (reviewed by Whitley and Gnann [13]). In the United States, the seroprevalence for HSV-1 increases from 20% to 40% in children under the age of 4 to approx 80% among individuals over the age of 60 (24).

The seroprevalence of HSV-2 is lower than that of HSV-1 primarily because its mode of transmission is most often through sexual encounters. Fleming and colleagues (25) recently reported that the age-adjusted seroprevalence of HSV-2 in the United States has risen 30% during the last 13 yr to 20.8% or one in five individuals. These rather disturbing results indicate that sexual transmission of HSV-2 has not abated, but has continued to increase to alarming levels.

Varicella zoster virus is fairly ubiquitous in the general population with the majority of individuals seroconverting during childhood (26). With the advent and use of the live attenuated varicella vaccine (LAVV), which is recommended to be given to pre-school-age children, the incidence of VZV infections should diminish. The LAVV vaccine has been shown to be quite effective (85-95%) in preventing development of chickenpox (27,28).

Overview of Replication

Our current understanding of the replication cycle of herpesviruses is due to the extensive amount of research performed on HSV-1 replication. For the purposes of this chapter, we use the replication cycle of HSV-1 as our model for herpesvirus replication. HSV replication begins with the enveloped virus particle binding to the outside of a susceptible cell resulting in a fusion between the viral envelope and cellular membrane (Fig. 3). As a result of membrane fusion, the nucleocapsid enters the cell cytoplasm and migrates to the nuclear membrane. The viral genome is released from the

Fig. 3. Schematic of herpes simplex virus replication cycle. 1. Virus particles bind to specific receptors on cell surface. Fusion occurs between the viral envelope and cell membrane, resulting in the release of the nucleocapsid into the cytoplasm. 2. Viral nucleocapsid migrates to the nuclear membrane. 3. Viral DNA is released from the nucleocapsid and enters the nucleus through a nuclear pore. 4. HSV transcription is initiated in a coordinated, cascade fashion producing the three classes of mRNA, a, P, and y. Viral mRNA is transported to the cytoplasm where translation occurs. 5. The different viral proteins are produced and transported to their appropriate cellular location. Alpha (a) proteins are involved in regulation of viral transcription; P proteins are involved primarily in DNA synthesis; y proteins represent primarily structural proteins. 6. Synthesis of viral DNA occurs through a rolling circle mechanism in the nucleus producing DNA concatamers. 7. Empty capsid structures are assembled in the nucleus and unit length viral DNA is packaged into the capsid producing a nucleocapsid. 8. The nucleocapsid buds through the nuclear membrane and is released from the cell (9).

Fig. 3. Schematic of herpes simplex virus replication cycle. 1. Virus particles bind to specific receptors on cell surface. Fusion occurs between the viral envelope and cell membrane, resulting in the release of the nucleocapsid into the cytoplasm. 2. Viral nucleocapsid migrates to the nuclear membrane. 3. Viral DNA is released from the nucleocapsid and enters the nucleus through a nuclear pore. 4. HSV transcription is initiated in a coordinated, cascade fashion producing the three classes of mRNA, a, P, and y. Viral mRNA is transported to the cytoplasm where translation occurs. 5. The different viral proteins are produced and transported to their appropriate cellular location. Alpha (a) proteins are involved in regulation of viral transcription; P proteins are involved primarily in DNA synthesis; y proteins represent primarily structural proteins. 6. Synthesis of viral DNA occurs through a rolling circle mechanism in the nucleus producing DNA concatamers. 7. Empty capsid structures are assembled in the nucleus and unit length viral DNA is packaged into the capsid producing a nucleocapsid. 8. The nucleocapsid buds through the nuclear membrane and is released from the cell (9).

capsid structure and enters the nucleus through nuclear pores. Once inside the nucleus, viral-specific transcription and translation, and replication of the DNA genome occur.

HSV genes are divided into three major temporal classes (a, P, and y) that are regulated in a coordinated, cascade fashion (for review see Roizman and Sears [1]). The a or immediate-early (IE) genes contain the major transcriptional regulatory proteins, and their production is required for the transcription of the P and y gene classes. P proteins are not produced in the absence of a proteins, and their synthesis is required for viral DNA replication. The P proteins consist primarily of proteins involved in viral nucleic acid metabolism. The y proteins reach peak rates of synthesis after the onset of DNA replication and consist primarily of viral structural proteins.

Once synthesized, the viral DNA is packaged into preformed capsid structures and the resulting nucleocapsid buds through the nuclear membrane, obtaining its envelope. The replication of HSV is fairly rapid, occurring within 15 h after infection, and it is extremely lethal to the cell resulting in cell lysis and death.

Latency

A hallmark of all herpesviruses is the ability to establish and maintain a latent infection. Latency is defined as a state of infection in which the viral genome persists in the infected cell in the absence of any viral replication, although depending on the specific herpesvirus, there may be a limited amount of viral transcription. Latency results in the long-term survival of the virus in its host and is why herpesvirus infections are described as once infected, always infected. Indeed, herpesvirus infections are for life.

Latent herpesvirus infections can be reactivated resulting in the production of a lytic cycle of replication and recrudescent disease. The frequency of reactivation and the type of recrudescent disease varies among the different human herpesviruses.

Members of the alphaherpesvirinae subfamily establish latent infections in sensory ganglia. Evidence from both human and animal models have demonstrated that the site for HSV latency is the neuron (29-31). Identification of the site of VZV latency is less clear with some laboratories advocating the neuron while others point to ganglionic cells surrounding the neuron (32,33).

Neurons latently infected with HSV do not produce virus or detectable virus-specific proteins. While the absence of virus production suggests that viral gene transcription is absent, a small subset of viral transcripts, termed the latency associated transcripts (LATs), are transcribed during active and latent infections (34-38). The function of the LAT transcripts is unclear. Viral deletion mutants indicate that the LATs are not required to establish latent infection (39,40), although a decreased frequency of reactivation in LAT mutants has been reported (41-44).

Reactivation of HSV begins within the latently infected neuron. Following reactivation, the virus is transported down the axon of the neuron and establishes a peripheral infection in the skin. Recurrent HSV infections are generally less severe compared to primary infections both in terms of number of lesions formed and length of appearance (45).

In immunocompetent hosts, active herpes simplex virus infections rapidly stimulate immune responses that function to restrict viral replication and the spread of virus. In addition, the host's immune response is most likely involved in the establishment of latent infections. In fact, the establishment of latency could be viewed as a double-edged sword. It provides the host with a mechanism to limit viral spread and cellular damage while, at the same time, ensuring the persistence and survival of the virus. In HSV-infected neonates and immunocompromised hosts, virus replicates to high titers, often with wide dissemination and generally extensive viral pathology. While the mechanisms involved in controlling HSV replication and establishment of latency are not completely understood, it has become increasingly evident that they involve interactions among nervous, immune and endocrine systems (reviewed in Turner and Jenkins [46]).

VZV latency appears to be quite different from HSV. There are no LAT homologs in VZV, and therefore there is no equivalent LAT gene expression during latency. Several laboratories have reported, however, the detection of gene expression from several

VZV genes in latently infected ganglia (47-49). Because these genes also are expressed during a lytic replication, what role, if any, they play in VZV latency is unclear (reviewed by Kinchington [50]). Reactivation of latent VZV causes the disease herpes zoster, or shingles. This reactivated disease is quite different from recurrent HSV lesions in that the resulting rash and blisters occur throughout an entire dermatome (an area of the skin that is innervated by a single spinal nerve [21]). The appearance of VZV vesicles in a dermatome is evidence that following viral reactivation, the infection spreads throughout the ganglia and is transported to the skin via the numerous axons associated with that ganglia. Fortunately, zoster rarely occurs more than once in a lifetime.

Was this article helpful?

0 0
How To Bolster Your Immune System

How To Bolster Your Immune System

All Natural Immune Boosters Proven To Fight Infection, Disease And More. Discover A Natural, Safe Effective Way To Boost Your Immune System Using Ingredients From Your Kitchen Cupboard. The only common sense, no holds barred guide to hit the market today no gimmicks, no pills, just old fashioned common sense remedies to cure colds, influenza, viral infections and more.

Get My Free Audio Book


Post a comment