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Cytomegalovirus History, Biology and Treatment

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Historical Aspect

Human CMV (HCMV) is a very common human DNA virus. Since the beginning of human life; it has co-evolved with its host (McGeoch et al., 1995). Although being a part of humankind, not everybody is infected (Alford et al., 1990). It was first isolated in 1956 by Smith where two strains were isolated from the salivary gland and kidney of two dying infants. Cytomegalic inclusion bodies had been found in both tissues. In 1957, Weller and colleagues isolated three strains of CMV from adenoid tissues of three asymptomatic children after surgical removal. Also in 1970, they isolated three other strains from liver biopsy and urine of three congenitally infected infants with CMV (Ho, 2008).

In 1881, Ribbert was the first who observed the characteristic cells in the kidney of a stillborn infant but without interpretation of these observations and that was the first description of histologic features of infection (Naraqi, 1991). The first histopathological evidenve of CMV infection was identified in 1904 by Ribbert in tissues from a congenitally infected infant. Mistakenly the large inclusion-bearing cells observed at autopsy was assumed to be from protozoa. As a result, these cells were called protozoa like cells and many workers thought that they were protozoa. After that, the similiraties between these cells and those infected by Varicella-Zoster virus and Herpes simplex virus raised the suspicion of a viral cause. In 1920, Good pasture hypothesized the viral cause of such inclusions (Ho, 2008).

The first name proposed for CMV was salivary gland virus or salivary gland inclusion disease virus. In 1921, Good pasture and Talbot used the word cytomegalia to describe the huge enlargement and alterations of infected cells. Such word was the origin of the term cytomegalovirus initially proposed by Weller and colleagues in 1960 (Weller and Hanshaw, 1962).

The role of the virus as an important pathogen with different clinical manifestations was significantly identified during the 1970s and 1980s. The molecular biology, immunology, and antiviral therapeutic agents had been characterized. However, establishment of preventive strategies of CMV infection and determining the role of certain genes in viral pathogenesis still need more efforts (Sung and Schleiss, 2010).

Classification

Human CMV, designated as HHV5, is a member of the Herpesviridae family of viruses. It is one of the 8 human herpesviruses (HHV) (Schleiss, 2009). The Herpesviridae family is divided into three subfamilies designated α, β, and γ. The classification into these subfamilies is based on the features of host range, duration of reproductive cycle, cytopathology and characteristics of latent infection. DNA sequence analysis, guanine and cytosine (G + C) content snd serologic reactivity of gene products are the main criteria for subdivision of each subfamily into genera (Hanley and Bollard, 2014). The α subfamily includes herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) and varicella-zoster virus (VZV); the β subfamily includes cytomegalovirus (CMV) and the roseolaviruses, human herpes viruses 6 and 7, which are responsible for the clinical syndrome of exanthem subitum (roseola infantum) in young children, and the γ subfamily includes Epstein-Barr virus and human herpes virus 8. All of these viruses share similarities in virion morphology and genome organization (Schleiss, 2009). Human herpesvirus classification is represented in table ( ) (Ryan and Ray, 2004).

Table (1): Humah haerpesvirus (HHV) classificstion

Type

Synonym

Subfamily

Primary Target Cell

Pathophysiology

Site of Latency

Means of Spread

HHV-1

Herpes simplex virus-1 (HSV-1)

α (Alpha)

Mucoepithelial

Oral and/or genital herpes (predominantly orofacial), as well as other herpes simplex infections

Neuron

Close contact (oral or sexually transmitted infection)

HHV-2

Herpes simplex virus-2 (HSV-2)

α

Mucoepithelial

Oral and/or genital herpes (predominantly genital), as well as other herpes simplex infections

Neuron

Close contact (sexually transmitted disease)

HHV-3

Varicella zoster virus (VZV)

α

Mucoepithelial

Chickenpox and shingles

Neuron

Respiratory and close contact

HHV-4

Epstein-Barr virus (EBV), lymphocryptovirus

γ (Gamma)

B cells and epithelial cells

Infectious mononucleosis, Burkitt' lymphoma, CNS lymphoma in AIDS patients, post-transplant lymphoproliferative syndrome (PTLD), nasopharyngeal carcinoma, HIV-associated hairy leucoplakia

B cell

Close contact, transfusions, tissue transplant, and congenital

HHV-5

Cytomegalovirus (CMV)

β(Beta)

Monocyte, lymphocyte, and epithelial cells

Infectious mononucleosis-like syndrome, retinitis, etc.

Monocyte, lymphocyte, and?

Saliva, urine, breast milk, etc

HHV-6A and 6B

Roseolavirus, Herpes lymphotropic virus

β

T cells and ?

Sixth disease (roseola infantum or exanthema subitum)

T cell and ?

Respiratory and close contact

HHV-7

Pityriasis Rosea

β

T cells and ?

? (roseola infantum or exanthema subitum)

T cell and ?

?

HHV-8

Kaposi's sarcoma -associated herpesvirus (KSHV), a type of rhadinovirus

γ

Lymphocyte, and other cells

Kaposi'sarcoma, primary effusion lymphoma, some types of multicentric Castleman's disease

B cell

Close contact (sexual), saliva?

Quoted from (Ryan and Ray , 2004).

Biology of Cytomegalovirus

Morphology:

Cytomegalovirus is an enveloped virus with a double-stranded DNA genome. The three distinct regions of the CMV virus particle include: an icosahedral capsid; the tegument layer; and an outer lipid envelope. The morphology of CMV is demonstrated in the electron microscopy (EM) studies shown in Fig. (). The capsid, which comprises 162 capsomere subunits arranged in an icosahedral symmetry, houses the viral genome, and is classically highly electron-dense when imaged by EM (Schleiss, 2011).

In the virus particle, the capsid is surrounded by the tegument, a protein-rich layer containing several of the dominant targets of the T-lymphocyte response to infection, including a 65-kilodalton (kDa) phosphoprotein (pp) referred to as pp65 (Kern etal., 2002). Surrounding the tegument is the envelope layer which contains several virally-encoded glycoproteins (g), including protein complexes designated as the gB complex, the gM/gN complex, and the gH/gL/gO complex. CMV-seropositive individuals mount an immune response characterized by neutralizing antibodies that target these glycoproteins (Bernstein, 2011). In addition to serving as targets of the humoral immune response, these glycoproteins also play a central role in the binding and entry of CMV into cells (Ryckman etal., 2006).    

As a result of the variability in the thickness of the tegument, the complete virion varies in size from 150 to 200 nm in diameter. The genome is about 64 nm in diameter with a molecular weight of 100 x 106 to 150 x 106. The capsid is 110 nm in diameter (Subhendu et al., 2007).

During the process of viral replication, a variety of types of CMV particles are generated. In cell culture, CMV infection leads to the assembly and release of, in addition to infectious virions, non-infectious defective particles termed "dense bodies" (DB), so designated because of their characteristic highly electron-dense appearance when imaged by EM. Another type of body, designated as a "noninfectious enveloped particle" (NIEP), is also generated during viral replication as designated in Fig. () (Pepperl etal., 2000). The structure and protein composition of NIEPs are comparable to those of virions, but they lack DNA and are therefore not infectious (Schleiss, 2011). DBs are enveloped spherical structures that lack capsid proteins and DNA (Pepperl etal., 2000). They consist mainly of viral tegument proteins and glycoproteins. In cell culture, the biology of DBs mimics that of infectious virus, since DBs enter cells efficiently and deliver their protein components intracellularly (Mersseman etal., 2008). In principle, DBs could induce a broad range of humoral and cellular immune responses (Schleiss, 2011).

Cytomegalovirus particles exhibit additional levels of complexity. Using CMV gene array technology, a class of viral RNA transcripts, termed virion RNAs, has been identified in infectious virions (Bresnahan and Shenk, 2000). These RNAs, which are packaged during virion assembly, are delivered to the host cell immediately on infection, potentially allowing viral gene products to be expressed in an infected cell before any viral transcription or host immune response occurs. The role of virion


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