**6. Polyomaviruses (BKV, JCV)**

ever, IVIG or VZV immunoglobulin (VZIG) have been used in those with severe infection. Patients with disseminated or organ invasive herpes zoster should be treated with IV acyclovir. Localized nonsevere dermatomal herpes zoster can be treated with oral acyclovir, valacyclovir

Oral acyclovir and its pro-drugs have been shown to prevent VZV reactivation in immuno‐ suppressed population. During the early post-transplant period, many current regimens used for CMV prevention will likely prevent VZV reactivation. In patients who do not receive CMV prophylaxis, short-term antivirals given for HSV prophylaxis may also be effective against VZV during the period immediately post-transplant [65]. Other authors recommended one year prophylactic with acyclovir, which has been shown to effectively prevent VZV-reactiva‐

In the U.S., potential transplant recipients who are susceptible to VZV should be given varicella vaccination (one or two doses) with live attenuated Oka vaccine (Varivax, Merck & Co., Inc., Whitehouse Station, NJ, USA). There is currently a herpes zoster vaccine (Zostavax, Merck & Co., Inc.) that has not been studied in patients with end-organ disease awaiting transplantation. The Oka varicella vaccines have been shown to be safe in select children undergoing chemo‐ therapy, and studies have shown that they can be given safely to posttransplant recipients receiving immunosupression. Inactivated VZV vaccines, which are in development, may

Herpes simplex virus type 1 (HSV1) and herpes simplex virus type 2 (HSV2) are members of the Herpesvirus family and is transmitted via close personal contact. Seroprevalence studies indicated that infections are common worldwide and increases with age [2, 69]. More than 90% of adult have acquired HSV infection by their fifth decade of live, though only a minority develop clinically apparent disease at the time of acquisition [70]. After the first contagion, HSV stays in latent condition for a lifetime. HSV1 is acquired predominantly during childhood age, while HSV2 is acquired by sexual contact. A recent study indicated that HSV1 can also cause genital herpes (71). In immunocompetent individuals, symptomatic disease is presented as orolabial or genital herpes [72, 73]. Symptomatic disease may occur as a first episode that heals in 10–21 days, followed by the establishment of latency and the risk of subsequent episodes of reactivation. Cell-mediated immunity plays an important role in host defense and the containment of infection [74]. Individuals with impaired cell-mediated immunity, such as immunosupressed and transplanted patients, are subject to more frequent episodes of reactivation, prolonged duration of symptoms and shedding, increased severity of infection, and a greater potential for dissemination [75]. Solid organ transplant patients have had pretransplant HSV seropositivity rates and age distributions similar to the general population. In the absence of antiviral prophylaxis, seropositive recipients often experience reactivation of latent infection within one or two months after transplantation [76]. Mucocutaneous lesions are the majority of HSV disease in transplant population, mainly with orolabial and anogenital

tion after allogeneic hematopoietic stem cell transplantation [61].

eventually provide another option for this high-risk population [65–68].

or famcyclovir [65].

110 Immunopathology and Immunomodulation

**5. Herpes simplex virus**

Polyomaviruses are ubiquitous, infecting many different mammalian species including humans. Most human polyoma-diseases are caused by JCV and BKV. The prevalence of infections differs in geographical and age distribution, suggesting they circulate independ‐ ently. BKV infection is acquired in early childhood, whereas JC presents later. Transmission of BKV occurs typically via oral and respiratory routes, but data suggests transmission via cells and tissues, in particular by kidney transplantation [81]. Approximately 50%–80% of humans have seropositivity to JCV and BKV viruses due to multiple routes of transmission [82, 83]. Clinically apparent diseases in immunocompetent hosts are extremely rare and are not associated with any well-defined clinical syndrome. After primary infection, viruses remain latent possibly in the lymphoid organs, neuronal tissue, kidney, and tubular epithelial cells. About 5% of healthy individuals intermittently reactivate BKV replication with detectible viruria [84]. Under the circumstances of severe immunosuppression both viruses reactivate. BKV can cause pneumonitis, hepatitis, retinitis, and meningoencephalitis [85]. Hemorrhagic cystitis is seen in 25–60% of bone marrow transplant patients, usually 2 weeks after transplan‐ tation [86]. Up to 80% of renal transplant patients have BK viruria, and 5%–10% progress to BKV nephropathy (BKVN) [87]. Given that polyomavirus is widely latent in the kidney, renal transplantation is believed to be an important mode of infection in patients with end stage kidney disease. Graft loss rate have been reported to be as high as 30%–50% following a diagnosis of BKVN [88]. More recent data indicate that with early diagnosis of BK viremia or viruria using regular screening, the majority of patients respond favorably [89, 90].

Serologic testing may be used in risk-assessment of virus transmission via organ transplanta‐ tion. The greatest risk of post-transplant viral reactivation is associated with positive serostatus of both the donor and recipient. The presence of IgG antibody to BKV-VP-1 in serum is associated with increased risk of virus transmission and disease in renal allograft recipient [91]. To detect viral replication in urine and blood, real time PCR is the method of choice for diagnosis of BKVN [92] and screening every 3 months for the first two years after transplant or when allograft dysfunction occurs is recommended [93].

The first line of treatment of BKV nephropathy is reduction of immunosupression [92, 93]. A variety of drugs with possible anti-BKV activity that are being utilized as adjuvant therapy but fraught with side-effects are cidofovir, leflunomide, and intravenous immunoglobulin [94]. Fluoroguinolons have been reported to display anti-BK activity because of its large Tantigen helicase activity [95]. Further studies are needed to firmly establish the role of polyoma viruses in human cancer [96].

Other polyomavirus with importance of human pathology is JCV. Progressive multifocal leukoencephalopathy (PML) is a progressive demyelinating central nervous system disorder involving cerebral white matter caused by the JCV. It most often presents as an opportunistic infection in HIV patients with lymphopenia but has recently been seen with new immuno‐ suppressives. After reactivation in severely immunosuppressed states, the virus travels to the central nervous system through infected B-lymphocytes, where it produces lytic destruction of myelin producing glial cells (i.e., oligodendrocytes) and non-lytic infection of astrocytes, causing progressive disease in central nervous system. Typical PML patients have very low CD4+T cell counts even less than 200/mm2 [97, 98]. The estimated incidence of PML in HIV patients is 5%, but is decreasing with the introduction of highly active anti-retroviral therapy (HAART) [99]. The differential diagnosis of PML is HIV-associated encephalopathy and primary CNS lymphoma. Brain biopsy is the gold standard for diagnosis. Staining with immunohistochemistry using antibodies directed to SV40-T antigen is confirmatory. Analysis of cerebrospinal fluid for JCV by PCR has a sensitivity of to 92% and specificity up to 100% (100). For patients with PML and HIV, introduction or optimization of HAART needs to be implemented to decrease viral replication. In non-HIV patients, such as organ transplant patients, immunosupression needs to be decreased or stopped [101]. At this stage, there is no specific antiviral agent for JC virus [97].
