Herpesviruses & Poxviruses

Herpesviruses are large enveloped viruses containing double-stranded DNA. The viral genome is transcribed by cellular DNA-dependent RNA polymerases and regulated by viral encoded and cellular nuclear factors. Replication of the viral genome is performed by viral encoded DNA polymerase. There are 3 subgroups of herpesviruses; (1) alpha which have latency in the CNS, (2) beta which have latency in monocytes and (3) gamma which have latency in lymphoctyes and have oncogenic potential.

Herpes Simplex Virus 1 & 2 (HSV-1) are closely related (~50% nucleic acid identity and over 70% amino acid identity) of the alpha subgroup.

HSV-1 is usually associated with infections above the waist and is typically spread by oral contact (kissing) or by sharing glasses, tooth brushes and other saliva contaminating items.  Most people infected with HSV-1 are asymptomatic. However, primary infection of the head or genital areas can occur (e.g., gingivostomatitis, herpes labialis, keratitis) and can be very serious in the immuncompromised. The primary infection can be spread as by eczema (condition of the skin). Reactivation of the virus (e.g., recurrent cold sores)  is less severe than primary infection.

HSV-2 is associated with infections below the waist (e.g., 90% of genital herpes is HSV-2, 10% HSV-1) and is mainly spread by sexual contact or from the mother at birth. HSV-2 has a greater potential to cause viremia and associated systemic flu-like symptoms. As with HSV-1, reactivation is less severe than a primary infection.

HSV-1 and HSV-2 initially infect and replicate in mucoepithelial cells and then establish latent infection of the innervating neurons. There are various stages of pathology on mucous membranes and skin; 1) macule (flat, often red discolaration), 2) papule (raised bump like), 3) vesicle (raised skin), 4) pustule (vesicular rash infected with bacterial; puss formation), 5) ulcer and 6) crust.

In latent infection, the virus travels through axons to the nuclei of ganglion where the viral genome circularizes. During a latent infection, a specific RNA is the only detectable viral product synthesized in infected cells (latency associated transcript (LAT) and virus replication does not proceed further. The virus can be reactivated (reversal of latency) due to various stimuli (e.g., stress, sunlight).  LAT and thymidine kinase genes are required for reactivation. During reactivation, the virus travels back down the neuron back up to the skin.

Most anti-herpes drugs are nucleotide analogues or inhibitors of the viral DNA polymerase. Acyclovir (ACV) is currently the most effective. ACV is activated by the viral thymidine kinase and then used as a substrate by the viral DNA polymerase. It is then incorporated into, and prevents elongation of the viral DNA. Derivatives of ACV which are more stable that may be used include amciclovir and valacyclovir.

Monkey B virus is closely related to HSV-1/2. Human infection is by saliva or bites and the virus is 70% lethal. It can also spread from person to person. Monkey B virus is naturally occurring herpesvirus in macaques. The virus is not as sensitive to acyclovir as with HSV.

Varicella zoster virus (VZV) is closely related to herpes simplex viruses and causes Chicken pox.. It initially infects the respiratory tract and spreads to the skin after about 13 days. infects lymphocytes and causes viremia. Various stages of lesions are seen simultaneously like macules, papules, vesicles, pustules, ulcers and crusts. VCV is highly contagious and there is over 90% infection with VZV before age 10. All kids are now immunized for VZV. Adults who have never contracted the disease or have been immmunized can get a severe adult chickenpox. Neonatal chickenpox is also very severe. Reactivation of VZV can occur in and cause herpes zoster or shingles. This is a frequent occurrence in aging individuals and cancer patients. Treatment of uncomplicated VZV is not necessary. Otherwise, treatment can include high does of ACV, amciclovir or valacyclovir. Immunsuppressed children may receive preventive high titer IgG within 72 h of exposure.

HHV-6 is of the beta-herpesviruses which is common in very young children (6 months to 4 years of age). AFter primary infection CD4 T cells are the site of life-long latency.

HHV-7 is sometimes called an "orphan" virus in that it has no disease association. It has been shown present in AIDS patients.

Cytomegalovirus (CMV):  CMV is a member of the beta-herpesviruses. CMV often causes retinitis in patients with immunodeficiency (e.g., AIDS). The histological hallmark of CMV infection and a way of diagnosis is the cytomegalic (enlarged) cells which contain a dense central "owl's eye" intranuclear inclusion.

50% of the US population is + for CMV. Semen is a major vector for sexual spread of CMV and thus the use of condoms limits its spread. It is also a congential infection (infection through the placenta) .

The virus establishes latent infection in CD33pos BM precursors of DCs and can be reactivated from blood cells bearing DC markers by stimulation with allogeniec cells. HCMV enters immature myloid DCs via DC-SIGN, leading to trans infection of human lung fibroblasts. Infection of imamture MDDCs or Langerhans-like DCs by HCMV inhibits their maturation and caapcity to activate T cells. Infection of mature myloid DCs upregulateds CD95L (FasL) and TNF-related apoptosis inducing ligand (TRAIL_, leading to apoptosis in T cells. Furthermore, HCMV infection of mature myloid DCs downregulates HLA class I expression, possibly mediated through US11 and US2 coded proteins of the virus.

CMV causes persistent infection, which can lead to diseases affecting various organs in immunosuppressed persons. CMV can be reactivated from latency in immunocompromised states such as those persons with HIV. The upregulation of CMV infection by TNF is mediated via the TNF receptor I (p55) with a downstream signaling process that involves activation of protein kinase C and NFkB. The activated p65/050 NFkB translocates into the nucleus and binds to the 18-base pair repetitive sequence motifs with the human CMV immediate early 1 enhancer region.

Ganciclovir and cidofovir are used for treatment.

Epstein-Barr Virus (EBV)

Kaposi's sarcoma-associated herpesvirus (KSHV)

Murine gamma herpesvirus 68 (MHV-68) is a member of the gamma-2 subgroup.

Herpesvirus saimiri (HVS) is a member of the gamma-2 subgroup. The squirrel monkey is the natural host of HVS. STP (Saimiri Transforming Protein), TIP (Tyrosine Kinase interacting protein) LANA (latency-Associated Nuclear Antigen) and HSURs (herpesvirus Saimiri U-type RNA) are all associated with ongogenesis in HVS. STP-A activates c-ras and along with STP-c activates c-Src which turns on STATS as well as NF-KB. TIP binds the Lck protein and is essential for immortalization of T cells. HSURs are RNA polymerase II transcripts which contain AUUUA repeats and compete for AU-Binding Factors (AUBF). They exclude RNAse and prevent RNA degradation. LANA upregulates B-catenin which is also an oncogene and displaces repressive transcription factors and histone deacetylase.

Poxviruses are large double-stranded, DNA, enveloped viruses.

Variola: Variola caused worldwide epidemics. It has been eradicated, although US and Russian laboratories and perhaps others have stocks. 2-10 days post infection, one develops chills, myalgia and fever and then a few days later hemorrhagic vesicles on head and extremities. Immunity is lifelong. Treatment is as with CMV; cidofovir.

Monkey-Pox: is endemnic in Africa and is listed as potential agent for terrorism.