Human Cytomegalovirus (HCMV/HHV-5)

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HHV-5 infection is common; 60% of the UK population have experienced infection by the age of 40. Most infections are asymptomatic. Apart from during pregnancy and newborn infants exposed in utero, active (as opposed to latent) HHV-5 infection only occurs in people with immune defects, specifically T-cell defects, e.g. AIDS patients and immunosuppressed transplant patients:

Transmission is believed to be by oral/respiratory route. Infection produces enlargement of cells and nuclear inclusion bodies in a wide range of tissues - systemic infection.

Healthy HHV-5 seropositive blood donors can sometimes transmit HHV-5 infection to recipients. The risk of transmission by blood is reduced by using leukocyte depleted blood products, suggesting that one site of carriage of this virus is in the peripheral blood compartment. However, it is difficult, if not impossible, to isolate HHV-5 directly from the blood of healthy donors. Consequently, while peripheral blood of healthy seropositive individuals does not carry infectious virus, the virus must be in a form that is reactivatable. Using PCR, a number of laboratories have demonstrated the presence of HHV-5 DNA and/or RNA in the blood of seropositive individuals. Such analyses suggest that the frequency of cells that carry the HHV-5 genome is extremely low (probably less than 1 in 10,000 PBMC) and it is perhaps for this reason that other laboratories have been unable to detect HHV-5 DNA in the blood of healthy carriers. Monocytes appear to be the major site of carriage of HHV-5 DNA in healthy carriers with little viral DNA detectable in T or B cells. In vitro, long-term culture of peripheral blood monocytes towards a macrophage phenotype results in a cell population that is permissive for HHV-5. Thus there is a link between the state of differentiation of myeloid cells and their permissiveness for HHV-5 infection. As with all lymphoid and myeloid cells, monocytes arise from pleuripotent CD34⁺ stem cells present in bone marrow. These cells can be infected with clinical isolates of HHV-5, but little or no viral lytic gene expression occurs until they have been cultured long term in the presence of haemopoetic growth factors (e.g. GM-CSF). Bone marrow does appear to act as a reservoir for HHV-5 in vivo.

However, little or no viral gene expression is detectable in blood of healthy carriers. HHV-5 lytic gene expression (IE genes) is absent in monocytes, consistent with the inability to culture virus from these cells. Consequently, it would appear that HHV-5 is carried in a true latent state with little or no accompanying lytic gene expression. Reactivation and shedding of HHV-5 may be reactivated in astronauts by microgravity during spaceflight!

Compared with HHV-1, relatively little is known about latency in HHV-5. However, there may be a novel promoter slightly upstream of the major IE promoter/enhancer which generates novel spliced and unspliced RNA transcripts mapping to both strands of the HHV-5 major IE region, which may be functionally equivalent to HHV-1 latency associated transcripts (LATs) or HHV-4 EBNAs (Sinclair J, Sissons P. Latency and reactivation of human cytomegalovirus. J Gen Virol. 2006 87: 1763-1779).

Cytomegalovirus escapes Natural Killer cells through HLA-E upregulation (Tomasec P. et al. Science 287, 1031, 2000).

In spite of the widespread distribution, HHV-5-related illness is rare and occurs only in two groups:

Immunocompromised: Evidence that the host immune response (particularly cell-mediated) plays a role in latency comes from the evidence of what occurs on immunosuppression. Latent virus is reactivated and AIDS/transplant patients experience frequent and severe infections with the potential for involvement of many possible organs. Foetal Infections: Particularly a problem when primary infection of the mother occurs, resulting in congenital abnormalities in a proportion of cases. Online HHV-5 Experiment: Mr Campbell's Kidney

Activation of latent HHV-5 (common) to a lytic state of infection (rarer) therefore appears to require one (or both) of two conditions:

• Differentiation of myeloid precursors containing latent virus
• Immunodeficiency

• Streblow DN, Nelson JA. Models of HCMV latency and reactivation. Trends in Microbiol. 11:293-295, 2003.
• Herpesvirus infections of the nervous system. Nat Clin Pract Neurol. 2007 3: 82-94

Therapy - Gancyclovir and Valcyte (valganciclovir), a tablet form of ganciclovir taken orally which achieves systemic exposure to ganciclovir comparable to that delivered by intravenous ganciclovir. The clinical toxicity of Valcyte, which is metabolized to ganciclovir, includes granulocytopenia, anemia and thrombocytopenia. In animal studies ganciclovir is carcinogenic, teratogenic and caused aspermatogenesis. Other side effects (in clinical trials) greater than or equal to 5% include diarrhea, fever, nausea, neutropenia, headache, vomiting, insomnia, abdominal pain, retinal detachment, peripheral neuropathy and paresthesia.

• Search MEDLINE for the latest publications on this topic

• Herpesviruses: general information

• Herpes simplex virus (HSV-1/HSV-2, HHV1/2)

• Varicella zoster virus (VZV/HHV-3)

• Epstein Barr virus (EBV/HHV-4)

• Human herpesvirus 6, 7 (HHV-6, HHV-7)

• Human herpesvirus 8 (HHV-8/KSHV)

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