Where do we Stand after Decades of Studying Human Cytomegalovirus?

Abstract

Human cytomegalovirus (HCMV), a linear double-stranded DNA betaherpesvirus belonging to the family of Herpesviridae, is characterized by widespread seroprevalence, ranging between 56% and 94%, strictly dependent on the socioeconomic background of the country being considered. Typically, HCMV causes asymptomatic infection in the immunocompetent population, while in immunocompromised individuals or when transmitted vertically from the mother to the fetus it leads to systemic disease with severe complications and high mortality rate. Following primary infection, HCMV establishes a state of latency primarily in myeloid cells, from which it can be reactivated by various inflammatory stimuli. Several studies have shown that HCMV, despite being a DNA virus, is highly prone to genetic variability that strongly influences its replication and dissemination rates as well as cellular tropism. In this scenario, the few currently available drugs for the treatment of HCMV infections are characterized by high toxicity, poor oral bioavailability, and emerging resistance. Here, we review past and current literature that has greatly advanced our understanding of the biology and genetics of HCMV, stressing the urgent need for innovative and safe anti-HCMV therapies and effective vaccines to treat and prevent HCMV infections, particularly in vulnerable populations.

Keywords: antiviral therapy; genetic variability; human cytomegalovirus; pathogenesis; viral dissemination.

Figure 1

Structure of HCMV virion. Mature virions are coated by an envelope, from which viral glycoproteins protrude, and contain a double-stranded DNA genome enclosed within an icosahedral symmetry capsid, that is surrounded by tegument.

Figure 2

HCMV clinical manifestations in immunocompetent individuals with severe HCMV infection, in immunocompromised people, especially in acquired immune deficiency syndrome (AIDS) patients, transplant recipients, and upon congenital infection.

Figure 3

HCMV can be transmitted directly from person to person through bodily fluids including saliva, urine, cervical, and vaginal secretions, breast milk, semen, blood, and tears. It infects a new host usually by getting in through the upper gastrointestinal gastrointestinal tract or the respiratory tract. Here, the epithelial cells are often the first site of infection and from there HCMV infects leucocytes that traffic around the body. This is correlated with a process called primary viral dissemination that leads to the infection of multiple tissues, such as lungs, liver, and spleen. Afterwards, secondary viral dissemination spreads the infection to secretion-producing organs, such as salivary and mammary glands and kidneys, which shed the virus.

Figure 4

Latency. Following primary infection, HCMV can establish latency in CD34⁺ myeloid progenitor cells and is carried down the myeloid lineage. In latently-infected CD34⁺ cells and monocytes, there is a targeted suppression of lytic viral gene expression. HCMV utilizes several viral proteins and small RNA transcripts, including viral and cellular miRNAs, during latent infection to alter the signaling environment within the cell to maintain the status of latency. Differentiation of these cells to macrophages and DCs causes the derepression of the MIEP and allows initiation of the lytic transcription program, which involves a temporal cascade of viral gene transcription, allowing reactivation of de novo virus production. HCMV, human cytomegalovirus; DC, dendritic cell; HSC, hematopoietic stem cell; lncRNA, long non-coding RNA; IE, immediate-early; E, early; L, late.