Abstract:
Human cytomegalovirus (HCMV) is a large, double-stranded DNA virus belonging to the Herpesviridae family. Its seroprevalence is estimated to reach up to 100% in certain geographical areas. The virus has been co-evolving with humans for thousands of years, during which time it has established a complex mechanism to evade antiviral immunity and to successfully establish an infection. Although an HCMV infection is usually asymptomatic for immunocompetent individuals, it poses high risk for immunosuppressed patients, including AIDS patients and transplant recipients. Furthermore, it is the primary cause of congenital infections, which can result in severe complications for the newborn. Currently, there is a treatment available for HCMV, but it is accompanied by certain limitations including toxicity and the emergence of resistant strains. This highlights the urgent need for the development of new treatments to combat HCMV and minimize its complications.
The initial section of this thesis examines the potential of novel antiviral compounds. The antiviral host cell protein SAMHD1, is subject to downregulation by HCMV. One of the mechanisms by which HCMV achieves this is through the induction of SAMHD1 phosphorylation by a viral kinase, pUL97. The current thesis demonstrates that phosphorylation occurs during the early stages of infection and is a conserved mechanism among clinical isolates of HCMV. These findings highlight the importance of this process for viral fitness. Therefore, it was investigated as a potential therapeutic target. Subsequently, Abemaciclib (AC), a CDK4/6 inhibitor, was identified as an antiviral compound that targets HCMV replication in macrophages. It is noteworthy that AC was observed to specifically inhibit the pUL97-mediated phosphorylation of SAMHD1, which provides insight into the mechanism of its antiviral activity. Moreover, LDC4297, a CDK7 inhibitor, has been demonstrated to exhibit antiviral activity against HCMV, specifically by blocking SAMHD1-phosphorylation in the context of HCMV infection. Furthermore, another antiviral compound, the human defensin HD5, was investigated. It was observed that an HD5-derived peptide, HD5(1-9), exhibits antiviral effect against HCMV by enhancing the innate immune response upon infection.
The second part of the study focused on CD84, CD164 and CD180. These are three surface receptors that undergo downregulation upon HCMV infection. The objective was to analyze the functional importance of this modulation. Although the knockout of CD84, CD164, and CD180 did not significantly affect viral replication, overexpression of CD164 indicated a potential restriction in viral replication, thereby suggesting a vital role for CD164 in HCMV restriction.
Taken together, the findings of this study elucidate new mechanisms through which HCMV circumvents the host immune response and offers insights into the mode of action of emerging antiviral compounds.
HCMV