scholarly journals Antiviral Agents as Therapeutic Strategies Against Cytomegalovirus Infections

Viruses ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 21 ◽  
Author(s):  
Shiu-Jau Chen ◽  
Shao-Cheng Wang ◽  
Yuan-Chuan Chen
Keyword(s):  
Opportunistic Infections ◽  
Antiviral Agents ◽  
Life Cycles ◽  
Adoptive T Cell Therapy ◽  
Transcription Activator ◽  
T Cell Therapy ◽  
Latently Infected ◽  
Infected Cells ◽  
Human Cmv ◽  
Cytomegalovirus Infections

Cytomegalovirus (CMV) is a threat to human health in the world, particularly for immunologically weak patients. CMV may cause opportunistic infections, congenital infections and central nervous system infections. CMV infections are difficult to treat due to their specific life cycles, mutation, and latency characteristic. Despite recent advances, current drugs used for treating active CMV infections are limited in their efficacy, and the eradication of latent infections is impossible. Current antiviral agents which target the UL54 DNA polymerase are restricted because of nephrotoxicity and viral resistance. CMV also cannot be prevented or eliminated with a vaccine. Fortunately, letermovir which targets the human CMV (HCMV) terminase complex has been recently approved to treat CMV infections in humans. The growing point is developing antiviral agents against both lytically and latently infected cells. The nucleic acid-based therapeutic approaches including the external guide sequences (EGSs)-RNase, the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system and transcription activator-like effector nucleases (TALENs) are being explored to remove acute and/or latent CMV infections. HCMV vaccine is being developed for prophylaxis. Additionally, adoptive T cell therapy (ACT) has been experimentally used to combate drug-resistant and recurrent CMV in patients after cell and/or organ transplantation. Developing antiviral agents is promising in this area to obtain fruitful outcomes and to have a great impact on humans for the therapy of CMV infections.

scholarly journals Potential Therapeutic Approaches Against Brain Diseases Associated with Cytomegalovirus Infections

2020 ◽  
Vol 21 (4) ◽  
pp. 1376
Author(s):  
Shao-Cheng Wang ◽  
Shiu-Jau Chen ◽  
Yuan-Chuan Chen
Keyword(s):  
Adverse Reactions ◽  
Opportunistic Infections ◽  
Brain Diseases ◽  
Latent Infections ◽  
Transcription Activator ◽  
Therapeutic Approaches ◽  
Rna Targeting ◽  
Alternative Modality ◽  
Human Cmv ◽  
Cytomegalovirus Infections

Cytomegalovirus (CMV) is one of the major human health threats worldwide, especially for immunologically comprised patients. CMV may cause opportunistic infections, congenital infections, and brain diseases (e.g., mental retardation and glioblastoma). The etiology of brain diseases associated with human CMV (HCMV) infections is usually complex and it is particularly difficult to treat because HCMV has a life-long infection in its hosts, high mutation rate, and latent infections. Moreover, it is almost impossible to eradicate latent viruses in humans. Although there has been progress in drug discovery recently, current drugs used for treating active CMV infections are still limited in efficacy due to side effects, toxicity, and viral resistance. Fortunately, letermovir which targets the HCMV terminase complex rather than DNA polymerase with fewer adverse reactions has been approved to treat CMV infections in humans. The researchers are focusing on developing approaches against both productive and latent infections of CMV. The gene or RNA targeting approaches including the external guide sequences (EGSs)-RNase, the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system and transcription activator-like effector nucleases (TALENs) are being investigated to remove acute and/or latent CMV infections. For the treatment of glioblastoma, vaccine therapy through targeting specific CMV antigens has improved patients’ survival outcomes significantly and immunotherapy has also emerged as an alternative modality. The advanced research for developing anti-CMV agents and approaches is promising to obtain significant outcomes and expecting to have a great impact on the therapy of brain diseases associated with CMV infections.

scholarly journals Interaction between Endogenous Bacterial Flora and Latent HIV Infection

2013 ◽  
Vol 20 (6) ◽  
pp. 773-779 ◽  
Author(s):  
Ann Florence B. Victoriano ◽  
Kenichi Imai ◽  
Takashi Okamoto
Keyword(s):  
Hiv Infection ◽  
Opportunistic Infections ◽  
Bacterial Flora ◽  
Anaerobic Bacteria ◽  
Hiv Replication ◽  
Latently Infected ◽  
Potential Link ◽  
Infected Cells ◽  
Latent Hiv

ABSTRACTHuman commensal bacteria do not normally cause any diseases. However, in certain pathological conditions, they exhibit a number of curious behaviors. In HIV infection, these bacteria exhibit bidirectional relationships: whereas they cause opportunistic infections based on immunological deterioration, they also augment HIV replication, in particular, viral replication from latently infected cells, which is attributable to the effect of butyric acid produced by certain anaerobic bacteria by modifying the state of chromatin. Here, we review recent evidence supporting the contributory role of such endogenous microbes in disrupting HIV latency and its potential link to the clinical progression of AIDS.

scholarly journals Transient Oral Human Cytomegalovirus Infections Indicate Inefficient Viral Spread from Very Few Initially Infected Cells

2017 ◽  
Vol 91 (12) ◽  
Author(s):  
Bryan T. Mayer ◽  
Elizabeth M. Krantz ◽  
David Swan ◽  
James Ferrenberg ◽  
Karen Simmons ◽  
...  
Keyword(s):  
Oral Route ◽  
Oral Exposure ◽  
Cmv Infection ◽  
Viral Spread ◽  
Infected Cells ◽  
High Level ◽  
Human Cmv ◽  
Cytomegalovirus Infections ◽  
Oral Cells ◽  
Insight Into

ABSTRACT Cytomegalovirus (CMV) is acquired by the oral route in children, and primary infection is associated with abundant mucosal replication, as well as the establishment of latency in myeloid cells that results in lifelong infection. The efficiency of primary CMV infection in humans following oral exposure, however, is unknown. We consistently detected self-limited, low-level oral CMV shedding events, which we termed transient CMV infections, in a prospective birth cohort of 30 highly exposed CMV-uninfected infants. We estimated the likelihood of transient oral CMV infections by comparing their observed frequency to that of established primary infections, characterized by persistent high-level shedding, viremia, and seroconversion. We developed mathematical models of viral dynamics upon initial oral CMV infection and validated them using clinical shedding data. Transient infections comprised 76 to 88% of oral CMV shedding events. For this high percentage of transient infections to occur, we identified two mathematical prerequisites: a very small number of initially infected oral cells (1 to 4) and low viral infectivity (<1.5 new cells infected/cell). These observations indicate that oral CMV infection in infants typically begins with a single virus that spreads inefficiently to neighboring cells. Thus, although the incidence of CMV infection is high during infancy, our data provide a mechanistic framework to explain why multiple CMV exposures are typically required before infection is successfully established. These findings imply that a sufficiently primed immune response could prevent CMV from establishing latent infection in humans and support the achievability of a prophylactic CMV vaccine. IMPORTANCE CMV infects the majority of the world's population and is a major cause of birth defects. Developing a vaccine to prevent CMV infection would be extremely valuable but would be facilitated by a better understanding of how natural human CMV infection is acquired. We studied CMV acquisition in infants and found that infections are usually brief and self-limited and are successfully established relatively rarely. Thus, although most people eventually acquire CMV infection, it usually requires numerous exposures. Our analyses indicate that this is because the virus is surprisingly inefficient, barely replicating well enough to spread to neighboring cells in the mouth. Greater knowledge of why CMV infection usually fails may provide insight into how to prevent it from succeeding.

Cytomegalovirus after kidney transplantation in 2020: moving towards personalized prevention

2020 ◽  
Author(s):  
Rachel Hellemans ◽  
Daniel Abramowicz
Keyword(s):  
Kidney Transplantation ◽  
T Cell ◽  
Antiviral Agents ◽  
Mammalian Target Of Rapamycin ◽  
Adoptive T Cell Therapy ◽  
Preventive Strategy ◽  
T Cell Therapy ◽  
Individual Patient Level ◽  
Cell Assays ◽  
The Individual

Abstract Cytomegalovirus (CMV)-related complications after kidney transplantation remain a substantial challenge. Rather than applying one preventive strategy to all at-risk patients, we can now adapt our strategy at the individual patient level. Antiviral prophylaxis or a strict pre-emptive strategy may be optimal for patients at the highest risk for CMV, while patients at lower risk may benefit particularly from pre-emptive monitoring and the administration of therapy only if needed. CMV-specific T-cell assays may be useful for further refining the pre-transplant determination of CMV risk, and for guiding decisions about antiviral therapy need or duration. An immunosuppressive regimen including a mammalian target of rapamycin inhibitor reduces CMV risk and may thus be an attractive option in some patients. New antiviral agents may further expand our therapeutic arsenal in the near future, and the prospects of CMV vaccination and adoptive T-cell therapy appear to be on the horizon.

scholarly journals Antiviral Treatment: From Concept to Reality

1997 ◽  
Vol 8 (6_suppl) ◽  
pp. 5-10 ◽  
Author(s):  
R Boon
Keyword(s):  
Antiviral Treatment ◽  
Antiviral Agents ◽  
Antiviral Agent ◽  
Life Cycles ◽  
The Body ◽  
Assay System ◽  
Major Step ◽  
Initial Development ◽  
Varicella Zoster ◽  
Infected Cells

The initial development of antiviral compounds was slow, with the first clinical antiviral agent not available until the 1960s. Early development was hindered by the lack of understanding of virus life-cycles and the absence of an assay system for antiviral activity. The appearance of the first assay system, the fertilized egg yolk sac, led to the identification of methisazone. This was the first antiviral agent to be used clinically. The improvement in antiviral assay systems, and the start of directed research programmes led to the development of the first antiherpes agents idoxuridine, trifluorothymidine (TFT) and vidarabine. However, all of these agents were associated with significant adverse effects. Antiherpes therapy took a major step forward with the development of the acyclic nucleoside analogue, aciclovir. Aciclovir is much more potent than previous antiherpesvirus agents. Its mode of action results in selectivity for herpesvirus-infected cells, thus significantly reducing the side-effects seen with earlier agents. Because of this, it became the standard therapy for herpes simplex virus type 1 (HSV-1), HSV-2 and varicella zoster virus infections. However, the bioavailability of oral aciclovir is poor, requiring high and frequent doses. This led to the search for better absorbed agents and to the development of two prodrugs, famciclovir and valaciclovir. Both famciclovir and valaciclovir offer much improved bioavailability of the nucleosides penciclovir and aciclovir, compared with aciclovir. Once in the body the conversion of valaciclovir to aciclovir means that the two agents have similar pharmacokinetic properties. Similarly, famciclovir is converted to penciclovir in the body. Penciclovir, when phosphorylated in virus-infected cells, persists within the cell for a much longer period than aciclovir triphosphate. Over the last 10 years we have seen an acceleration in the development of antiviral agents and some major advances in antiviral therapy. Many challenges, however, still lie ahead.

scholarly journals Designed Transcription Activator-Like Effector Proteins Efficiently Induced the Expression of Latent HIV-1 in Latently Infected Cells

2015 ◽  
Vol 31 (1) ◽  
pp. 98-106 ◽  
Author(s):  
Xiaohui Wang ◽  
Pengfei Wang ◽  
Zheng Fu ◽  
Haiyan Ji ◽  
Xiying Qu ◽  
...  
Keyword(s):  
Effector Proteins ◽  
Transcription Activator ◽  
Latently Infected ◽  
Infected Cells ◽  
Latent Hiv ◽  
Hiv 1

scholarly journals Protective Effect of Anti-Phosphatidylserine Antibody in a Guinea Pig Model of Advanced Hemorrhagic Arenavirus Infection

2017 ◽  
Vol 11 (1) ◽  
pp. 303-315
Author(s):  
John M. Thomas ◽  
Philip E. Thorpe
Keyword(s):  
Antiviral Activity ◽  
Human Monoclonal Antibody ◽  
Antiviral Agents ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Pichinde Virus ◽  
Glycoprotein I ◽  
Infected Cells ◽  
Guinea Pig Model ◽  
Cytomegalovirus Infections ◽  
Mouse Antibody

Objective:Host derived markers on virally infected cells or virions may provide targets for the generation of antiviral agents. Recently, we identified phosphatidylserine (PS) as a host marker of virions and virally-infected cells.Methods and Materials:Under normal physiological conditions, PS is maintained on the inner leaflet of the plasma membrane facing the cytosol. Following viral infection, activation or pre-apoptotic changes cause PS to become externalized. We have previously shown that bavituximab, a chimeric human-mouse antibody that binds PS complexed with β2-glycoprotein I (β2GP1), protected rodents against lethal Pichinde virus and cytomegalovirus infections.Results:Here, we determined the antiviral activity of a fully human monoclonal antibody, PGN632, that directly binds to PS. Treatment with PGN632 protected 20% of guinea pigs with advanced infections of the hemorrhagic arenavirus, Pichinde, from death. Combining PGN632 with ribavirin improved the antiviral activity of both agents, such that the combination rescued 50% of animals from death.Conclusion:The major mechanisms of action of PGN632 appear to be opsonization of virus and antibody-dependent cellular cytotoxicity of virally-infected cells. PS-targeting agents may have utility in the treatment of viral diseases.

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