Animal Models Of Virus Infection Research Articles

The antimicrobial peptide Sparamosin26–54 exhibits antiviral activity against three aquatic enveloped viruses through lipid-binding-mediated virus lysis

The aquaculture industry is faced with huge economic losses caused by various enveloped virus infections, such as white spot syndrome virus (WSSV), Rana grylio virus (RGV), and Anguillid Herpesvirus 1 (AngHV). The urgent need for readily available broad-spectrum antiviral agents has led to the exploration of antiviral peptides (AVPs), among which antimicrobial peptides (AMPs) with antiviral activity have attracted increasing attention. Sparamosin26–54 (derived from Scylla paramamosain) is a promising antimicrobial agent. In this study, we found that Sparamosin26–54 significantly inhibited WSSV transcription and replication (as indicated by VP28 gene and protein levels), irreversibly inactivated virions, and impeded viral entry before binding to the cell. Transmission electron microscopy observations showed that Sparamosin26–54 had a direct destructive effect on WSSV virions. Lipidomic analysis and ELISA assay highlighted that Sparamosin26–54 had a potent affinity for phosphatidic acid (PA) and phosphatidylserine (PS) of WSSV. Liposome leakage assays further revealed a pronounced effect of Sparamosin26–54 on membrane lipid compositions, emphasizing its efficacy against the other two enveloped viruses (RGV and AngHV), but not against the non-enveloped virus, American eel adomavirus (AEAdov). Notably, in three animal models of viral infection, Sparamosin26–54 reduced viral loads in tissues, increased survival, or decreased infection rates in a concentration-dependent manner. Importantly, Sparamosin26–54 showed no animal toxicity under different modes of administration and could maintain antiviral activity in the complex aquatic environment. Taken together, Sparamosin26–54 was proved to be effective against three enveloped viruses, possibly inducing viral lysis via lipid-binding, providing an alternative approach for combating enveloped virus infections.

A Novel Fluorescent and Bioluminescent Bireporter Influenza A Virus To Evaluate Viral Infections.

Studying influenza A virus (IAV) requires the use of secondary approaches to detect the presence of virus in infected cells. To overcome this problem, we and others have generated recombinant IAV expressing fluorescent or luciferase reporter genes. These foreign reporter genes can be used as valid surrogates to track the presence of virus. However, the limited capacity for incorporating foreign sequences in the viral genome forced researchers to select a fluorescent or a luciferase reporter gene, depending on the type of study. To circumvent this limitation, we engineered a novel recombinant replication-competent bireporter IAV (BIRFLU) expressing both fluorescent and luciferase reporter genes. In cultured cells, BIRFLU displayed growth kinetics comparable to those of wild-type (WT) virus and was used to screen neutralizing antibodies or compounds with antiviral activity. The expression of two reporter genes allows monitoring of viral inhibition by fluorescence or bioluminescence, overcoming the limitations associated with the use of one reporter gene as a readout. In vivo, BIRFLU effectively infected mice, and both reporter genes were detected using in vivo imaging systems (IVIS). The ability to generate recombinant IAV harboring multiple foreign genes opens unique possibilities for studying virus-host interactions and for using IAV in high-throughput screenings (HTS) to identify novel antivirals that can be incorporated into the therapeutic armamentarium to control IAV infections. Moreover, the ability to genetically manipulate the viral genome to express two foreign genes offers the possibility of developing novel influenza vaccines and the feasibility for using recombinant IAV as vaccine vectors to treat other pathogen infections.IMPORTANCE Influenza A virus (IAV) causes a human respiratory disease that is associated with significant health and economic consequences. In recent years, the use of replication-competent IAV expressing an easily traceable fluorescent or luciferase reporter protein has significantly contributed to progress in influenza research. However, researchers have been forced to select a fluorescent or a luciferase reporter gene due to the restricted capacity of the influenza viral genome for including foreign sequences. To overcome this limitation, we generated, for the first time, a recombinant replication-competent bireporter IAV (BIRFLU) that stably expresses two reporter genes (one fluorescent and one luciferase) to track IAV infections in vitro and in vivo The combination of cutting-edge techniques from molecular biology, animal research, and imaging technologies brings researchers the unique opportunity to use this new generation of reporter-expressing IAV to study viral infection dynamics in both cultured cells and animal models of viral infection.

The 13th International Double-Stranded RNA Virus Symposium, Houffalize, Belgium, 24 to 28 September 2018.

The triennial International Double-Stranded RNA Virus Symposium, this year organized by J. Matthijnssens, J. S. L. Parker, P. Danthi, and P. Van Damme in Belgium, gathered over 200 scientists to discuss novel observations and hypotheses in the field. The keynote lecture on functional interactions of bacteria and viruses in the gut microbiome was presented by Julie Pfeiffer. Workshops were held on viral diversity, molecular epidemiology, molecular virology, immunity and pathogenesis, virus structure, the viral use and abuse of cellular pathways, and applied double-stranded RNA (dsRNA) virology. The establishment of a plasmid only-based reverse genetics system for rotaviruses by several Japanese research groups in 2017 has now been reproduced by various other research groups and was discussed in detail. The visualization of dsRNA virus replication steps in living cells received much attention. Mechanisms of the cellular innate immune response to virus infection and of viral pathogenesis were explored. Knowledge of the gut microbiome's influence on specific immune responses has increased rapidly, also due to the availability of relevant animal models of virus infection. The method of cryo-electron microscopic (cryo-EM) tomography has elucidated various asymmetric structures in viral particles. The use of orthoreoviruses for oncolytic virotherapy was critically assessed. The application of llama-derived single chain nanobodies for passive immunotherapy was considered attractive. In a satellite symposium the introduction, impact and further developments of rotavirus vaccines were reviewed. The Jean Cohen Lecturer of this meeting was Harry B. Greenberg, who presented aspects of his research on rotaviruses over a period of more than 40 years. He was also interviewed at the meeting by Vincent Racaniello for the 513th session of This Week in Virology.

Viruses Teaching Immunology: Role of LCMV Model and Human Viral Infections in Immunological Discoveries.

Virology has played an essential role in deciphering many immunological phenomena, thus shaping our current understanding of the immune system. Animal models of viral infection and human viral infections were both important tools for immunological discoveries. This review discusses two immunological breakthroughs originally identified with the help of the lymphocytic choriomeningitis virus (LCMV) model; immunological restriction by major histocompatibility complex and immunotherapy using checkpoint blockade. In addition, we discuss related discoveries such as development of tetramers, viral escape mutation, and the phenomenon of T-cell exhaustion.

Molecular characterization of the 2′,5′-oligoadenylate synthetase family in the Chinese tree shrew (Tupaia belangeri chinensis)

Virus infection induces type I interferons (IFNs) that in turn exert their pleiotropic effects through inducing a large number of interferon-stimulated genes (ISGs). The IFN-induced 2′,5′-oligoadenylate synthetases (OASs) have been identified as a member of the ISGs family characterized by the ability to synthesize 2′,5′-oligoadenylate (2-5A), which can induce the degradation of viral RNA by activating RNase L within the infected cells to block viral replications. In this study, we characterized the OASs of the Chinese tree shrew (Tupaia belangeri chinensis), a small mammal genetically close to primates and has the potential as animal model for viral infections. We identified 4 putative tree shrew OASs (tOASs, including tOAS1, tOAS2, tOASL1, and tOASL2) and characterized their roles in antiviral responses. Tree shrew lost tOAS3 that was presented in human and mouse. Phylogenetic analyses based on the protein sequences showed a close relationship of tOASs with those of mammals. Constitutive mRNA expression of tOASs was found in seven tissues (heart, liver, spleen, lung, kidney, small intestine and brain). Moreover, tOASs were significantly up-regulated upon various virus infections. Overexpression of tOASs significantly inhibited DNA virus and RNA virus replications in tree shrew primary renal cells. tOAS1 and tOAS2, but not tOASL1 and tOASL2, exerted their anti-HSV activity in an RNase L-dependent pathway. Collectively, our results revealed the evolutionary conservation of tOASs in tree shrew and might offer helpful information for creating viral infection models using the Chinese tree shrew.

The effect of volume of interest definition on quantification of lymph node immune response to a monkeypox virus infection assessed by (18)F-FDG-PET.

Background2-deoxy-2-[18F]fluoro-D-glucose-positron emission tomography (18F-FDG-PET) is applied in the clinic for infection assessment and is under consideration for investigating the inflammatory/immune response in lymphoid tissue in animal models of viral infection. Assessing changes in 18F-FDG uptake of lymph nodes (LNs), primary lymphoid tissues targeted during viral infection, requires suitable methods for image analysis. Similar to tumor evaluation, reliable quantitation of the LN function via multiple 18F-FDG-PET sessions will depend how the volume of interest is defined. Volume of interest definition has a direct effect on statistical outcome. The current study objective is to compare for the first time agreement between conventional and modified VOI metrics to determine which method(s) provide(s) reproducible standardized uptake values (SUVs) for 18F-FDG uptake in the LN of rhesus macaques.MethodsMultiple 18F-FDG-PET images of LNs in macaques were acquired prior to and after monkeypox virus intravenous inoculation. We compared five image analysis approaches, SUVmax, SUVmean, SUVthreshold, modified SUVthreshold, and SUVfixed volume, to investigate the impact of these approaches on quantification of the changes in LN metabolic activity denoting the immune response during viral infection progression.ResultsThe lowest data repeatability was observed with SUVmax. The best correspondence was between SUVfixed volume and conventional and modified SUVthreshold. A statistically significant difference in the LN 18F-FDG uptake between surviving and moribund animals was shown using modified SUVthreshold and SUVfixed volume (adjusted p = 0.0037 and p = 0.0001, respectively).ConclusionsQuantification of the LN 18F-FDG uptake is highly sensitive to the method applied for PET image analysis. SUVfixed volume and modified SUVthreshold demonstrate better reproducibility for SUV estimates than SUVmax, SUVmean, and SUVthreshold. SUVfixed volume and modified SUVthreshold are capable of distinguishing between groups with different disease outcomes. Therefore, these methods are the preferred approaches for evaluating the LN function during viral infection by 18F-FDG-PET. Validation of multiple approaches is necessary to choose a suitable method to monitor changes in LN metabolic activity during progression of viral infection.Electronic supplementary materialThe online version of this article (doi:10.1186/s13550-014-0049-z) contains supplementary material, which is available to authorized users.

Maternal viral infection during pregnancy impairs development of fetal serotonergic neurons.

Maternal viral infection during pregnancy induces morphological abnormalities in the fetus and may cause emotional and psychological problems in offspring through unknown mechanisms. We have previously shown that prenatal exposure of rats to chemicals such as thalidomide causes an autistic-like phenotype in offspring, indicating that prenatal events affecting serotonergic development may cause developmental disorder. We investigated whether prenatal viral infection altered the expression of neurotransmitters involved in the emotional or psychological status of offspring. We here took advantage of the polyriboinosinic:polyribocytidylic acid (poly I:C) system, the synthetic double-stranded RNA, which is often used in animal models of viral infection. Ten mg/kg of poly I:C was intraperitoneally injected on gestational day (GD) 9 and counted the numbers of serotonin-immunopositive cells on GD15 using flat whole-mount preparation method, resulting 11.1% of increase in the number of serotonergic neurons in poly I:C group. Furthermore, there was a significant decrease in hippocampal serotonin content in offspring by postnatal day 50 following poly I:C administration by high-performance liquid chromatography. Since serotonin is known to link with behavior and emotion after birth, these results suggest that maternal viral infection might cause, in addition to morphological abnormalities, serotonin-related pathogenesis such as neurodevelopmental disorders including autism spectrum disorders.

IFN-α subtypes: distinct biological activities in anti-viral therapy.

During most viral infections, the immediate host response is characterized by an induction of type I IFN. These cytokines have various biological activities, including anti-viral, anti-proliferative and immunomodulatory effects. After induction, they bind to their IFN-α/β receptor, which leads to downstream signalling resulting in the expression of numerous different IFN-stimulated genes. These genes encode anti-viral proteins that directly inhibit viral replication as well as modulate immune function. Thus, the induction of type I IFN is a very powerful tool for the host to fight virus infections. Many viruses evade this response by various strategies like the direct suppression of IFN induction or inhibition of the IFN signalling pathway. Therefore, the therapeutic application of exogenous type I IFN or molecules that induce strong IFN responses should be of great potential for future immunotherapies against viral infections. Type I IFN is currently used as a treatment in chronic hepatitis B and C virus infection, but as yet is not widely utilized for other viral infections. One reason for this restricted clinical use is that type I IFN belongs to a multigene family that includes 13 different IFN-α subtypes and IFN-β, whose individual anti-viral and immunomodulatory properties have so far not been investigated in detail to improve IFN therapy against viral infections in humans. In this review, we summarize the recent achievements in defining the distinct biological functions of type I IFN subtypes in cell culture and in animal models of viral infection as well as their clinical usage in chronic hepatitis virus infections.

PD-1 Blockage Reverses Immune Dysfunction and Hepatitis B Viral Persistence in a Mouse Animal Model

Persistent hepatitis B viral (HBV) infection results in chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). Recent studies in animal models of viral infection indicate that the interaction between the inhibitory receptor, programmed death (PD)-1, on lymphocytes and its ligand (PD-L1) play a critical role in T-cell exhaustion by inducing T-cell inactivation. High PD-1 expression levels by peripheral T-lymphocytes and the possibility of improving T-cell function by blocking PD-1-mediated signaling confirm the importance of this inhibitory pathway in inducing T-cell exhaustion. We studied T-cell exhaustion and the effects of PD-1 and PD-L1 blockade on intrahepatic infiltrating T-cells in our recently developed mouse model of HBV persistence. In this mouse animal model, we demonstrated that there were increased intrahepatic PD-1-expressing CD8+ and CD4+ T cells in mice with HBV persistence, but PD-1 upregulation was resolved in mice which had cleared HBV. The Intrahepatic CD8+ T-cells expressed higher levels of PD-1 and lower levels of CD127 in mice with HBV persistence. Blockade of PD-1/PD-L1 interactions increased HBcAg-specific interferon (IFN)-γ production in intrahepatic T lymphocytes. Furthermore, blocking the interaction of PD-1 with PD-L1 by an anti-PD-1 monoclonal antibody (mAb) reversed the exhausted phenotype in intrahepatic T lymphocytes and viral persistence to clearance of HBV in vivo. Our results indicated that PD-1 blockage reverses immune dysfunction and viral persistence of HBV infection in a mouse animal model, suggesting that the anti-PD-1 mAb might be a good therapeutic candidate for chronic HBV infection.

PD-1 blockage reverses immune dysfunction and hepatitis B viral persistence in a mouse animal model (105.23)

Abstract Persistent hepatitis B viral (HBV) infection results in chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). Recent studies in animal models of viral infection indicate that the interaction between the inhibitory receptor, programmed death (PD)-1, on lymphocytes and its ligand (PD-L1) play a critical role in T-cell exhaustion by inducing T-cell inactivation. We studied T-cell exhaustion and the effects of PD-1 and PD-L1 blockade on intrahepatic infiltrating T-cells in our recently developed mouse model of HBV persistence. In this mouse animal model, we demonstrated that there were increased intrahepatic PD-1-expressing CD8+ T-cells and increased CD4+ FoxP3+ T cells in mice with HBV persistence, but PD-1 upregulation was resolved in mice which had cleared HBV. The Intrahepatic CD8+ T-cells expressed higher levels of PD-1 and lower levels of CD127 in mice with HBV persistence. Blockade of PD-1/PD-L1 interactions increased HBcAg-specific interferon (IFN)-γ production in intrahepatic T lymphocytes. Furthermore, blocking the interaction of PD-1 with PD-L1 by an anti-PD-1 monoclonal antibody (mAb) reversed the exhausted phenotype in intrahepatic T lymphocytes and viral persistence to clearance of HBV in vivo. Our results indicated that PD-1 blockage reverses immune dysfunction and viral persistence of HBV infection in a mouse animal model, suggesting that the anti-PD-1 mAb might be a good therapeutic candidate for chronic HBV infection.

PD-1 blockage reverses immune dysfunction and viral persistence to Hepatitis B virus infection in mouse animal model (67.16)

Abstract Recent studies in animal models of virus infection, indicate that the interaction between the inhibitory receptor programmed death (PD)-1 on lymphocytes and its ligands plays a critical role in T-cell exhaustion by inducing T-cell inactivation, and high PD-1 expression levels on peripheral T-lymphocytes as well as the possibility to improve the T-cell function by blocking PD-1-mediated signaling to confirm the importance of this inhibitory pathway in inducing T-cell exhaustion. We studied T-cell exhaustion and the effects of PD-1/PD-L1 blockade on intrahepatic infiltrating T cells in our recently developed mouse model of hepatitis B virus (HBV) persistence with hydrodynamic injection of HBV DNA. In this mouse animal model, we demonstrated that there were increased intrahepatic PD-1 expressing CD8+ T cells and increased CD4+ FoxP3+ T cells in the mice with HBV persistence. Blockade of PD-1/PD-L1 interaction increased HBcAg-specific IFN-gamma production in intrahepatic T lymphocytes. Furthermore, blocking the interaction of PD-1 with its ligand PD-L1 by anti-PD-1 mAb reversed the viral persistence to clearance of HBV viral constructs in vivo. Our results indicated that PD-1 blockage reverses immune dysfunction and viral persistence to HBV infection in mouse animal model, suggesting anti-PD-1 mAb might be a good therapeutic candidate for chronic HBV infection.

Hydrodynamic Gene Delivery and Its Applications in Pharmaceutical Research

Hydrodynamic delivery has emerged as the simplest and most effective method for intracellular delivery of membrane-impermeable substances in rodents. The system employs a physical force generated by a rapid injection of large volume of solution into a blood vessel to enhance the permeability of endothelium and the plasma membrane of the parenchyma cells to allow delivery of substance into cells. The procedure was initially established for gene delivery in mice, and its applications have been extended to the delivery of proteins, oligo nucleotides, genomic DNA and RNA sequences, and small molecules. The focus of this review is on applications of hydrodynamic delivery in pharmaceutical research. Examples are provided to highlight the use of hydrodynamic delivery for study of transcriptional regulation of CYP enzymes, for establishment of animal model for viral infections, and for gene drug discovery and gene function analysis.

Synthesis of Cidofovir and (S)‐HPMPA Ether Lipid Prodrugs

Cidofovir [(S)-1-(3-hydroxy-2-phosphonomethoxypropyl)cytosine] and (S)-HPMPA [(S)-9-(3-hydroxy-2-phosphonomethoxypropyl)adenine] are potent nucleoside phosphonate antiviral agents that are not orally bioavailable unless one or both of their negative charges are masked. This unit describes the synthesis of hexadecyloxypropyl esters of cidofovir and (S)-HPMPA. These prodrugs are readily absorbed after oral administration and are converted intracellularly to the corresponding diphosphates. The hexadecyloxypropyl esters of cidofovir and (S)-HPMPA are orally active in animal models of viral infection. Two synthetic strategies are employed. In the first, cyclic cidofovir is coupled to 3-hexadecyloxy-1-propanol using the Mitsunobu reaction (triphenylphosphine, DIAD), followed by basic hydrolysis of the cyclic ester. In the second, the lipid moiety is incorporated into a phosphonate synthon and a stepwise approach is used to assemble the (S)-HPMPA analog.

The ORF3 Protein of Hepatitis E Virus Binds to Src Homology 3 Domains and Activates MAPK

The hepatitis E virus (HEV) is the causative agent of hepatitis E, an acute form of viral hepatitis. The biology and pathogenesis of HEV remain poorly understood. We have used in vitro binding assays to show that the HEV ORF3 protein (pORF3) binds to a number of cellular signal transduction pathway proteins. This includes the protein tyrosine kinases Src, Hck, and Fyn, the p85alpha regulatory subunit of phosphatidylinositol 3-kinase, phospholipase Cgamma, and the adaptor protein Grb2. A yeast two-hybrid assay was used to further confirm the pORF3-Grb2 interaction. The binding involves a proline-rich region in pORF3 and the src homology 3 (SH3) domains in the cellular proteins. Competition assays and computer-assisted modeling was used to evaluate the binding surfaces and interaction energies of the pORF3.SH3 complex. In pORF3-expressing cells, pp60(src) was found to associate with an 80-kDa protein, but no activation of the Src kinase was observed in these cells. However, there was increased activity and nuclear localization of ERK in the pORF3-expressing cells. These studies suggest that pORF3 is a viral regulatory protein involved in the modulation of cell signaling. The ORF3 protein of HEV appears to be the first example of a SH3 domain-binding protein encoded by a virus that causes an acute and primarily self-limited infection.

Back to basics: host responses to infection.

1. Armond S. Goldman, MD* 1. 2. *Department of Pediatrics, Division of Immunology/Allergy/Rheumatology, The University of Texas Medical Branch, Galveston, TX, USA. Dr. Goldman is the recipient of several small grants from Wyeth Nutritional International for research concerning bioactive factors in human milk. An understanding of host responses to infections is important to pediatricians for five major reasons: 1) The manifestations of infectious diseases are due not only to microbial pathogens but also to their interactions with the immune system of the host. 2) Both the type of immune response and the infecting agent dictates whether the disease will be acute or protracted. 3) Because the immune responses of the child are age-related, manifestations and outcomes of certain infections depend on the child’s developmental status. 4) The immune state of the infant is modified by maternal factors transferred during fetal life via the placenta and during infancy via the mammary gland. Therefore, resistance to infection is decreased if the duration or degree of placental transfer is decreased or if infants are not breastfed. These factors can be modified to some extent by pediatricians and their colleagues. 5) Because resistance to many common infections can be induced by immunizations, it is important for pediatricians to understand the immunologic strategies used to develop immunizing agents. In childhood, the external environment initially is encountered by the skin, the respiratory tract, and the alimentary tract. The skin defines the external limits of the organism, aids in temperature regulation, and is a site of insensible water loss. The respiratory tract regulates respiratory gas exchange and insensible water loss. The alimentary tract is responsible for ingestion, digestion, and absorption of nutrients; some insensible water loss; and excretion of waste products. Each of these vital systems is exposed to environmental pathogens. Innate and specific adaptive defenses have evolved to protect these vital structures and systemic sites that may become invaded if first lines of defense at the skin or mucosa fail (Table 1⇓ and Fig. 1⇓ ). View this table: Table 1. Major Features of Innate and Specific Adaptive Immunity ### INNATE DEFENSES Innate defenses are …

Back to Basics: Host Responses to Infection

Back to Basics: Host Responses to Infection

Treatment of primary herpes simplex virus infection in guinea pigs by imiquimod

Imiquimod (also known as R-837 and S-26308) is an imidazoquinoline immune response modifier and is available in the US and several other countries for the treatment of external genital warts. Imiquimod has no direct antiviral activity but demonstrates efficacy in several animal models of virus infection. The drug is recognized by antigen presenting cells including monocytes, macrophages, B-cells and dendritic cells and induces these cells to produce cytokines including interferon-α (IFN-α) and others. Imiquimod’s ability to inhibit primary lesion development in the guinea pig model of Herpes simplex virus (HSV) intravaginal infection was studied. Imiquimod given intravaginally reduced primary lesions, reduced virus shedding and reduced virus content of spinal cords from HSV infected guinea pigs. A single drug application of 0.5 mg/kg reduced lesion frequency when given between 24 h before inoculation to 16 h after inoculation. A single drug application of 5 mg/kg reduced lesion frequency and severity when administered between 72 h before inoculation to 24 h after inoculation. The antiviral effect resulting from interferon induction in the animal lasts much longer than the drug itself, thus imiquimod is different than drugs having direct antiviral activity. Twice daily drug application for 4 days was effective when initiated up to 72 h after inoculation, however, once lesions began to appear, imiquimod treatment was not able to stop lesion development. Imiquimod treatment inhibited lesion development and/or virus shedding in guinea pigs inoculated with HSV-1, HSV-2 or virus isolates resistant to acyclovir. Imiquimod is currently in clinical trials for treating human HSV infections.

Cidofovir, a New Agent with Potent Anti-Herpesvirus Activity

Cidofovir is a potent, broad spectrum antiviral agent with activity in vitro and in vivo against cytomegalovirus and other members of the herpesvirus family, as well as certain other DNA viruses. After uptake into cells it is converted enzymatically to cidofovir diphosphate, a structural analogue of deoxycytidine triphosphate, which selectively inhibits viral DNA polymerases relative to host cell polymerases. Cross-resistance to cidofovir is not usually seen with human cytomegalovirus isolates that are foscarnet-resistant, or isolates that are ganciclovir-resistant due to a deficiency in ganciclovir phosphorylation. Cross-resistance is seen, however, with isolates that are ganciclovir resistant due to polymerase mutations. A prolonged elimination phase seen in vivo, correlates with a long intracellular half-life seen in vitro and allows for efficacy in animal models of virus infection with infrequent dosing or prophylaxis. Clinical studies of intravenous cidofovir in cytomegalovirus retinitis in patients with AIDS are claimed to show delay of retinitis progression with maintenance doses given once every 2 weeks.