Rauscher Murine Leukemia Virus Research Articles

Antiviral and Possible Prophylactic Significance of Myricetin for COVID-19

Myricetin (3,5,7,3′,4′,5′ -hexahydroxyflavone), a common dietary flavonoid, has been reported for its roles in improving health due to various pharmacological activities, such as antioxidant, antimicrobial, anti-inflammatory, analgesic, antitumor, hepatoprotective, and antidiabetic. Myricetin has also been shown to have a broad spectrum of antiviral effects against a variety of viruses including Rauscher murine leukemia virus (RLV), human immunodeficiency virus (HIV), Coxsackie virus, Ebolavirus, Zika virus, herpes simplex virus (HSV-1 and HSV-2), dengue virus, murine norovirus, infectious bronchitis virus, African swine fever virus, and both DNA polymerase α and DNA polymerase I. Intensive research suggests that the remarkable potential of myricetin in promoting either the prevention or overcoming of SARS-CoV-2 infection is due to the wide range of its effects on SARS-COV-2 proteases, including modulation of inflammatory processes and immune responses. In silico and in vitro studies demonstrated that myricetin can effectively interfere at various stages of viral infection, including the coronavirus entry and replication cycle due to its high-binding affinity with S-protein, ACE2 receptor, PLpro, Mpro, RdRp, exonuclease, and endoribonuclease. Based on the findings discussed in this review, myricetin, its glycosides, and dihydromyricetin, can be considered as multi-targeted agents having beneficial effects in combatting COVID-19.

A Descriptive Study of Viral RNA Sequences Identified from Single-Cell Analysis of Acute Myeloid Leukemia

Acute Myeloid Leukemia (AML) is a hematopoietic disease responsible for a large number of cancer-related deaths, with an estimated 10,600 deaths in 2017. Viruses are known causative agents for murine and avian myeloid leukemias; however, a viral etiology has not been definitively established for human AML. Identifying an infectious etiology may lead to an improved understanding of the disease which in turn leads to potential better diagnostics and therapeutic strategies. In this study, single-cell RNA sequencing was employed to analyse the transcriptomic landscape of mononuclear cells found in AML patients in an unbiased way. The sequencing data obtained were then mapped to a viral nucleotide database to identify potential viral RNA transcripts in the cells.White blood cells or mononuclear cells were isolated from the bone marrow samples obtained from 3 AML patients by pre-staining with Hoescht, which selects for all white blood cells. Anti-CD34 antibody was also used to select for CD34 cells, which are known multipotent progenitor cells in the blood. Using the Automated Microfluidic C1 System, the isolated cells were lysed and the mRNA obtained was reverse transcribed and amplified. Using the Nextera XT DNA Sample preparation kit, cDNA library was prepared from the individual cells and processed on Illumina Next Sequencing (NexSeq) and HiSequencing 2000 (HiSeq) platform. Paired reads were generated for downstream analysis. The sequencing data were then mapped to a viral nucleotide database and mapped reads were analysed using an in-house virus identification script to determine the validity of the viral RNA transcripts found.Single-Cell RNA sequencing was performed on 212 mononuclear cells, comprising 132 CD34 cells and 80 non-CD34 cells. The sequencing data obtained from 73 cells were successfully mapped to 13 different viruses. 44 of these cells observed to have viral RNA transcripts were CD34 cells. Some of the viruses that were found included Moloney Murine Leukemia Virus (M-MuLV), Murine Osteosarcoma Virus (MSV), Feline Sarcoma Virus (FeSV), Friend Murine Leukemia Virus (F-MuLV), Fujinami Sarcoma Virus (FJSV), Hepatitis C Virus (HCV), HERV-K Provirus (HERV-K), Adenovirus (ADV), Moloney Murine Sarcoma Virus (M-MuSV), Rauscher Murine Leukemia Virus (R-MuLV) and Tomato Mosaic Virus (ToMV).Single-cell RNA sequencing was the method of choice as it enables us to analyze the transcriptomic landscapes at a single cell level, eliminating the likelihood of any minute viral RNA transcripts from being eclipsed as is the case with bulk sequencing. Through this, we have identified a variety of viral RNA sequences and it was observed that CD34 cells were found to harbor more viral RNA transcripts relative to non-CD34 cells. The presence of viruses in CD34 cells may cause genetic instability and lead to alteration of oncogenes or tumour-suppressor genes. These mutations in the progenitor cells could then be passed down to the cells it would differentiate to. However, further work is required to validate these observations and determine the properties of the identified viral sequences to be able to understand its role in tumorigenicity [Display omitted] DisclosuresChng:Janssen China R&D: Research Funding.

Investigation of the Structure and Dynamics of Antiviral Drug Adefovir Dipivoxil by Site-Specific Spin-Lattice Relaxation Time Measurements and Chemical Shift Anisotropy Tensor Measurements.

Adefovir is regarded as a potential antiviral agent. However, it cannot be considered as a valuable drug candidate due to its high polarity that limits its permeability across the human intestinal mucosa. When the ribose phosphate group of adefovir is replaced by the isopolar phosphonomethyl ether functionality, it neutralizes the negative charge of the drug. This makes the drug lipid-soluble and potent to diffuse across the cell membrane. The prodrug adefovir dipivoxil is regarded as a potent antiviral drug against hepatitis B virus (HBV), human immunodeficiency virus (HIV), Rauscher murine leukemia virus (R-MuLV), murine cytomegalovirus (MCMV), herpes simplex virus (HSV), simian immunodeficiency virus (SIV), and feline immunodeficiency virus (FIV). The correlation between the structure and the dynamics of adefovir dipivoxil is determined by measuring the principal components of chemical shift anisotropy (CSA) tensor, site-specific spin–lattice relaxation time, and molecular correlation time at crystallographically different carbon nuclei sites. The CSA parameters, spin–lattice relaxation time, and molecular correlation time of phosphorous nucleus of the organophosphate group of adefovir dipivoxil molecule are also determined. The spin–lattice relaxation time of carbon nuclei varies from 1 to 107 s. The range of molecular correlation time also varies from 10–4 to 10–8 s. These remarkable diversities of motional dynamics of the molecules imply that there exist various motional degrees of freedom within this valuable drug and these motional degrees of freedom are independent of each other, which may be the reason for the biological activities exhibited by the drug. The correlation between structure and dynamics of such an important antiviral drug adefovir dipivoxil can be visualized by these types of extensive spectroscopic measurements, which will enlighten the path of inventing advanced medicine in the pharmaceutical industry, and it will also illuminate the understanding of the structure–activity relationships of antiviral drug.

Gammaretrovirus-specific antibodies in free-ranging and captive Namibian cheetahs.

The cheetah population in Namibia is the largest free-ranging population in the world and a key population for research regarding the health status of this species. We used serological methods and quantitative real-time PCR to test free-ranging and captive Namibian cheetahs for the presence of feline leukemia virus (FeLV), a gammaretrovirus that can be highly aggressive in populations with low genetic diversity, such as cheetahs. We also assessed the presence of antibodies to other gammaretroviruses and the responses to a FeLV vaccine developed for domestic cats. Up to 19% of the free-ranging cheetahs, 27% of the captive nonvaccinated cheetahs, and 86% of the captive vaccinated cheetahs tested positive for FeLV antibodies. FeLV-antibody-positive free-ranging cheetahs also tested positive for Rauscher murine leukemia virus antibodies. Nevertheless, FeLV was not detectable by quantitative real-time PCR and no reverse transcriptase activity was detectable by product-enhanced reverse transcriptase assay in the plasma of cheetahs or the supernatants from cultures of peripheral blood mononuclear cells. The presence of antibodies to gammaretroviruses in clinically healthy specimens may be caused either by infection with a low-pathogenic retrovirus or by the expression of endogenous retroviral sequences. The strong humoral immune responses to FeLV vaccination demonstrate that cheetahs can respond to the vaccine and that vaccination against FeLV infection may be beneficial should FeLV infection ever become a threat, as was seen in Iberian lynx and Florida panthers.

Leukemogenesis by murine leukemia viruses: lessons for koala retrovirus (KoRV)

Murine leukemia viruses (MuLVs) are the prototypical gammaretroviruses, and they have been extensively studied with regard to how they cause disease. Leukemogenesis by two MuLVs is reviewed here: the endogenous Akv MuLV of AKR mice, and exogenous Moloney MuLV. Important features of MuLV leukemogenesis include the in vivo generation of envelope recombinants (MCFs) through recombination with endogenous MuLVs, and induction of preleukemic changes typified by splenic hyperplasia secondary to bone marrow defects. Studies of MuLV leukemogenesis help to frame virological questions about how koala retrovirus (KoRV) may induce neoplastic or other diseases in koalas. Fan, Hung. 2014. Leukemogenesis by murine leukemia viruses: lessons for koala retrovirus (KoRV). In The Koala and its Retroviruses: Implications for Sustainability and Survival, ed. Geoffrey W. Pye, Rebecca N. Johnson and Alex D. Greenwood. Technical Reports of the Australian Museum, Online 24: 83–88. The discovery of koala retrovirus (KoRV) in free-ranging and captive koalas (Phascolarctos cinereus) has been viewed with concern and interest. The primary concern is that KoRV-associated disease such as neoplasms, while yet to be conclusively proven to be KoRV caused, could increase the threats to survival of these animals. In the scientific community there is interest for several reasons: KoRV may be associated with lymphoma in koalas, it appears to be recently introduced into this species, and endogenization is an ongoing process. KoRV infection in koalas may provide an opportunity to study introduction and spread of a gammaretrovirus into a new host species and its accompanying effects. This process has happened in other species, notably mice, but in the more distant past, so some of the processes can only be deduced. At the same time, information learned from the relationship of murine gammaretroviruses and their hosts may provide lessons for understanding the potential relationships of KoRV and disease in koalas. The recent discovery of a second KoRV (KoRV-B) that may be associated with leukemogenicity (Xu et al., 2013) has similarities to oncogenesis in murine leukemia viruses (MuLVs). Leukemogenesis by MuLVs will be summarized here and possible implications to KoRV pathogenesis will be pointed out. Murine leukemia viruses MuLVs were first discovered in inbred mouse strains that had high incidences of leukemia. These studies resulted in isolation of several MuLV strains that cause leukemias of different hematopoietic lineages. For instance Moloney MuLV (M-MuLV) and Gross MuLV induce T-lymphoma, while Friend (F-MuLV) and Rauscher MuLV (R-MuLV) induce erythroleukemia and myeloid leukemia (Fan, 1997). These are the predominant MuLVs used in studies of MuLV leukemogenesis. They are prototypical retroviruses of the gammaretrovirus family. MuLVs can be classified into types based on their envelope proteins and the kinds of cells that they infect, determined by the cell surface proteins that they bind. The leukemogenic MuLVs are mostly ecotropic; they infect cells of mice and rats, but they do not infect most

Design, Synthesis and Evaluation of Novel 1,4‐Naphthoquinone Derivatives as Antifungal and Anticancer Agents.

A series of 1,4-naphthoquinone derivatives were synthesized and tested for antifungal and antitumor activity against a number of fungal disease causative species and Walker 256 carcinoma cell lines. The results show that the compounds 8a,e and 11b possess pronounced antifungal profile where as 7b and f were found to be active against Walker 256 carcinoma cell lines. Moreover 7c and 11a showed inhibitory effect against reverse transcriptase enzyme from Rauscher Murine Leukemia Virus.

Design, synthesis and evaluation of novel 1,4-naphthoquinone derivatives as antifungal and anticancer agents

A series of 1,4-naphthoquinone derivatives were synthesized and tested for antifungal and antitumor activity against a number of fungal disease causative species and Walker 256 carcinoma cell lines. The results show that the compounds 8a,e and 11b possess pronounced antifungal proifile where as 7b and f were found to be active against Walker 256 carcinoma cell lines. Moreover 7c and 11a showed inhibitory effect against reverse transcriptase enzyme from Rauscher Murine Leukemia Virus.

Characterization of a novel murine retrovirus mixture that facilitates hematopoiesis.

A new virus previously arose in BALB/c females mated repeatedly to C57BL/6 (B6) males and then injected with fixed, activated B6 male spleen cells (V. S. Ter-Grigorov, O. Krifuks, E. Liubashevsky, A. Nyska, Z. Trainin, and V. Toder, Nat. Med. 3:37-41, 1997). In the present study, BALB/cJ mice inoculated with virus-containing plasma from affected mice developed splenomegaly, which was caused by increased numbers of Sca-1(+) Lin(-) hematopoietic stem cells (HSC) and their differentiated progeny. Biological and molecular analyses of a new virus revealed a mixture of murine leukemia viruses (MuLVs). These MuLVs comprised ecotropic and mink lung cell focus-forming (MCF) virus classes and are termed Rauscher-like MuLVs because they bear numerous similarities to the ecotropic and MCF viruses of the Rauscher MuLV complex but do not include a spleen focus-forming virus. The ecotropic virus component alone transferred some disease characteristics, while MCF virus alone did not. Thus, we have described a novel virus mixture, termed Rauscher-like MuLV, that causes an increase in hematopoiesis due to activation of pluripotent HSC. Experiments using mice and a protocol that replicated the pregnancy and immunization strategy of the original experiment demonstrated that endogenous BALB/c mouse ecotropic and xenotropic MuLVs are activated by these treatments. Emv1 was expressed in the spleens of multiparous mice but not in those of virgin mice, and Bxv1Emv1-pseudotyped MuLVs were recovered following injection of fixed, activated B6 cells. Thus, multiple pregnancies and allostimuli appear to have provided the signals required for activation of and recombination among endogenous viruses and could have resulted in generation of the Rauscher-like MuLV mixture.

Phylogenetic Relationship of the Complete Rauscher Murine Leukemia Virus Genome with Other Murine Leukemia Virus Genomes

We report the complete nucleotide sequence of the genome of Rauscher murine leukemia virus (R-MuLV), the replication-competent helper virus present in the Rauscher virus complex, and its phylogenetic relationship with other murine leukemia virus genomes. An overall sequence identity of 97.6% was found between R-MuLV and the Friend helper virus (F-MuLV), and the two viruses were closely related on the phylogenetic trees constructed from eithergag, pol,orenvsequences. Moloney murine leukemia virus (Mo-MuLV) was the next closest relative to R-MuLV and F-MuLV on all trees, followed by Akv and radiation leukemia virus (RadLV). The most distantly related helper virus was Hortulanus murine leukemia virus (Ho-MuLV). Interestingly, Cas-Br-E branched with Mo-MuLV on thegagandpoltrees, whereas on theenvtree, it revealed the highest degree of relatedness to Ho-MuLV, possibly due to an ancient recombination with an Ho-MuLV ancestor. In summary, a phylogenetic analysis involving various MuLVs has been performed, in which the postulated close relationship between R-MuLV and F-MuLV has been confirmed, consistent with the pathobiology of the two viruses.

Identification of a gag-encoded cytotoxic T-lymphocyte epitope from FBL-3 leukemia shared by Friend, Moloney, and Rauscher murine leukemia virus-induced tumors.

FBL-3 is a highly immunogenic murine leukemia of C57BL/6 origin induced by Friend murine leukemia virus (MuLV). Immunization of C57BL/6 mice with FBL-3 readily elicits CD8+ cytotoxic T lymphocytes (CTL) capable of lysing FBL-3 as well as syngeneic leukemias induced by Moloney and Rauscher MuLV. The aim of this current study was to identify the immunogenic epitope(s) recognized by the FBL-3-specific CD8+ CTL. A series of FBL-3-specific CD8+ CTL clones were generated from C57BL/6 mice immunized to FBL-3. The majority of CTL clones (32 of 38) were specific for F-MuLV gag-encoded antigen. By using a series of recombinant vaccinia viruses expressing full-length and truncated F-MuLV gag genes, the antigenic epitope recognized by the FBL-3 gag-specific CTL clones, as well as by bulk-cultured CTL from spleens of mice immune to FBL-3, was localized to the leader sequence of gPr80gag protein. The precise amino acid sequence of the CTL epitope in the leader sequence was identified as CCLCLTVFL (positions 85-93) by examining lysis of targets incubated with a series of synthetic leader sequence peptides. No evidence of other CTL epitopes in the gPr80gag or Pr65gag core virion structural polyproteins was found. The identity of CCLCLTVFL as the target peptide was validated by showing that immunization with the peptide elicited CTL that lysed FBL-3. The CTL elicited by the Gag peptide also specifically lysed syngeneic leukemia cells induced by Moloney and Rauscher MuLV (MBL-2 and RBL-5). The transmembrane peptide was shown to be the major gag-encoded antigenic epitope recognized by bulk-cultured CTL derived from C57BL/6 mice immunized to MBL-2 or RBL-5. Thus, the CTL epitope of FBL-3 is localized to the transmembrane anchor domain of the nonstructural Gag polyprotein and is shared by leukemia/lymphoma cell lines induced by Friend, Moloney, and Rauscher MuLV.

Antiviral activity of biological response modifiers in a murine model of aids. requirement for augmentation of natural killer cell activity and synergy with oral AZT

We employed the Rauscher murine leukemia virus (RMuLV) as a murine retrovirus model of AIDS, to test biological response modifiers (BRM) and antiviral agents for potential therapeutic activity against the human immunodeficiency virus (HIV). We examined the relationship between the augmentation of natural killer (NK) cell activity and antiviral efficacy of a series of BRM, most of which are known inducers of interferon, in this model. Poly [I,C]-LC, MVE-2, and CL 246,738, but not Ampligen, soluble glucan, or 7-thia-8-oxoguanosine, consistently produced antiviral activity. In addition, the combination of suboptimal doses of oral 3'-azido-3'-deoxythymidine (AZT) (in drinking water) and poly [1,C]-LC produced a synergistic antiviral effect. With all the BRM tested, a consistent pattern emerged, namely that antiviral activity always correlated with the augmentation of splenic NK cell activity in infected animals. For instance, poly [I,C]-LC boosted NK activity much more in infected mice treated therapeutically (treatment initiated after infection) than prophylactically (treatment initiated before infection), and it had greater antiviral activity therapeutically than prophylactically. For the BRM tested, antiviral activity did not occur without augmentation of NK activity in infected mice. In contrast, augmentation of NK activity in uninfected mice bore no relationship to antiviral activity. Furthermore, elimination of NK cells by treating mice with anti-asialo GM 1 abolished the antiviral activity of poly [I,C]-LC. Although splenic NK activity was ablated by anti-asialo GM, serum interferon levels were not affected by this treatment. These results point to a causal connection between the augmentation of NK cell activity and the antiviral efficacy of these BRM in this murine AIDS model. NK cells thus appear to play a key role in resistance to this retrovirus, as has been suggested for HIV.

Optimization of the reverse transcriptase assay for the detection of viral burden in mice infected with Rauscher murine leukemia virus.

Rauscher murine leukemia virus induces an erythroleukemia in susceptible strains of mice that is associated with splenomegaly and viremia. This animal model has been used for evaluating the in vivo efficacy of potential anti-HIV agents. The in vivo antiviral activity of therapeutic agents has usually been determined by measuring a reduction in the spleen weights of compound-treated mice or by quantitating viremia with the UV-XC plaque assay. The UV-XC assay, however, is time-consuming and labor-intensive. Virions of Rauscher murine leukemia virus, like other retroviruses, contain the enzyme reverse transcriptase. Quantitating the level of this enzyme in infected mouse sera provides a more rapid measure of viremia in the animal. We have examined the effects of several reagents, including detergent, KCl, EGTA, dGMP, spermine, as well as protease and RNase inhibitors, on the reverse transcriptase assay. The optimized assay method was effective in evaluating the antiviral activity of AZT in the Rauscher murine leukemia virus in vivo model. The assay is also amenable to automation if large numbers of assays are required.

Effects of SKF 108922, an HIV-1 protease inhibitor, on retrovirus replication in mice

Rationally designed synthetic inhibitors of retroviral proteases inhibit the processing of viral polypeptides in cultures of human T lymphocytes infected with human immunodeficiency virus type 1 (HIV-1) and therefore suppress the infectivity of HIV-1 in vitro. We have previously reported the antiviral activity in vitro of HIV-1 protease inhibitors against the C-type retrovirus Rauscher murine leukemia virus (RMuLV) and the lentivirus simian immunodeficiency virus (SIV). The same compounds which blocked the infectivity of HIV-1 also inhibited the infectivity of RMuLV and SIV in vitro. This report extends these findings by testing the antiviral activity of HIV-1 protease inhibitors in vivo in the RMuLV model. RMuLV-infected mice were treated twice a day (bid) with either an active (SKF 108922) or inactive (SKF 109273) compound for fourteen days by the intraperitoneal (IP) route. Compared with excipient control, SKF 108922, formulated with hydroxypropyl-β-cyclodextrin (HPB), reduced virus-induced splenomegaly, viremia, and serum reverse transcriptase (RT) levels, while SKF 109273 was inactive. The HPB vehicle by itself enhanced replication of RMuLV. The effects of changing the formulation and the route of administration were examined. SKF 108922, formulated in HPB, had similar antiviral activity when administered by the IP or subcutaneous (SC) routes. However, SKF 108922 administered as a colloidal suspension in cholesterol sulfate (CS) had no detectable antiviral effect. Measurements of the circulating levels of the protease inhibitor in plasma explained this result. Plasma concentrations of SKF 108922 exceeded 1000 nM within 10 min after SC administration of the compound solubilized in HPB, but SKF 108922 was not detected in plasma after SC administration of the same dose formulated with CS. Information on optimal conditions for administering these agents should prove useful in guiding their clinical application Therefore, RMuLV should provide a good model for the preclinical evaluation and development of this class of agents for the treatment of HIV.

In vitro and in vivo enhancement of ddI activity against Rauscher murine leukemia virus by ribavirin

Ribavirin has been reported to enhance the activity of ddI against HIV. We explored this enhancement of antiviral activity in Rauscher murine leukemia virus (RMuLV) models in vitro and in vivo. The significant finding in these studies was that combinations of the drugs exhibited virus titer reductions that were greater than would be expected if the drug interactions were simply additive. These effects were designated synergistic by the method of Prichard and Shipman (Prichard, M.N. and Shipman, C., Jr. (1990) A three-dimensional model to analyze drug-drug interactions, Antiviral Res. 14, 181–206). In addition to the antiviral synergy, we also observed some synergistic toxicity in the animal model.

PMEA has immunomodulatory activity and inhibits reverse transcriptase in the Rauscher murine leukemia virus (RMuLV) model: S. C. Kunder, P. L. Black, B. E. Hall, and M. A. Ussery. U.S.F.D.A., Rockville, Md, USA

Caco‐2 monolayers (in vitro), rat intestinal sheets mounted in modified Ussing Chambers (ex vivo), and in situ intestinal perfusion of rat ileum were used as models to determine and compare the absorption characteristics of the antiviral agent 9‐[2‐(phosphonomethoxy)ethyl]adenine (PMEA, adefovir) and its bis(pivaloyloxymethyl)‐ester prodrug [bis(POM)‐PMEA, adefovir dipivoxil]. Although metabolism of adefovir dipivoxil was more pronounced in the ex vivo and in situ models than in the Caco‐2 system, the transport of ‘total adefovir’ [= adefovir dipivoxil and its metabolites mono(POM)‐PMEA and adefovir] was comparable in the three models. Compared with transport of the parent compound (adefovir), use of adefovir dipivoxil resulted in a significant increase in transport of total adefovir in the in vitro (∼100‐fold) and the in situ (∼10‐fold) models; in contrast, the ex vivo method failed to demonstrate a remarkable transport enhancement when using the ester prodrug. Similar to the results obtained in the Caco‐2 model, the inclusion of the P‐glycoprotein inhibitor verapamil resulted in transport enhancement during in situ perfusion of rat ileum with adefovir dipivoxil; however, no effect of verapamil could be observed in the ex vivo model. The results of this study confirm the utility of both the in vitro and in situ models to assess intestinal transport and metabolism of adefovir dipivoxil. The ex vivo model appeared to be less appropriate because of its inability to discriminate transport following administration of adefovir or adefovir dipivoxil and because of the absence of an effect of verapamil on transport when using adefovir dipivoxil. © 2000 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 89: 1054–1062, 2000

In vitro and in vivo enhancement of ddI activity against rauscher murine leukemia virus (RMuLV) by ribavirin : D. C. Quenelle, L. B. Allen, L. Westbrook, B. A. Taylor, M. N. Prichard, A. D. Brazier, M. G. Hollingshead, and W. M. Shannon. Southern Research Institute, Birmingham, AL 35255

In vitro and in vivo enhancement of ddI activity against rauscher murine leukemia virus (RMuLV) by ribavirin : D. C. Quenelle, L. B. Allen, L. Westbrook, B. A. Taylor, M. N. Prichard, A. D. Brazier, M. G. Hollingshead, and W. M. Shannon. Southern Research Institute, Birmingham, AL 35255

Antiretroviral activity of ribonucleotide reductase inhibitors hydroxyurea, didox and trimidox in the in vivo Rauscher murine leukemia virus (RMuLV) model : PL. Black 1, S. C. Kunder 1, B. E. Hall 1, H.L. Elford 2, and M. A. Ussery 1. 1U.S.ED.A., Rockville, MD; 2Molecules for Health, Richmond, VA

Antiretroviral activity of ribonucleotide reductase inhibitors hydroxyurea, didox and trimidox in the in vivo Rauscher murine leukemia virus (RMuLV) model : PL. Black 1, S. C. Kunder 1, B. E. Hall 1, H.L. Elford 2, and M. A. Ussery 1. 1U.S.ED.A., Rockville, MD; 2Molecules for Health, Richmond, VA

The gag proteins of human immunodeficiency virus type 1: mechanisms of virus assembly and possibilities for interference.

Using two different experimental systems we were able to define two distinct regions in the sequence of gag proteins of HIV which function in the assembly of structural components of the virus and particle morphogenesis. Since assembly could be inhibited by addition of synthetic non-toxic peptide compounds, a new group of antiviral agents may be developed. This approach represents a completely new inhibitory principle. Besides irreversibly blocking the synthesis of progeny virus, this class of peptidomimetic inhibitors might be of special interest since non-infectious particles are released which should still be capable of stimulating the immune system and helping to induce an improved immune status. Those effects have been observed when mice were vaccinated with Rauscher murine leukemia virus and treated simultaneously with zidovudine and interferon-α [69]. Besides the development of antiviral compounds active viral protein regions actively involved in morphogenesis may be developed for applications in gene therapy using assembly defective gag proteins to negatively influence virus production via transdominant-negative effects.

Effects of tamoxifen, droloxifene and 17β-estradiol on Rauscher mouse leukemogenesis

The effects of tamoxifen (TAM), its 3-hydroxy congener droloxifene (DROL) and 17β-estradiol were investigated on leukemogenesis induced in BALB c mice by Rauscher murine leukemia virus (RLV). Multiple applications of each compound, in a dose-dependent manner, resulted in reduced virus titer in the serum, delayed onset of splenomegaly and significant prolongation of survival. Although 17β-estradiol proved most effective, prevention of disease was not achieved either by short- or long-term treatment with any of the drugs tested.

55 Optimization of the reverse transcriptase assay for the detection of viral burden in mice infected with rauscher murine leukemia virus: E.L. White, L. Westbrook, M.G. Hollingshead, and W.M. Shannon. Southern Research Institute, Birmingham, AL USA

55 Optimization of the reverse transcriptase assay for the detection of viral burden in mice infected with rauscher murine leukemia virus: E.L. White, L. Westbrook, M.G. Hollingshead, and W.M. Shannon. Southern Research Institute, Birmingham, AL USA