HIV-1 Reverse Transcriptase Inhibitors Research Articles

A new perspective on risk factors for progressive liver fibrosis in patients with HIV, HBV, HCV superinfection

Topicality. One of the risk factors for the progression of the fibrotic process in the liver in triple superinfection with HIV/HBV/HCV may be the order of entry of viral pathogens into the human body, as well as the time interval between the entry of different pathogens. The aim of the study was to assess the effect on the course of liver fibrosis in HIV/HBV/HCV superinfection of the sequence of pathogens entering the human body and the time between superinfection.Materials and methods. 97 people with a verified diagnosis of HIV/HBV/HCV superinfection were subjected to a retrospective analysis depending on the timing of pathogen intake, the severity of liver fibrosis and antiviral therapy. Among the examined, 80% were men. The age category of 18-44 years included 84% and the remaining patients were in the category of 45–49 years. All patients received antiviral therapy. Liver fibrosis was assessed using dynamic liver elastography.Outcomes. The most favorable from the point of view of the progression of liver fibrosis was the primary HIV infection with an interval of 1–5 years between infection with hepatitis B and C viruses. The predominance of the progressive course of the fibrotic process in the liver occurred in cases where the first pathogen was HBV, and the interval between superinfection with another virus (HIV, HCV) exceeded 10 years. In cases not included in this category of patients, a HCV viral load above 1,700,000 copies/ml may be a risk factor for triple superinfection.Findings. 1. In HIV/HBV/HCV superinfection, a high risk of progressive liver fibrosis is associated with situations when: the first superinfecting pathogen is HIV at an interval of 1–5 years before superinfection with hepatitis B and/or C viruses; the first superinfecting pathogen is HBV with an interval of more than 10 years prior to HIV and/or HCV superinfection. 2. In HIV/HBV/HCV superinfection, in the absence of a priority for superinfection, a HCV viral load of more than 1700000 copies/ml may be a risk factor for advanced liver fibrosis. A rational regimen for antiretroviral therapy in triple superinfection with HIV/HBV/HCV is a combination of nucleotide inhibitors of HIV and HBV reverse transcriptase and HIV protease inhibitors.

Discovery of Novel Amino Acids (Analogues)-Substituted Thiophene[3,2-d]pyrimidine Derivatives as Potent HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors: Design, Synthesis, and Biological Evaluation.

Inspired by our previous work on the modification of diarylpyrimidine-typed non-nucleoside reverse transcriptase inhibitors (NNRTIs) and the reported crystallographic studies, a series of novel amino acids (analogues)-substituted thiophene[3,2-d]pyrimidine derivatives were designed and synthesized by targeting the solvent-exposed region of the NNRTI-binding pocket. The biological evaluation results showed that compound 5k was the most active inhibitor, exhibiting moderate-to-excellent potency against HIV-1 wild-type (WT) and a panel of NNRTI-resistant strains, with EC50 values ranging from 0.042 μM to 7.530 μM. Of special note, 5k exhibited the most potent activity against single-mutant strains (K103N and E138K), with EC50 values of 0.031 μM and 0.094 μM, being about 4.3-fold superior to EFV (EC50 = 0.132 μM) and 1.9-fold superior to NVP (EC50 = 0.181 μM), respectively. In addition, 5k demonstrated lower cytotoxicity (CC50 = 27.9 μM) and higher selectivity index values. The HIV-1 reverse transcriptase (RT) inhibition assay was further performed to confirm their binding target. Moreover, preliminary structure-activity relationships (SARs) and molecular docking studies were also discussed in order to provide valuable insights for further structural optimizations. In summary, 5k turned out to be a promising NNRTI lead compound for further investigations of treatments for HIV-1 infections.

Anti-Human Immunodeficiency Virus-1 Property of Thai Herbal Extract Kerra™.

Kerra™, a Thai traditional herbal medicine derived from the "Tak-Ka-Si-La Scripture" and composed of nine medicinal plants, has demonstrated potential antiviral properties against HIV. This study investigated the inhibitory effects of Kerra™ on HIV-1 reverse transcriptase (RT) and its ability to prevent pseudo-HIV viral infection in HEK293 cells. The results showed that Kerra™ extract achieved a 95.73 ± 4.24% relative inhibition of HIV-1 RT, with an IC50 value of 42.66 ± 8.74 µg/mL. Docking studies revealed that key phytochemicals in Kerra™, such as oleamide, formononetin, and biochanin A, interact with several residues in the RT non-nucleoside binding pocket, contributing to their inhibitory effects. Furthermore, Kerra™ was able to reduce pseudo-HIV infection in HEK293 cells at a concentration of 10 µg/mL, suggesting its potential as a supplementary treatment for HIV.

Exploration of carboxamide hybrid indolyl aryl sulfones as antiretroviral agents by HIV-1 reverse transcriptase inhibition and antioxidant effects: Synthesis, biochemical screening and computational analysis

Indolyl aryl sulfones (IASs) have been under investigation as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) since the discovery of Merck's compound l-737,126. This research work reports the synthesis of a novel series of indolyl aryl sulfonyl carboxamides (11 to 21 and 25 to 28) and their biological evaluation. Among the synthesized compounds, 15 (IC50 = 57.4 ± 10.1 µM) and 26 (IC50 = 34.0 ± 1.9 µM) demonstrated potent inhibitory activity in RNA-dependent DNA polymerization (RDDP) reactions. In addition, radical inhibition activity was performed by reacting the synthesized compounds against 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical and it was observed that compounds 20 (IC50 = 8.2 ± 0.2 µM) and 21 (IC50 = 9.3 ± 0.5 µM) showed promising antioxidant properties. Additionally, Two-Dimensional Quantitative Structure Activity Relationship (2D-QSAR) and molecular docking studies were employed to provide insight into the molecular mechanism of RDDP inhibition.

From Intercalation to External Binding: Ru(II) Complexes with a Spiro Ligand for TAR RNA Selective Binding and HIV-1 Reverse Transcriptase Inhibition.

As a typical RNA virus, the genetic information on HIV-1 is entirely stored in RNA. The reverse transcription activity of HIV-1 reverse transcriptase (RT) plays a crucial role in the replication and transmission of the virus. Non-nucleoside RT inhibitors (NNRTIs) block the function of RT by binding to the RNA binding site on RT, with very few targeting viral RNA. In this study, by transforming planar conjugated ligands into a spiro structure, we convert classical Ru(II) DNA intercalators into a nonintercalator. This enables selective binding to HIV-1 transactivation response (TAR) RNA on the outer side of nucleic acids through dual interactions involving hydrogen bonds and electrostatic attraction, effectively inhibiting HIV-1 RT and serving as a selective fluorescence probe for TAR RNA.

Identification of new triazolo annulated dipyridodiazepine derivatives as HIV-1 reverse transcriptase inhibitors: Design, synthesis, DFT, molecular modelling and in silico studies

With the tremendous increase in viral infection spread and drug resistance, it is imperative to explore new efficient antiviral agents. Two series of novel compounds, triazole-annulated dipyridodiazepines 9(a–e) and methyl-substituted triazole-annulated dipyridodiazepines 10(a–e), were successfully synthesised and characterised by IR, NMR spectroscopy and mass spectrometry. The in vitro reverse transcriptase inhibitory ability of synthesized derivatives was determined using an HIV-1 reverse transcriptase assay kit. Results revealed that 9a and 10a were most potent with an IC50 of 66 and 71 nM compared with reference drug nevirapine 88nM. A density functional theory (DFT) study of the synthesized compound showed that both triazole series possess noticeably distorted butterfly-like structures, triazole and pyridine rings tilted relative to the diazepine ring and the phenyl ring is perpendicular to the diazepine ring. Significant HOMO/LUMO gap values for both series, 3.71–4.59 eV for the compounds 9(a–e) and 3.69–4.68 eV for compounds 10(a–e), suggest their quite noticeable stability. Further, these analogues were in silico analysed for molecular docking, drug-likeness, physicochemical and ADMET studies. The good binding scores (high interaction energies) obtained in the molecular docking studies are in good agreement with the molecular electrostatic potential (MEP) analysis results showing accumulations of negative and positive electrostatic potential on different parts of the molecules of the compounds studied. In conclusion, all these results suggest that synthesized analogues could be a potential candidate to inhibit HIV-1 reverse transcriptase and may be considered as lead molecules in the development of new anti-reverse transcriptase agents.

In Silico Study of Bioactive Compounds in Herba Sambiloto (Andrographis paniculata Burm. F. Nees) as HIV-1 Reverse Transcriptase Inhibitor

A medicinal plant known as sambiloto (Andrographis paniculata Burm. F. Nees) contains certain active compounds that potentially are anti-HIV. However, it is not yet known which compounds are involved in inhibiting HIV activity. This study aimed to identify potentially active compounds from the sambiloto plant that could inhibit the HIV-1 reverse transcriptase enzyme using the in-silico method. In silico methods that will be carried out are internal validation, molecular docking, ADMET prediction, and molecular dynamics. The molecular docking results showed that the five best compounds have potential as anti-HIV drugs compared to efavirenz with the rerank score -152.119 until -125.177 kcal/mol. In contrast, the rerank score of the comparison ligand is -94.7639 kcal/mol. The ADMET prediction showed that the selected compounds have a good pharmacokinetics profile and are nontoxic. The molecular dynamic results showed that deoxy-11,12-didehydroandrographiside and andropraphiside are stable and have potential as anti-HIV drugs with average RMSD values of 1.88 and 2.02 Å while the comparison ligand is 1.67 Å.

IMPULSIVE DIFFERENTIAL EQUATION MODEL IN HIV-1 INHIBITION: ADVANCES IN DUAL INHIBITORS OF HIV-1 RT AND IN FOR THE PREVENTION OF HIV-1 REPLICATION

Reverse transcriptase (RT) and integrase (IN) are two pivotal enzymes in HIV-1 replication. RT converts the single-stranded viral RNA genome into double-stranded DNA and IN catalyzes the integration of viral double-stranded DNA into host DNA. Currently, dual inhibitors of HIV-1 RT and IN have become a hotspot in new anti-HIV drug research and development. A dual inhibitor of HIV-1 RT/IN does the same thing as the two independent drugs would do. In this paper, we develop a mathematical model comprising a system of nonlinear differential equations describing HIV-1 RT/IN catalyzed biochemical reactions based on Michaelis–Menten enzyme kinetic reaction. In the formulated model we incorporate HIV-1 RT/IN dual inhibitor which simultaneously works as a non-nucleoside RT inhibitor and IN inhibitor. To examine the efficacy of HIV-1 RT/IN dual inhibitor in the treatment of HIV-1 infection, we have introduced a one-dimensional impulsive differential equation model and determined an effective dosing regimen for applying the inhibitor numerically. Furthermore, the exact closed form solution of the impulsive differential equation model is carried out by using the Lambert W function and the local stability of the periodic solution is also obtained analytically. The results obtained from analytical as well as numerical studies provide a basic idea to investigate the minimum dose with the highest efficacy for administering HIV-1 RT/IN dual inhibitors to prevent HIV-1 infection.

In-silico Docking and ADME Studies of Natural Phytoconstituents from Different Medicinal Plants as Potential HIV Reverse Transcriptase Inhibitors

In-silico Docking and ADME Studies of Natural Phytoconstituents from Different Medicinal Plants as Potential HIV Reverse Transcriptase Inhibitors

Profiling the Interaction between Human Serum Albumin and Clinically Relevant HIV Reverse Transcriptase Inhibitors.

Tenofovir (TFV) is the active form of the prodrugs tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF), both clinically prescribed as HIV reverse transcriptase inhibitors. The biophysical interactions between these compounds and human serum albumin (HSA), the primary carrier of exogenous compounds in the human bloodstream, have not yet been thoroughly characterized. Thus, the present study reports the interaction profile between HSA and TFV, TDF, and TAF via UV-Vis, steady-state, and time-resolved fluorescence techniques combined with isothermal titration calorimetry (ITC) and in silico calculations. A spontaneous interaction in the ground state, which does not perturb the microenvironment close to the Trp-214 residue, is classified as weak. In the case of HSA/TFV and HSA/TDF, the binding is both enthalpically and entropically driven, while for HSA/TAF, the binding is only entropically dominated. The binding constant (Ka) and thermodynamic parameters obtained via ITC assays agree with those obtained using steady-state fluorescence quenching measurements, reinforcing the reliability of the data. The small internal cavity known as site I is probably the main binding pocket for TFV due to the low steric volume of the drug. In contrast, most external sites (II and III) can better accommodate TAF due to the high steric volume of this prodrug. The cross-docking approach corroborated experimental drug-displacement assays, indicating that the binding affinity of TFV and TAF might be impacted by the presence of different compounds bound to albumin. Overall, the weak binding capacity of albumin to TFV, TDF, and TAF is one of the main factors for the low residence time of these antiretrovirals in the human bloodstream; however, positive cooperativity for TAF and TDF was detected in the presence of some drugs, which might improve their residence time (pharmacokinetic profile).

Machine Learning Model and Molecular Docking for Screening Medicinal Plants as HIV-1 Reverse Transcriptase Inhibitors

Machine Learning Model and Molecular Docking for Screening Medicinal Plants as HIV-1 Reverse Transcriptase Inhibitors

Multiple spectroscopic and computational studies on binding interaction of 2-phenylamino-4-phenoxyquinoline derivatives with bovine serum albumin

Binding characteristics of potent non-nucleoside HIV-1 reverse transcriptase inhibitors, 4-(2′,6′-dimethyl-4′-formylphenoxy)-2-(5″-cyanopyridin-2″ylamino) quinoline (1) and 4-(2′,6′-dimethyl-4′-cyanophenoxy)-2-(5″-cyanopyridin-2″ylamino) quinoline (2), to bovine serum albumin (BSA) under simulative physiological conditions were investigated by multiple spectroscopic and computational methods. The experimental results demonstrated that (1) and (2) bound to BSA at site III (subdomain IB), and quenched BSA fluorescence through a static quenching process. The binding interaction of (1) or (2) to BSA forms stable complexes with the binding constants (Kb) at the level of 104 L/mol and the number of binding site was determined to be 1 for both systems, indicating that new synthesized compounds occupied one site in BSA with moderate binding affinities. Based on the analysis of the thermodynamic parameters, it can be indicated that the main binding forces for interaction between BSA and both compounds were hydrogen bonding and van der Waals force. Synchronous fluorescence results revealed that the interaction of two compounds with BSA led to modifications in the microenvironment surrounding tryptophan residue of BSA. Circular dichroism spectra demonstrated alterations in the secondary structure of BSA induced by (1) and (2). Moreover, the experimental data of molecular docking and molecular dynamics (MD) simulations supported the results obtained from multiple spectroscopic techniques, confirming the binding interactions between both compounds and BSA.

Proposal of pharmacophore model for HIV reverse transcriptase inhibitors: Combined mutational effect analysis, molecular dynamics, molecular docking and pharmacophore modeling study.

Antiretroviral therapy (ART) efficacy is jeopardized by the emergence of drug resistance mutations in HIV, compromising treatment effectiveness. This study aims to propose novel analogs of Effavirenz (EFV) as potential direct inhibitors of HIV reverse transcriptase, employing computer-aided drug design methodologies. Three key approaches were applied: a mutational profile study, molecular dynamics simulations, and pharmacophore development. The impact of mutations on the stability, flexibility, function, and affinity of target proteins, especially those associated with NRTI, was assessed. Molecular dynamics analysis identified G190E as a mutation significantly altering protein properties, potentially leading to therapeutic failure. Comparative analysis revealed that among six first-line antiretroviral drugs, EFV exhibited notably low affinity with viral reverse transcriptase, further reduced by the G190E mutation. Subsequently, a search for EFV-similar inhibitors yielded 12 promising molecules based on their affinity, forming the basis for generating a pharmacophore model. Mutational analysis pinpointed G190E as a crucial mutation impacting protein properties, potentially undermining therapeutic efficacy. EFV demonstrated diminished affinity with viral reverse transcriptase, exacerbated by the G190E mutation. The search for EFV analogs identified 12 high-affinity molecules, culminating in a pharmacophore model elucidating key structural features crucial for potent inhibition. This study underscores the significance of EFV analogs as potential inhibitors of HIV reverse transcriptase. The findings highlight the impact of mutations on drug efficacy, particularly the detrimental effect of G190E. The generated pharmacophore model serves as a pivotal reference for future drug development efforts targeting HIV, providing essential structural insights for the design of potent inhibitors based on EFV analogs identified in vitro.

Making new drugs the hard way.

A new drug can have its origin in either pharma, biotech or academia. In general, discovery scientists working in pharma and biotech are advantaged over their academic counterparts and the relative advantages and disadvantages associated are discussed in depth. Against all odds, an increasing number of important drugs have had their origins in academia. This article reports three case studies from the Liotta Research Group (LRG), which explores the special circumstances that allowed these drug development campaigns to be successful. The first involves the antiretroviral agent, emtricitabine. In this case efficient synthetic methodology, developed in the LRG, coupled with some key university and commercial sector partnerships, enabled a group of academic collaborators to discover and develop a highly effective HIV reverse transcriptase inhibitor. The second case study involves the discovery and development of the breakthrough hepatitis C drug, sofosbuvir. Based on key input from Professors Schinazi and Liotta at Emory University, scientists at the Emory startup, Pharmasset, identified the nucleoside core of the drug that would become sofosbuvir. Subsequent analysis of its phosphorylation profile by Pharmasset scientists suggested that converting it to its corresponding monophosphate prodrug would circumvent a kinase block and enable it to be an effective hepatitis C polymerase inhibitor. The third case study describes the formation of DRIVE (Drug Innovation Ventures at Emory)/EIDD (Emory Institute for Drug Development), which were created to circumvent unintended impediments for carrying out academic drug discovery and development. Although DRIVE/EIDD is a wholly-owned, not-for-profit subsidiary of Emory University, it contains many attributes that enables it to operate much more nimbly than a typical academic laboratory. With an experienced drug development team and no shareholders to distract them, DRIVE/EIDD was able to focus its attention of the development of drugs to address viral diseases of global concern. In particular, their strategy to identify and develop an antiviral agent active against multiple single-stranded RNA viruses led to molnupiravir, a broadly active, oral drug that received Emergency Use Authorization for the treatment of SARS-CoV-2 infections (i.e., COVID-19).

Current insights and molecular docking studies of HIV-1 reverse transcriptase inhibitors.

Human immunodeficiency virus (HIV) causes acquired immunodeficiency syndrome (AIDS), a lethal disease that is prevalent worldwide. According to the Joint United Nations Programme on HIV/AIDS (UNAIDS) data, 38.4 million people worldwide were living with HIV in 2021. Viral reverse transcriptase (RT) is an excellent target for drug intervention. Nucleoside reverse transcriptase inhibitors (NRTIs) were the first class of approved antiretroviral drugs. Later, a new type of non-nucleoside reverse transcriptase inhibitors (NNRTIs) were approved as anti-HIV drugs. Zidovudine, didanosine, and stavudine are FDA-approved NRTIs, while nevirapine, efavirenz, and delavirdine are FDA-approved NNRTIs. Several agents are in clinical trials, including apricitabine, racivir, elvucitabine, doravirine, dapivirine, and elsulfavirine. This review addresses HIV-1 structure, replication cycle, reverse transcription, and HIV drug targets. This study focuses on NRTIs and NNRTIs, their binding sites, mechanisms of action, FDA-approved drugs and drugs in clinical trials, their resistance and adverse effects, their molecular docking studies, and highly active antiretroviral therapy (HAART).

Identification of a Non-Nucleoside Reverse Transcriptase Inhibitor against Human Immunodeficiency Virus-1.

The HIV-1 infection epidemic remains a global health problem. Current antiretroviral treatments are effective in controlling the progression of a severe infection. However, the emergence of drug resistance requires an urgent identification of new treatment regimes. HIV-1 reverse transcriptase (RTs) has been a successful therapeutic target owing to its high specificity and potent antiviral properties; therefore, it has become an essential component of current HIV-1 standard treatments. This study identified a new HIV-1 RTs inhibitor (Compound #8) that is structurally unique and greatly effective against HIV-1 through chemical library screening and a medicinal chemistry program by analyzing the structure-activity relationship (SAR). Further analysis of molecular docking and mechanisms of action demonstrated that Compound #8 is a novel type of HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI) with a flexible binding mode. Therefore, it exhibits great therapeutic potential when combined with other existing HIV-1 drugs. Our current studies suggest that Compound #8 is a promising novel scaffold for the development of new HIV-1 treatments.

Analysis of Biochemical and Antimicrobial Properties of Bioactive Molecules of Argemone mexicana.

This study identified phytochemicals in Argemone mexicana (A. mexicana) extracts that are responsible for its medicinal properties, and the best solvent for their extraction. The extracts of the stem, leaves, flowers, and fruits of A. mexicana were prepared at low (corresponding to room temperature) and high temperatures (corresponding to the boiling points) in various solvents, viz., hexane, ethyl acetate, methanol, and H2O. The UV-visible absorption spectra of various phytoconstituents in the isolated extracts were determined through spectrophotometry. Qualitative tests for the screening of phytoconstituents in the extracts were performed to identify various phytochemicals. We identified the presence of terpenoids, alkaloids, cardiac glycosides, and carbohydrates in the plant extracts. The antioxidant and anti-human immunodeficiency virus type 1 reverse transcriptase (anti-HIV-1RT) potential, as well as the antibacterial activity of various A. mexicana extracts were determined. These extracts showed strong antioxidant activities. The extracts exhibited antimicrobial activities against Salmonella typhi, Staphylococcus epidermis, Citrobacter, Neisseria gonorrhoeae, and Shigella flexineri. These extracts significantly inhibited HIV-1 reverse transcriptase activity. The aqueous leaf extract prepared at a temperature equivalent to the boiling point, i.e., 100 °C, was identified to be the most active against pathogenic bacteria and HIV-1 RT.

Targeting HIV-1 Reverse Transcriptase Using a Fragment-Based Approach.

Human immunodeficiency virus type I (HIV-1) is a retrovirus that infects cells of the host's immune system leading to acquired immunodeficiency syndrome and potentially death. Although treatments are available to prevent its progression, HIV-1 remains a major burden on health resources worldwide. Continued emergence of drug-resistance mutations drives the need for novel drugs that can inhibit HIV-1 replication through new pathways. The viral protein reverse transcriptase (RT) plays a fundamental role in the HIV-1 replication cycle, and multiple approved medications target this enzyme. In this study, fragment-based drug discovery was used to optimize a previously identified hit fragment (compound B-1), which bound RT at a novel site. Three series of compounds were synthesized and evaluated for their HIV-1 RT binding and inhibition. These series were designed to investigate different vectors around the initial hit in an attempt to improve inhibitory activity against RT. Our results show that the 4-position of the core scaffold is important for binding of the fragment to RT, and a lead compound with a cyclopropyl substitution was selected and further investigated. Requirements for binding to the NNRTI-binding pocket (NNIBP) and a novel adjacent site were investigated, with lead compound 27-a minimal but efficient NNRTI-offering a starting site for the development of novel dual NNIBP-Adjacent site inhibitors.

The Categories, Mechanisms and Features of Nonnucleoside Reverse Transcriptase Inhibitors of HIV-1

AIDS, or acquired immune deficiency syndrome is a dangerous disease of our age, and is mainly caused by HIV-1. In the last decades, researchers have paid attention to the inhibitors of reverse transcriptase (RT) of HIV-1 as a promising candidate for antiviral drugs. The reverse transcriptase (RT) is a crucial enzyme in the life cycle of HIV-1, responsible for the conversion of viral RNA to proviral DNA which will be later integrated with the genome of infected cells. RT is composed of two function domains: an RNA and DNA-dependent polymerase domain and an RNase H domain, which are respectively responsible for the synthesis and hydrolysis of proviral DNA strands. A number of drugs targeting one of the domains or both have been designed, tested or approved for clinical use, among which the nonnucleoside reverse transcriptase inhibitors (NNRTIs) have gained their status for various advantages. Herein, the molecular mechanism of four kinds of main RT inhibitors-polymerase inhibitors, RNase H active site inhibitors, RNase H allosteric inhibitors and dual inhibitors are introduced, as well as the advantages, drawbacks and challenges of these drugs. Their mechanisms and challenges are discussed to promote a comprehensive understanding of the development of NRRTIs.

Mouse mammary tumor virus is implicated in severity of colitis and dysbiosis in the IL-10−/− mouse model of inflammatory bowel disease

BackgroundFollowing viral infection, genetically manipulated mice lacking immunoregulatory function may develop colitis and dysbiosis in a strain-specific fashion that serves as a model for inflammatory bowel disease (IBD). We found that one such model of spontaneous colitis, the interleukin (IL)-10 knockout (IL-10−/−) model derived from the SvEv mouse, had evidence of increased Mouse mammary tumor virus (MMTV) viral RNA expression compared to the SvEv wild type. MMTV is endemic in several mouse strains as an endogenously encoded Betaretrovirus that is passaged as an exogenous agent in breast milk. As MMTV requires a viral superantigen to replicate in the gut-associated lymphoid tissue prior to the development of systemic infection, we evaluated whether MMTV may contribute to the development of colitis in the IL-10−/− model.ResultsViral preparations extracted from IL-10−/− weanling stomachs revealed augmented MMTV load compared to the SvEv wild type. Illumina sequencing of the viral genome revealed that the two largest contigs shared 96.4–97.3% identity with the mtv-1 endogenous loci and the MMTV(HeJ) exogenous virus from the C3H mouse. The MMTV sag gene cloned from IL-10−/− spleen encoded the MTV-9 superantigen that preferentially activates T-cell receptor Vβ-12 subsets, which were expanded in the IL-10−/− versus the SvEv colon. Evidence of MMTV cellular immune responses to MMTV Gag peptides was observed in the IL-10−/− splenocytes with amplified interferon-γ production versus the SvEv wild type. To address the hypothesis that MMTV may contribute to colitis, we used HIV reverse transcriptase inhibitors, tenofovir and emtricitabine, and the HIV protease inhibitor, lopinavir boosted with ritonavir, for 12-week treatment versus placebo. The combination antiretroviral therapy with known activity against MMTV was associated with reduced colonic MMTV RNA and improved histological score in IL-10−/− mice, as well as diminished secretion of pro-inflammatory cytokines and modulation of the microbiome associated with colitis.ConclusionsThis study suggests that immunogenetically manipulated mice with deletion of IL-10 may have reduced capacity to contain MMTV infection in a mouse-strain-specific manner, and the antiviral inflammatory responses may contribute to the complexity of IBD with the development of colitis and dysbiosis.8hbTGJzMzAHuPYE9uy6yoBVideo