Lowering mortality risk in CR-HvKP infection in intestinal immunohistological and microbiota restoration.

Gut damage during carbapenem-resistant and hypervirulent Klebsiella pneumoniae (CR-HvKP) infection is associated with a death risk. Understanding the mechanisms by which CR-HvKP causes intestinal damage and gut microbiota alteration, and the impact on immunity, is crucial for developing therapeutic strategies. This study investigated if gastrointestinal tract damage and disruption of gut microbiota induced by CR-HvKP infection undermined host immunity and facilitated multi-organ invasion of CR-HvKP; whether the therapeutic value of the rifampicin (RIF) and zidovudine (ZDV) combination was attributed to their ability to repair damages and restore host immunity was determined. A sepsis model was utilized to assess the intestinal pathological changes. Metagenomic analysis was performed to characterize the alteration of gut microbiota. The effects of the RIF and ZDV on suppressing inflammatory responses and improving immune functions and gut microbiota were evaluated by immunopathological and transcriptomic analyses. Rapid colonic damage occurred upon activation of the inflammation signaling pathways during lethal infections. Gut inflammation compromised host innate immunity and led to a significant decrease in probiotics abundance, including Bifidobacterium and Lactobacillus. Treatment with combination drugs significantly attenuated the inflammatory response, up-regulated immune cell differentiation signaling pathways, and promoted the abundance of Bifidobacterium (33.40 %). Consistently, supplementation of Bifidobacterium alone delayed the death in sepsis model. Gut inflammation and disrupted microbiota are key disease features of CR-HvKP infection but can be reversed by the RIF and ZDV drug combination. The finding that these drugs can restore host immunity through multiple mechanisms is novel and deserves further investigation of their clinical application potential.

Giardia intestinalis thymidine kinase is a high-affinity enzyme crucial for DNA synthesis and an exploitable target for drug discovery.

Giardiasis is a diarrheal disease caused by the unicellular parasite Giardia intestinalis, for which metronidazole is the main treatment option. The parasite is dependent on exogenous deoxyribonucleosides for DNA replication and thus is also potentially vulnerable to deoxyribonucleoside analogs. Here, we characterized the G. intestinalis thymidine kinase, a divergent member of the thymidine kinase 1 family that consists of two weakly homologous parts within one polypeptide. We found that the recombinantly expressed enzyme is monomeric, with 100-fold higher catalytic efficiency for thymidine compared to its second-best substrate, deoxyuridine, and is furthermore subject to feedback inhibition by dTTP. This efficient substrate discrimination is in line with the lack of thymidylate synthase and dUTPase in the parasite, which makes deoxy-UMP a dead-end product that is potentially harmful if converted to deoxy-UTP. We also found that the antiretroviral drug azidothymidine (AZT) was an equally good substrate as thymidine and was active against WT as well as metronidazole-resistant G. intestinalis trophozoites. This drug inhibited DNA synthesis in the parasite and efficiently decreased cyst production in vitro, which suggests that it could reduce infectivity. AZT also showed a good effect in G. intestinalis-infected gerbils, reducing both the number of trophozoites in the small intestine and the number of viable cysts in the stool. Taken together, these results suggest that the absolute dependency of the parasite on thymidine kinase for its DNA synthesis can be exploited by AZT, which has promise as a future medication effective against metronidazole-refractory giardiasis.

Metabolomic profiling of preterm birth in pregnant women living with HIV.

BACKGROUND: Preterm birth is a leading cause of death in children under the age of five. The risk of preterm birth is increased by maternal HIV infection as well as by certain antiretroviral regimens, leading to a disproportionate burden on low- and medium-income settings where HIV is most prevalent. Despite decades of research, the mechanisms underlying spontaneous preterm birth, particularly in resource limited areas with high HIV infection rates, are still poorly understood and accurate prediction and therapeutic intervention remain elusive. OBJECTIVES: Metabolomics was utilized to identify profiles of preterm birth among pregnant women living with HIV on two different antiretroviral therapy (ART) regimens. METHODS: This pilot study comprised 100 mother-infant dyads prior to antiretroviral initiation, on zidovudine monotherapy or on protease inhibitor-based antiretroviral therapy. Pregnancies that resulted in preterm births were matched 1:1 with controls by gestational age at time of sample collection. Maternal plasma and blood spots at 23-35 weeks gestation and infant dried blood spots at birth, were assayed using an untargeted metabolomics method. Linear regression and random forests classification models were used to identify shared and treatment-specific markers of preterm birth. RESULTS: Classification models for preterm birth achieved accuracies of 95.5%, 95.7%, and 80.7% in the untreated, zidovudine monotherapy, and protease inhibitor-based treatment groups, respectively. Urate, methionine sulfone, cortisone, and 17α-hydroxypregnanolone glucuronide were identified as shared markers of preterm birth. Other compounds including hippurate and N-acetyl-1-methylhistidine were found to be significantly altered in a treatment-specific context. CONCLUSION: This study identified previously known as well as novel metabolomic features of preterm birth in pregnant women living with HIV. Validation of these models in a larger, independent cohort is necessary to ascertain whether they can be utilized to predict preterm birth during a stage of gestation that allows for therapeutic intervention or more effective resource allocation.

Zidovudine and Interferon Alfa based regimens for the treatment of adult T-cell leukemia/lymphoma (ATLL): a systematic review and meta-analysis.

BACKGROUND: ATLL (Adult T-Cell Leukemia/Lymphoma) is an aggressive hematological malignancy. This T-cell non-Hodgkin lymphoma, caused by the human T-cell leukemia virus type 1 (HTLV-1), is challenging to treat. There is no known treatment for ATLL as of yet. However, it is recommended to use Zidovudine and Interferon Alfa-based regimens (AZT/IFN), chemotherapy, and stem cell transplant. This study aims to review the outcome of patients with different subtypes of ATLL treated with Zidovudine and Interferon Alfa-based regimens. METHODS: A systematic search was carried out for articles evaluating outcomes of ATLL treatment by AZT/IFN agents on human subjects from January 1, 2004, until July 1, 2022. Researchers assessed all studies regarding the topic, followed by extracting the data. A random-effects model was used in the meta-analyses. RESULTS: We obtained fifteen articles on the AZT/IFN treatment of 1101 ATLL patients. The response rate of the AZT/IFN regimen yielded an OR of 67% [95% CI: 0.50; 0.80], a CR of 33% [95% CI: 0.24; 0.44], and a PR of 31% [95% CI: 0.24; 0.39] among individuals who received this regimen at any point during their treatment. Our subgroup analyses' findings demonstrated that patients who received front-line and combined AZT/IFN therapy responded better than those who received AZT/IFN alone. It is significant to note that patients with indolent subtypes of disease had considerably higher response rates than individuals with aggressive disease. CONCLUSION: IFN/AZT combined with chemotherapy regimens is an effective treatment for ATLL patients, and its use in the early stages of the disease may result in a greater response rate.

Toxicological evaluation of zidovudine and novel chalcogen derivatives in Drosophila melanogaster.

Zidovudine (AZT) is the most commonly prescribed antiviral drug for the treatment of human immunodeficiency virus (HIV) infection. However, its chronic administration causes toxic side effects limiting its use. This study aimed to evaluate the toxicity of different concentrations of AZT and novel chalcogen derivatives (7A, 7D, 7G, 7K, 7M) on locomotion, mitochondrial dysfunction, acetylcholinesterase (AChE) activity, and production of reactive oxygen species (ROS) in adult Drosophila melanogaster. Our results show that AZT and its derivative 7K at a concentration of 10 µM impaired flies' locomotor behavior. Furthermore, AZT and the derivatives 7K, 7A, and 7M induced mitochondrial dysfunction observed by a decrease in oxygen flux through mitochondrial complexes I and II. Neither of the compounds tested affected AChE activity or ROS production in flies. According to these data, AZT derivatives presented the following decreasing order of toxicity: 7K > AZT > 7G > 7A > 7M > 7D. Based on the chemical structure, it is possible to infer that the presence of the seleno-phenyl group in 7A and 7G increases their toxicity compared to compounds 7D and 7M. In addition, compounds 7G, 7M, and 7K with three carbon atoms as spacer were more toxic than analogs containing one carbon atom (7A and 7D). Finally, the insertion of a p-methoxyl group enhances toxicity (7K). Based on these results, excepting 7K, all other chalcogen derivatives presented lower toxicity than AZT and are potential drug candidates.

HIV Replication Increases the Mitochondrial DNA Content of Plasma Extracellular Vesicles.

Extracellular vesicles (EVs) and their cargo have been studied intensively as potential sources of biomarkers in HIV infection; however, their DNA content, particularly the mitochondrial portion (mtDNA), remains largely unexplored. It is well known that human immunodeficiency virus (HIV) infection and prolonged antiretroviral therapy (ART) lead to mitochondrial dysfunction and reduced mtDNA copy in cells and tissues. Moreover, mtDNA is a well-known damage-associated molecular pattern molecule that could potentially contribute to increased immune activation, oxidative stress, and inflammatory response. We investigated the mtDNA content of large and small plasma EVs in persons living with HIV (PLWH) and its implications for viral replication, ART use, and immune status. Venous blood was collected from 196 PLWH, ART-treated or ART-naïve (66 with ongoing viral replication, ≥20 copies/mL), and from 53 HIV-negative persons, all recruited at five HIV testing or treatment centers in Burkina Faso. Large and small plasma EVs were purified and counted, and mtDNA level was measured by RT-qPCR. Regardless of HIV status, mtDNA was more abundant in large than small EVs. It was more abundant in EVs of viremic than aviremic and control participants and tended to be more abundant in participants treated with Tenofovir compared with Zidovudine. When ART treatment was longer than six months and viremia was undetectable, no variation in EV mtDNA content versus CD4 and CD8 count or CD4/CD8 ratio was observed. However, mtDNA in large and small EVs decreased with years of HIV infection and ART. Our results highlight the impact of viral replication and ART on large and small EVs' mtDNA content. The mechanisms underlying the differential incorporation of mtDNA into EVs and their effects on the surrounding cells warrant further investigation.

Antiviral Effect of 5'-Arylchalcogeno-3-aminothymidine Derivatives in SARS-CoV-2 Infection.

The understanding that zidovudine (ZDV or azidothymidine, AZT) inhibits the RNA-dependent RNA polymerase (RdRp) of SARS-CoV-2 and that chalcogen atoms can increase the bioactivity and reduce the toxicity of AZT has directed our search for the discovery of novel potential anti-coronavirus compounds. Here, the antiviral activity of selenium and tellurium containing AZT derivatives in human type II pneumocytes cell model (Calu-3) and monkey kidney cells (Vero E6) infected with SARS-CoV-2, and their toxic effects on these cells, was evaluated. Cell viability analysis revealed that organoselenium (R3a-R3e) showed lower cytotoxicity than organotellurium (R3f, R3n-R3q), with CC50 ≥ 100 µM. The R3b and R3e were particularly noteworthy for inhibiting viral replication in both cell models and showed better selectivity index. In Vero E6, the EC50 values for R3b and R3e were 2.97 ± 0.62 µM and 1.99 ± 0.42 µM, respectively, while in Calu-3, concentrations of 3.82 ± 1.42 µM and 1.92 ± 0.43 µM (24 h treatment) and 1.33 ± 0.35 µM and 2.31 ± 0.54 µM (48 h) were observed, respectively. The molecular docking calculations were carried out to main protease (Mpro), papain-like protease (PLpro), and RdRp following non-competitive, competitive, and allosteric inhibitory approaches. The in silico results suggested that the organoselenium is a potential non-competitive inhibitor of RdRp, interacting in the allosteric cavity located in the palm region. Overall, the cell-based results indicated that the chalcogen-zidovudine derivatives were more potent than AZT in inhibiting SARS-CoV-2 replication and that the compounds R3b and R3e play an important inhibitory role, expanding the knowledge about the promising therapeutic capacity of organoselenium against COVID-19.

Selective modulation of placental and fetal MDR transporters by chronic in utero exposure to NRTIs in Sprague-Dawley rats: Importance for fetoprotection.

Multidrug resistance (MDR) transporters present in placenta and fetal tissues reduce intracellular accumulation of their substrates. Consequently, induction of protein expression may further reduce toxic effects of specific xenobiotics. This work aimed to study whether sustained drug treatments in utero could modulate MDR transporters P-gp, BCRP, and MRP2 and thus impact their fetoprotective action. Pregnant Sprague-Dawley rats were daily treated by gavage with zidovudine (AZT, 60 mg/kg) or lamivudine (3TC, 30 mg/kg) from gestation day (GD) 11 to 20. On GD 21, DNA damage and MDR protein abundance were assessed by comet assay and western blotting, respectively. Moreover, a single IV dose of AZT or 3TC was administered on GD 21 and drug concentrations were measured in maternal blood and fetal liver by HPLC-UV. Chronic exposure to 3TC caused significantly higher DNA damage than AZT in fetal liver cells, whereas no differences were observed in maternal blood cells. Increased levels of BCRP protein were found in the placenta and fetal liver after AZT, but not 3TC, chronic in utero exposure. Contrarily, no modifications in the protein abundance of P-gp or MRP2 were found after sustained exposure to these drugs. The area under the curve of AZT in fetal liver was significantly lower in the AZT-pretreated rats than in the VEH or 3TC groups. Moreover, pre-administration of the BCRP inhibitor gefitinib (20 mg/kg, IP) increased AZT levels to the values observed in the VEH-treated group in this tissue. On the other hand, the disposition of 3TC in maternal blood or fetal liver was not modified after chronic treatment in either group. In conclusion, chronic exposure to AZT selectively induces BCRP expression in the placenta and fetal liver decreasing its own accumulation which may account for the lower DNA damage observed for AZT compared to 3TC in fetal liver cells.

Antiviral drugs suppress infection of 2019-nCoV spike pseudotyped virus by interacting with ACE2 protein.

The outbreak of coronavirus disease 2019 (COVID-19) has induced a large number of deaths worldwide. Angiotensin-converting enzyme 2 (ACE2) is the entry receptor for the 2019 novel coronavirus (2019-nCoV) to infect the host cells. Therefore, ACE2 may be an important target for the prevention and treatment of COVID-19. The aim of this study was to investigate the inhibition effect of valaciclovir hydrochloride (VACV), zidovudine (ZDV), saquinavir (SQV), and efavirenz (EFV) on 2019-nCoV infection. The results of molecule docking and surface plasmon resonance showed that VACV, ZDV, SQV, and EFV could bind to ACE2 protein, with the KD value of (4.33 ± 0.09) e-8 , (6.29 ± 1.12) e-6 , (2.37 ± 0.59) e-5 , and (4.85 ± 1.57) e-5 M, respectively. But only ZDV and EFV prevent the 2019-nCoV spike pseudotyped virus to enter ACE2-HEK293T cells with an EC50 value of 4.30 ± 1.46 and 3.92 ± 1.36 µM, respectively. ZDV and EFV also have a synergistic effect on preventing entry of virus into cells. In conclusion, ZDV and EFV suppress 2019-nCoV infection of ACE2-HEK293T cells by interacting with ACE2.

Fetal-Maternal Surgery for Spina Bifida in a HIV-Infected Mother.

INTRODUCTION: In select cases, in utero surgery for myelomeningocele (MMC) leads to better outcomes than postnatal repair. However, maternal HIV infection constitutes a formal exclusion criterion due to the potential of vertical HIV transmission. Encouraged by a previous case of a successful fetal spina bifida repair in a Hepatitis Bs antigen-positive woman, a plan was devised allowing for fetal surgery. CASE REPORT: In utero MMC repair was performed although the mother was HIV-infected. To minimize the risk of in utero HIV transmission, the mother was treated by highly active antiretroviral therapy throughout gestation as well as intravenous zi-dovudine administration during maternal-fetal surgery. The mother tolerated all procedures very well without any sequelae. The currently 20 month-old toddler is HIV negative and has significantly benefitted from fetal surgery. DISCUSSION/CONCLUSION: This case shows that maternal HIV is not a priori a diagnosis that excludes fetal surgery. Rather, it might be a surrogate for moving towards personalized medicine and away from applying too rigorous exclusion criteria in the selection of candidates for maternal-fetal surgery.

The Use of Zidovudine Pharmacophore in Multi-Target-Directed Ligands for AIDS Therapy.

The concept of polypharmacology embraces multiple drugs combined in a therapeutic regimen (drug combination or cocktail), fixed dose combinations (FDCs), and a single drug that binds to different targets (multi-target drug). A polypharmacology approach is widely applied in the treatment of acquired immunodeficiency syndrome (AIDS), providing life-saving therapies for millions of people living with HIV. Despite the success in viral load suppression and patient survival of combined antiretroviral therapy (cART), the development of new drugs has become imperative, owing to the emergence of resistant strains and poor adherence to cART. 3'-azido-2',3'-dideoxythymidine, also known as azidothymidine or zidovudine (AZT), is a widely applied starting scaffold in the search for new compounds, due to its good antiretroviral activity. Through the medicinal chemistry tool of molecular hybridization, AZT has been included in the structure of several compounds allowing for the development of multi-target-directed ligands (MTDLs) as antiretrovirals. This review aims to systematically explore and critically discuss AZT-based compounds as potential MTDLs for the treatment of AIDS. The review findings allowed us to conclude that: (i) AZT hybrids are still worth exploring, as they may provide highly active compounds targeting different steps of the HIV-1 replication cycle; (ii) AZT is a good starting point for the preparation of co-drugs with enhanced cell permeability.

Targeting Apoptosis Signal-Regulating Kinase-1 (ASK-1) As a Biomarker of Monocrotaline-Induced Pulmonary Hypertension following Administration of Antiretroviral Medications in Rat Model.

BACKGROUND: Apoptosis resistance is a recognized pathogenetic mechanism in pulmonary hypertension. However, the link between apoptosis signal-regulating kinase-1 (ASK-1) and pulmonary hypertension (PH) is unclear. This study was conducted to elucidate ASK-1 as a potential biomarker in PH. The study aimed to identify the role of ASK-1 in the mechanism of monocrotaline-induced PH in rats. METHODS: Forty adult male Sprague-Dawley rats (body weight: 200-250 g) were randomly divided into five groups (n=8 per group). The four treatment groups received a single intraperitoneal injection of monocrotaline (MCT) at a dose of 60 mg. kg-1 while the control group received an equivalent volume of intraperitoneal saline injection. Zidovudine (100mg. kg-1), ritonavir (30mg. kg-1), or combination of both drugs (zidovudine 100mg. kg-1 and ritonavir 30mg. kg-1) were administrated daily for the study period of 28 days to the rats in three of the four treatment groups with MCT for 28 days. On the twenty-eighth day of the study, rats were sacrificed, and organ harvested with the heart analyzed using RT-PCR for ASK-1. Antioxidant enzyme activities were determined using the colorimetric method. RESULTS: Animal survival rate was one hundred percent in the treated and control groups while the untreated group recorded 62% survival rate. There was significantly lower mRNA gene expression of ASK-1 in the heart tissues of the treated rats with zidovudine (2.67 ± 0.09, p < 0.0001), ritonavir (2.57 ±0.11, p < 0.0001) and a combination of both (2.75 ± 0.06, p < 0.0001) when compared to rats in the untreated group. An overexpressed mRNA gene of ASK-1 in the untreated rats was observed (12.0 ± 0.90, p < 0.0001) when compared to the controls. CONCLUSION: ASK-1 is a veritable biomarker for anti-apoptotic characteristics of PH. Our findings will spur new investigations on the role of ASK-1 in PH and the potential therapeutic benefits of antiretroviral medications in the prevention of PH. CONTEXTE: La résistance à l'apoptose est une pathogénétique reconnue mécanisme dans l'hypertension pulmonaire. Cependant, le lien entrekinase-1 régulatrice du signal d'apoptose (ASK-1) et pulmonaire l'hypertension (HTP) n'est pas claire. La présente étude a été menée pour :élucider ASK-1 comme biomarqueur potentiel de l'HTP. L'étude visait à :identifier le rôle de l'ASK-1 dans le mécanisme induit par la monocrotalinePH chez le rat. MÉTHODES: Quarante rats Sprague-Dawley mâles adultes (poids corporel:200 à 250 g) ont été divisés au hasard en cinq groupes (n = 8 par groupe).Les quatre groupes de traitement ont reçu une seule injection intrapéritonéalede monocrotaline (TCM) à une dose de 60 mg. kg­1 pendant que le témoina reçu un volume équivalent d'injection intrapéritonéale de solution saline.Zidovudine (100 mg kg­1), ritonavir (30 mg kg­1) ou combinaison deles deux médicaments (zidovudine 100 mg. Kg­1 et ritonavir 30 mg. kg­1) étaient administré quotidiennement pendant la période d'étude de 28 jours aux rats dans trois des quatre groupes de traitement avec MCT pendant 28 jours. Sur levingt-huitième jour de l'étude, des rats ont été sacrifiés et des organesrécolté avec le cœur analysé à l'aide de rt-PCR pour ASK-1. Les activités enzymatiques antioxydantes ont été déterminées à l'aide de la colorimétrieméthode. RÉSULTATS: Le taux de survie des animaux était de cent pour cent dans les groupes traités et témoins tandis que le groupe non traité a enregistré 62 %taux de survie. L'expression des gènes de l'ARNm était significativement plus faible d'ASK-1 dans les tissus cardiaques des rats traités par la zidovudine (2.67 ± 0.09, p < 0.0001), ritonavir (2.57 ±0.11, p < 0.0001) et acombinaison des deux (2.75 ± 0.06, p < 0.0001) par rapport aux rats dans le groupe non traité. Un gène d'ARNm surexprimé d'ASK-1 dans les rats non traités ont été observés (12.0 ± 0.90, p < 0.0001) lorsque par rapport aux contrôles. CONCLUSION: ASK-1 est un véritable biomarqueur antiapoptotique caractéristiques du pH. Nos conclusions donneront lieu à de nouvelles enquêtes sur le rôle de l'ASK-1 dans l'HTP et les avantages thérapeutiques potentiels demédicaments antirétroviraux dans la prévention de l'HTP. Mots-clés: Hypertension pulmonaire, régulation du signal d'apoptosekinase 1 (ASK-1), zidovudine, ritonavir, VIH/SIDA.

Role of the SOS Response in the Generation of Antibiotic Resistance In Vivo.

The SOS response to DNA damage is a conserved stress response in Gram-negative and Gram-positive bacteria. Although this pathway has been studied for years, its relevance is still not familiar to many working in the fields of clinical antibiotic resistance and stewardship. Under some conditions, the SOS response favors DNA repair and preserves the genetic integrity of the organism. On the other hand, the SOS response also includes induction of error-prone DNA polymerases, which can increase the rate of mutation, called the mutator phenotype or "hypermutation." As a result, mutations can occur in genes conferring antibiotic resistance, increasing the acquisition of resistance to antibiotics. Almost all of the work on the SOS response has been on bacteria exposed to stressors in vitro. In this study, we sought to quantitate the effects of SOS-inducing drugs in vivo, in comparison with the same drugs in vitro. We used a rabbit model of intestinal infection with enteropathogenic Escherichia coli strain E22. SOS-inducing drugs triggered the mutator phenotype response in vivo as well as in vitro. Exposure of E. coli strain E22 to ciprofloxacin or zidovudine, both of which induce the SOS response in vitro, resulted in increased antibiotic resistance to 3 antibiotics: rifampin, minocycline, and fosfomycin. Zinc was able to inhibit the SOS-induced emergence of antibiotic resistance in vivo, as previously observed in vitro. Our findings may have relevance in reducing the emergence of resistance to new antimicrobial drugs.

Poor outcome and high prevalence of invasive fungal infections in patients with adult T-cell leukemia/lymphoma exposed to zidovudine and interferon alfa.

Patients treated for adult T-Cell leukemia/lymphoma (ATL) have a poor prognosis and are prone to infectious complications which are poorly described. As the French reference center for ATL, we retrospectively analyzed 47 consecutive ATL (acute, n = 23; lymphoma, n = 14; chronic, n = 8; smoldering, n = 2) patients between 2006 and 2016 (median age 51 years, 96% Afro-Caribbean origin). The 3-year overall survival (OS) was 15.8%, 11.3%, and 85.7% for acute, lymphoma, and indolent (chronic and smoldering) forms respectively. Among aggressive subtypes, 20 patients received, as frontline therapy, high dose of zidovudine and interferon alfa (AZT-IFN⍺) resulting in an overall response rate (ORR) of 39% (complete response [CR] 33%) and 17 chemotherapy resulting of an ORR of 59% (CR 50%). Ninety-five infections occurred in 38 patients, most of whom had an acute subtype (n = 73/95; 77%). During their follow-up, patients receiving frontline chemotherapy or frontline AZT-IFNα developed infections in 74% (n = 14/19) and 89% (n = 24/27) of the cases respectively. Sixty-four (67%) of infections were microbiologically documented. Among them, invasive fungal infections (IFI, n = 11) included 2 Pneumocystis jirovecii pneumonia, 5 invasive aspergillosis, and 4 yeast fungemia. IFI exclusively occurred in patients with acute subtype mostly exposed to AZT-IFNα (n = 10/11) and experiencing prolonged (> 10 days) grade 4 neutropenia. Patients with aggressive subtype experiencing IFI had a lower OS than those who did not (median OS 5.4 months versus 18.4 months, p = 0.0048). ATL patients have a poor prognosis even in the modern era. Moreover, the high rate of infections impacts their management especially those exposed to AZT-IFNα.

Magnitude and associated factors of anemia among AZT based HAART experienced adult HIV patients at University of Gondar Comprehensive Specialized Referral Hospital, Northwest, Ethiopia, 2019: a retrospective cohort study.

BACKGROUND: Anemia is the most common hematologic abnormalities in AIDS patients usually associated with disease progression and poor clinical outcomes. Zidovudine (AZT), which is one of the nucleoside reverse transcriptase inhibitor drug families of the first line antiretroviral therapy regimen for HIV/AIDS patients, causes anemia due to early long-term of higher-dose therapy. This study was aimed to assess the magnitude and associated factors of anemia among AZT containing HAART experienced adult HIV/ADIS patients at University of Gondar Comprehensive Specialized Referral Hospital, northwest, Ethiopia, 2019. METHODS: A retrospective cohort study was conducted among a total of 320 adult AZT based HAART experienced HIV/AIDS patients from January 2016 to December 2018. Systematic random sampling technique was used to select the patients' charts. All required data for this study were extracted from patients' medical charts. Data were coded, cleared and entered into Epi Info version 3.5.3, and transformed to SPSS version 20 for analysis. Descriptive statistics, bivariable and multivariable logistic regression models were fitted to identify associated factors of anemia and P-value < 0.05 was considered as statistically significance. RESULTS: A total of 320 adult AZT based HAART experienced HIV/AIDS patients' charts were assessed. Of the total patients, 198 (61.9%) were females and 133 (41.6%) were within the age range of 35-45 years. More than half, 237(76.9%) of the patients were from the urban area and 186 (58.1%) were on WHO clinical stage III at the baseline. The prevalence of anemia was 50% (95% CI 44.7-55.0%), 44.1% (95% CI 38.4-50.0%), 35.6% (95% CI 30.3-40.6%), 40% (95% CI 34.4-45.6%), 40.6% (95% CI 35.0-46.3) and 39.1% (95% CI 33.4-44.1%) at baseline, 6 months, 12 months, 18 months, 24 months and 30 months of follow-up period, respectively. The overall prevalence of anemia was 41.6%. Anemia had significant association with WHO clinical stage and base line Hgb values. CONCLUSIONS: A significant number of participants were anemic in this study. WHO clinical stage and baseline Hgb value were the contributing factors for anemia among these patients. Therefore, anemia needs an immediate intervention on associated factor to improve the anemic status and living condition of HIV patient.

Zidovudine inhibits telomere elongation, increases the transposable element LINE-1 copy number and compromises mouse embryo development.

PURPOSE: Millions of pregnant, HIV-infected women take reverse transcriptase inhibitors, such as zidovudine (azidothymidine or AZT), during pregnancy. Reverse transcription plays important roles in early development, including regulation of telomere length (TL) and activity of transposable elements (TE). So we evaluated the effects of AZT on embryo development, TL, and copy number of an active TE, Long Interspersed Nuclear Element 1 (LINE-1), during early development in a murine model. DESIGN: Experimental study. METHODS: In vivo fertilized mouse zygotes from B6C3F1/B6D2F1 mice were cultured for 48 h in KSOM with no AZT (n = 45), AZT 1 µM (n = 46) or AZT 10 µM (n = 48). TL was measured by single-cell quantitative PCR (SC-pqPCR) and LINE-1 copy number by qPCR. The percentage of morulas at 48 h, TL and LINE-1 copy number were compared among groups. RESULTS: Exposure to AZT 1 µM or 10 µM significantly impairs early embryo development. TL elongates from oocyte to control embryos. TL in AZT 1 µM embryos is shorter than in control embryos. LINE-1 copy number is significantly lower in oocytes than control embryos. AZT 1 µM increases LINE-1 copy number compared to oocytes controls, and AZT 10 µM embryos. CONCLUSION: AZT at concentrations approaching those used to prevent perinatal HIV transmission compromises mouse embryo development, prevents telomere elongation and increases LINE-1 copy number after 48 h treatment. The impact of these effects on the trajectory of aging of children exposed to AZT early during development deserves further investigation.

Karplus relationships of the 2 JHNα and 3 JΗΝß couplings in organic azides.

Density functional theory (DFT) and second-order polarization propagator approximation (SOPPA) computations in model organic azides revealed a Karplus-like dependence not only of the vicinal 3 JH-C-Nα-Nß coupling but also of the geminal 2 JH-C-Nα one, with the H-C-Nα Nß dihedral angle. Karplus equations were derived from the DFT computations on the isopropylazide model system. In light of these stablished relationships, natural abundance 1 H-15 N couplings obtained for the azide group of the zidovudine antiviral helped to probe its conformation around the C-Nα bond as being of the synclinal type.

Activity of Tigecycline or Colistin in Combination with Zidovudine against Escherichia coli Harboring tet(X) and mcr-1.

Alternative therapeutic options are urgently needed against multidrug-resistant Escherichia coli infections, especially in situations of preexisting tigecycline and colistin resistance. Here, we investigated synergistic activity of the antiretroviral drug zidovudine in combination with tigecycline or colistin against E. coli harboring tet(X) and mcr-1 in vitro and in a murine thigh infection model. Zidovudine and tigecycline/colistin combinations achieved synergistic killing and significantly decreased bacterial burdens by >2.5-log10 CFU/g in thigh tissues compared to each monotherapy.

Molecular targeting of PD-1 signaling pathway as a novel therapeutic approach in HTLV-1 infection.

HTLV-1, the first human oncogenic retrovirus, is a type C retrovirus that belongs to the Deltaretrovirus genus. The HTLV-1 genome has 8.5 kbp length, and consists of major genes such as gag, pol, pro, env, and pX region. This retrovirus is considered as one of the most deadly infectious agent for peripheral-blood mononuclear cells (PBMC). The infection of HTLV-1 can lead to dangerous complications, such as infective dermatitis (ID), uveitis, arthritis, lymphadenitis, arthropathies, Sjögren's Syndrome (SS), and particularly HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) or Adult T-Cell Leukemia Lymphoma (ATLL). At the moment, Zidovudine (AZT) plus IFN-α is the only treatment available for HTLV-1 infections. Based on scientific studies, alongside the therapeutic regimens, intrinsic mechanisms also play a determinant role in reducing the signs of disease. Programmed cell death-1 (PD-1) signaling pathway, one of the most important checkpoints, has recently received interest, such as the development of a novel generation of anti-tumors. In the present study, we discuss the role of PD-1 signaling pathway in HTLV-1 infection as well as its application as a novel approach for treatment of HTLV-1 infections.

Bile duct ligation enhances AZT CNS toxicity partly by impairing the expression and function of BCRP in rat brain.

Breast cancer resistance protein (BCRP) is one of ATP-binding cassette (ABC) transporters in brain microvessel endothelial cells that transport their substrates from brain to blood, thus limiting substrates to crossing into brain through blood-brain barrier. Our previous works show that bile duct ligation (BDL) impairs expression and function of brain BCRP in rats. Since zidovudine (AZT) is BCRP substrate, we investigated whether impaired expression and function of BCRP increased brain distribution and toxicity of AZT in BDL-D7 rats. After administration of AZT (10 mg/kg, i.v.), BDL markedly increased brain AZT concentrations, compared with sham-operated (SO) rats. The ratio of AZT brain-to-plasma area under concentration curve (AUC) in BDL rats was increased to 1.6-folds of SO rats. After treatment with AZT (100 mg/kg every day, i.v.) for 7 days, BDL significantly impaired cognitive functions compared with SO rats, evidenced by the significantly decreased percentage of alternation in Y-maze test and prolonged escaped latency in two-way passive avoidance trial. Furthermore, AZT treatment caused significant decrease in copies of mitochondrial DNA and mitochondrial membrane potential in hippocampus of BDL rats. Moreover, AZT treatment caused a significant decrease of cortex microtubule-associated protein 2 and hippocampus synaptophysin levels in BDL rats. AZT-induced CNS adverse alterations in BDL rats were not observed in SO rats treated with AZT. In conclusion, BDL decreases the function and expression of brain BCRP in rats, leading to increased brain distribution of AZT, which in turn enhances AZT CNS toxicity, leading to mitochondrial dysfunction, neuronal damage, and ultimately cognitive dysfunction.