Biology subjects

Naing, E.

Publications and source records attributed to Naing, E..

4 recordsLinked to original sources

bioRxiv2026

Dynamic Antigen Expression and Intrinsic CTL Resistance in HIV Reservoir Clones

Reservoirs of clonally expanded CD4+ T-cells harboring rebound-competent HIV proviruses persist lifelong during ART. Latency is considered the principal barrier to viral eradication and has resisted pharmacological reversal, yet it appears that sustained immune pressure may still erode reservoirs. Recent advances have yielded glimpses into these exceptionally rare reservoir-harboring cells, implicating intrinsic pro-survival properties in their persistence. Here, we isolate and characterize populations of authentic reservoir clones (ARCs) that robustly proliferate and accumulate while producing infectious virus, without overtly succumbing to viral cytopathic effects. At any given moment, only small fractions of ARCs expressed HIV proteins, a state remarkably unperturbed by potent TCR or mitogenic stimulation. Nevertheless, sustained co-culture with cytotoxic T-lymphocytes (CTL) revealed extensive time-integrated antigenic vulnerability, culling clonal expansion of some ARCs by >90%. Notably, a regulatory T-cell ARC displayed pronounced cell-intrinsic resistance to CTL - a longstanding hypothesis we now directly demonstrate - linked to low oxidative stress and reversed with desferoxamine, a hypoxic stress inducer and FDA-approved therapeutic. Overall, we provide novel insights into the vulnerabilities of reservoir clones to potent, sustained CTL pressure and highlight intrinsic resistance pathways as actionable therapeutic targets, opening opportunities for advancing immune-based HIV cure strategies.

immunology↗

bioRxiv2025

HIV Nef amplifies mechanical heterogeneity to promote immune evasion

Intracellular pathogens must evade cytotoxic immunity to establish persistent infection. Although immune escape is typically viewed through a biochemical lens, the ability of certain pathogens to alter the mechanical properties of infected cells suggests that biophysical mechanisms may also contribute to the process. Here, we show that a subset of CD4+ T cells infected with the human immunodeficiency virus (HIV) resist elimination through a soft phenotype that inhibits killing by mechanosensitive cytotoxic T lymphocytes (CTLs). This phenotype arises from the combined effects of the HIV virulence factor Nef, which remodels the actin cytoskeleton, and intrinsic heterogeneity in the basal cytoskeletal properties of infected T cells. Pharmacological or genetic perturbations that reverse Nef signaling to the cytoskeleton or that stiffen the filamentous-actin cortex sensitize infected cells to CTL-mediated lysis. Taken together, these findings define a novel, biophysical paradigm of immune evasion with implications for HIV cure strategies.

immunology↗

bioRxiv2024

Synthesis of Novel N-Substituted β-Amino Acid Derivatives Bearing 2-Hydroxyphenyl Moieties as Promising Antimicrobial Candidates Targeting Multidrug-Resistant Gram-Positive Pathogens

The increasing prevalence of antimicrobial resistance among ESKAPE group pathogens presents a significant challenge in the healthcare sector, contributing to higher morbidity and mortality rates globally. Thus, it is essential to develop novel antimicrobial agents effective against drug-resistant pathogens. In this study, we report the synthesis and in vitro antimicrobial activity characterization of novel N-substituted {beta}-amino acid derivatives bearing 2-hydroxyphenyl core against multidrug-resistant bacterial pathogens. The synthesized compounds (2-26) exhibited promising antimicrobial activity specifically against Gram-positive bacteria, with minimum inhibitory concentrations (MIC) ranging from 4 to 128 {micro}g/mL. None of the compounds demonstrated activity against Gram-negative pathogens or drug-resistant fungi. Compounds 9 (R = 4-nitrophenyl), 17 (R = 5-nitro-2-thienyl), 18 (R = 5-nitro-2-furyl), thiosemicarbazide 16, and 26 exhibited the most promising activity against Staphylococcus aureus MRSA USA300 lineage strain TCH-1516, with MIC values between 4 and 16 {micro}g/mL. Compound 26 demonstrated strong antimicrobial activity against both S. aureus TCH-1516 and E. faecalis AR-0781, with the activity comparable to control antibiotics. These findings indicate that N-substituted {beta}-amino acid derivatives with a 2-hydroxyphenyl core warrant further investigation as a potential scaffold for the further development of antimicrobial agents based on compound 26 targeting Gram-positive pathogens.

microbiology↗

bioRxiv2024

Bacteriophage Treatment against Carbapenem-resistant Klebsiella pneumoniae (KPC) in a Neutropenic Murine Model of Gastrointestinal Translocation and Renal Infection

BackgroundCarbapenemase producing Klebsiella pneumoniae (KPC) are globally emerging pathogens which that cause life-threatening infections. Novel treatment alternatives are urgently needed. MethodsWe therefore investigated the effectiveness of three novel bacteriophages (Spivey, Pharr and Soft) in a neutropenic murine model of KPC gastrointestinal colonization, translocation, and disseminated infection. Bacteriophage efficacy was determined by residual bacterial burden of KPC in kidneys. Parallel studies were conducted of bacteriophage pharmacokinetics and resistance.. ResultsTreatment of mice with 5x109 PFU of phage cocktail via intraperitoneal injection was effective in significantly reducing renal KPC burden by 102 CFU (p<0.01) when administered every 24 hours and 103 CFU (p<0.01) every 12 hours. Moreover, a combination of bacteriophage and ceftazidime-avibactam produced a synergistic effect, resulting in a 105 reduction in bacterial burden in caecum and kidney (p<0.001 in both tissues). Prophylactic administration of bacteriophages via oral gavage did not prevent KPC translocation to the kidneys. Bacteriophage decay determined by linear regression of the ln of mean concentrations demonstrated R2 values in plasma of 0.941, kidney 0.976, and caecum 0.918, with half-lives of 2.5h < t1/2 < 3.5 h. Furthermore, a phage-resistant mutant displayed increased sensitivity to serum killing in vitro, but did not show significant defects in renal infection in vivo. ConclusionsA combination of bacteriophages demonstrated significant efficacy alone and synergy with ceftazidime/avibactam in treatment of experimental disseminated KPC infection in neutropenic mice.

microbiology↗