In-vitro and in-vivo assessment of nirmatrelvir penetration into CSF, central nervous system cells, tissues, and peripheral blood mononuclear cells.

Three years after SARS-CoV-2 emerged as a global infectious threat, the virus has become endemic. The neurological complications such as depression, anxiety, and other CNS complications after COVID-19 disease are increasing. The brain, and CSF have been shown as viral reservoirs for SARS-CoV-2, yielding a potential hypothesis for CNS effects. Thus, we investigated the CNS pharmacology of orally dosed nirmatrelvir/ritonavir (NMR/RTV). Using both an in vitro and an in vivo rodent model, we investigated CNS penetration and potential pharmacodynamic activity of NMR. Through pharmacokinetic modeling, we estimated the median CSF penetration of NMR to be low at 18.11% of plasma with very low accumulation in rodent brain tissue. Based on the multiples of the 90% maximal effective concentration (EC90) for SARS-CoV-2, NMR concentrations in the CSF and brain do not achieve an exposure level similar to that of plasma. A median of only 16% of all the predicted CSF concentrations in rats were > 3xEC90 (unadjusted for protein binding). This may have implications for viral persistence and neurologic post-acute sequelae of COVID-19 if increased NMR penetration in the CNS leads to decreased CNS viral loads and decreased CNS inflammation.

"Mpox in MSM: Tackling Stigma, Minimizing Risk Factors, Exploring Pathogenesis, and Treatment Approaches".

Mpox is a zoonotic disease caused by the monkeypox virus (MPV), primarily found in Central and West African countries. The typical presentation of the disease before the 2022 mpox outbreak includes a febrile prodrome 5-13 days post-exposure, accompanied by lymphadenopathy, malaise, headache, and muscle aches. Unexpectedly, during the 2022 outbreak, several cases of atypical presentations of the disease were reported, such as the absence of prodromal symptoms and the presence of genital skin lesions suggestive of sexual transmission. As per the World Health Organization (WHO), as of March 20, 2024, 94,707 cases of mpox were reported worldwide, resulting in 181 deaths (22 in African endemic regions and 159 in non-endemic countries). The United States Centers for Disease Control and Prevention (CDC) reports a total of 32,063 cases (33.85% of total cases globally), with 58 deaths (32.04% of global deaths) due to mpox. Person-to-person transmission of mpox can occur through respiratory droplets and sustained close contact. However, during the 2022 outbreak of mpox, a high incidence of anal and perianal lesions among MSMs indicated sexual transmission of MPV as a major route of transmission. Since MSMs are disproportionately at risk for HIV transmission, this review discusses the risk factors, transmission patterns, pathogenesis, vaccine, and treatment options for mpox among MSM and people living with HIV (PLWH). Furthermore, we provide a brief perspective on the evolution of the MPV in immunocompromised people like PLWH.

SRX3177, a CDK4/6-PI3K-BET inhibitor, in combination with an RdRp inhibitor, Molnupiravir, or an entry inhibitor MU-UNMC-2, has potent antiviral activity against the Omicron variant of SARS-CoV-2.

Despite considerable progress in developing vaccines and antivirals to combat COVID-19, the rapid mutations of the SARS-CoV-2 genome have limited the durability and efficacy of the current vaccines and therapeutic interventions. Hence, it necessitates the development of novel therapeutic approaches or repurposing existing drugs that target either viral life cycle, host factors, or both. Here, we report that SRX3177, a potent triple-activity CDK4/6-PI3K-BET inhibitor, blocks replication of the SARS-CoV-2 Omicron variant with IC50 values at sub-micromolar concentrations without any impact on the cell proliferation of Calu-3 cells at and below its IC50 concentration. When SRX3177 is combined with EIDD-1931 (active moiety of a small-molecule prodrug Molnupiravir) or MU-UNMC-2 (a SARS-CoV-2 entry inhibitor) at a fixed doses matrix, a synergistic effect was observed, leading to the significant reduction in the dose of the individual compounds to achieve similar inhibition of SARS-CoV-2 replication. Herein, we report that the combination of SRX3177/MPV or SRX3177/UM-UNMC-2 has the potential for further development as a combinational therapy against SARS-CoV-2 and in any future outbreak of beta coronavirus.

Emergence of SARS-CoV-2 Omicron Variant JN.1 in Tamil Nadu, India - Clinical Characteristics and Novel Mutations.

In December 2023, we observed a notable shift in the COVID-19 landscape, when the JN.1 emerged as a predominant SARS-CoV-2 variant with a 95% incidence. We characterized the clinical profile, and genetic changes in JN.1, an emerging SARS-CoV-2 variant of interest. Whole genome sequencing was performed on SARS-CoV-2 positive samples, followed by sequence analysis. Mutations within the spike protein sequences were analyzed and compared with the previous lineages and sublineages of SARS-CoV-2, to identify the potential impact of these unique mutations on protein structure and possible functionality. Several unique and dynamic mutations were identified herein. Our data provides key insights into the emergence of newer variants of SARS-CoV-2 in our region and highlights the need for robust and sustained genomic surveillance of SARS-CoV-2.

Comparative analysis of human gut- and blood-derived mononuclear cells: contrasts in function and phenotype.

Introduction: Alterations in the gut immune system have been implicated in various diseases.The challenge of obtaining gut tissues from healthy individuals, commonly performed via surgical explants, has limited the number of studies describing the phenotype and function of gut-derived immune cells in health. Methods: Here, by means of recto-sigmoid colon biopsies obtained during routine care (colon cancer screening in healthy adults), the phenotype and function of immune cells present in the gut were described and compared to those found in blood. Results: The proportion of CD4+, CD8+, MAIT, γδ+ T, and NK cells phenotype, expression of integrins, and ability to produce cytokine in response to stimulation with PMA and ionomycin. T cells in the gut were found to predominantly have a memory phenotype as compared to T cells in blood where a naïve phenotype predominates. Recto-sigmoid mononuclear cells also had higher PD-1 and Ki67 expression. Furthermore, integrin expression and cytokine production varied by cell type and location in blood vs. gut. Discussion: These findings demonstrate the differences in functionality of these cells when compared to their blood counterparts and validate previous studies on phenotype within gut-derived immune cells in humans (where cells have been obtained through surgical means). This study suggests that recto-sigmoid biopsies collected during colonoscopy can be a reliable yet more accessible sampling method for follow up of alterations of gut derived immune cells in clinical settings.

SARS-CoV-2 Omicron Spike shows strong binding affinity and favourable interaction landscape with the TLR4/MD2 compared to other variants.

Emergences of SARS-CoV-2 variants have made the pandemic more critical. Toll-like receptor 4 (TLR4) recognizes the molecular patterns of pathogens and activates the production of proinflammatory cytokines to restrain the infection. We have identified a molecular basis of interaction between the Spike and TLR4 of SARS-CoV-2 and its present and past VOCs (variant- of concern) through in silico analysis. The interaction of wild type Spike with TLR4 showed 15 number hydrogen bonds formation. Similarly, the Alpha variants' Spike with the TLR4 has illustrated that 14 hydrogen bonds participated in the interaction. However, the Delta Spike and TLR4 interaction interface showed that 17 hydrogen bonds were formed during the interaction. Furthermore, Omicron S-glycoprotein and TLR4 interaction interface was depicted (interaction score: -170.3), and 16 hydrogen bonds were found to have been formed in the interaction. Omicron S-glycoprotein shows stronger binding affinity with the TLR4 than wild type, Alpha, and Delta variants. Similarly, the Alpha Spike shows higher binding affinity with TLR4 than the wild type and Delta variant. Now, it is an open question of the molecular basis of the interaction of Spike and TLR4 and the activated downstream signaling events of TLR4 for SARS-CoV-2 and its variants.

Dual role for microbial short-chain fatty acids in modifying SIV disease trajectory following anti-α4ß7 antibody administration.

BACKGROUND: Human Immunodeficiency Virus (HIV)/Simian Immunodeficiency Virus (SIV) infection is associated with significant gut damage, similar to that observed in patients with inflammatory bowel disease (IBD). This pathology includes loss of epithelial integrity, microbial translocation, dysbiosis, and resultant chronic immune activation. Additionally, the levels of all-trans-retinoic acid (atRA) are dramatically attenuated. Data on the therapeutic use of anti-α4ß7 antibodies has shown promise in patients with ulcerative colitis and Crohn's disease. Recent evidence has suggested that the microbiome and short-chain fatty acid (SCFA) metabolites it generates may be critical for anti-α4ß7 efficacy and maintaining intestinal homeostasis. MATERIALS AND METHODS: To determine whether the microbiome contributes to gut homeostasis after anti-α4ß7 antibody administered to SIV-infected rhesus macaques, faecal SCFA concentrations were determined, 16S rRNA sequencing was performed, plasma viral loads were determined, plasma retinoids were measured longitudinally, and gut retinoid synthesis/response gene expression was quantified. RESULTS: Our results suggest that anti-α4ß7 antibody facilitates the return of retinoid metabolism to baseline levels after SIV infection. Furthermore, faecal SCFAs were shown to be associated with retinoid synthesis gene expression and rebound viral loads after therapy interruption. CONCLUSIONS: Taken together, these data demonstrate the therapeutic advantages of anti-α4ß7 antibody administration during HIV/SIV infection and that the efficacy of anti-α4ß7 antibody may depend on microbiome composition and SCFA generation.

Genomic surveillance of omicron B.1.1.529 SARS-CoV-2 and its variants between December 2021 and March 2023 in Tamil Nadu, India-A state-wide prospective longitudinal study.

A state-wide prospective longitudinal investigation of the genomic surveillance of the omicron B.1.1.529 SARS-CoV-2 variant and its sublineages in Tamil Nadu, India, was conducted between December 2021 and March 2023. The study aimed to elucidate their mutational patterns and their genetic interrelationship in the Indian population. The study identified several unique mutations at different time-points, which likely could attribute to the changing disease characteristics, transmission, and pathogenicity attributes of omicron variants. The study found that the omicron variant is highly competent in its mutating potentials, and that it continues to evolve in the general population, likely escaping from natural as well as vaccine-induced immune responses. Our findings suggest that continuous surveillance of viral variants at the global scenario is warranted to undertake intervention measures against potentially precarious SARS-CoV-2 variants and their evolution.

Islatravir: evaluation of clinical development for HIV and HBV.

INTRODUCTION: Islatravir (ISL) is a nucleoside reverse transcriptase translocation inhibitor (NRTTI) that inhibits HIV RT through multiple mechanisms. Contrary to all approved NtRTIs, islatravir retains a 3'OH group. In vitro and clinical data show that ISL is an ultrapotent investigational drug with high tolerability. AREAS COVERED: The historical development of islatravir and its mechanisms of HIV and HBV inhibition and resistance are covered. Additionally, the outcomes of Phase I and Phase II clinical trials are discussed. EXPERT OPINION: Current first-line antiretroviral therapy, preexposure, and postexposure prophylactic interventions are highly effective in maintaining low or undetectable viral load. Despite these measures, an unusually high rate of new infections every year warrants developing novel antivirals that can suppress drug-resistant HIV and improve compliance. ISL, an NRTTI once deemed a long-acting drug, was placed on a clinical hold. The outcome of ongoing clinical trials with a reduced ISL dose will decide its future clinical application. Additionally, MK-8527, which inhibits HIV via same mechanism as that of ISL may supersede ISL. Data on ISL inhibition of HBV are scarce, and preclinical data show dramatically lower ISL efficacy against HBV than currently preferred nucleos(t)ide drugs, indicating that ISL may not be a potent anti-HBV drug.

Clinical characteristics and novel mutations of omicron subvariant XBB in Tamil Nadu, India - a cohort study.

Background: Despite the continued vaccination efforts, there had been a surge in breakthrough infections, and the emergence of the B.1.1.529 omicron variant of SARS-CoV-2 in India. There is a paucity of information globally on the role of newer XBB variants in community transmission. Here, we investigated the mutational patterns among hospitalised patients infected with the XBB omicron sub-variant, and checked if there was any association between the rise in the number of COVID-19 cases and the observed novel mutations in Tamil Nadu, India. Methods: Nasopharyngeal and oropharyngeal swabs, collected from symptomatic and asymptomatic COVID-19 patients were subjected to real-time PCR followed by Next Generation Sequencing (NGS) to rule out the ambiguity of mutations in viruses isolated from the patients (n = 98). Using the phylogenetic association, the mutational patterns were used to corroborate clinico-demographic characteristics and disease severity among the patients. Findings: Overall, we identified 43 mutations in the S gene across 98 sequences, of which two were novel mutations (A27S and T747I) that have not been reported previously with XBB sub-variants in the available literature. Additionally, the XBB sequences from our cohort had more mutations than omicron B.1.1.529. The phylogenetic analysis comprising six major branches clearly showed convergent evolution of XBB. Our data suggests that age, and underlying conditions (e.g., diabetes, hypertension, and cardiovascular disease) or secondary complications confers increased susceptibility to infection rather than vaccination status or prior exposure. Many vaccinated individuals showed evidence of a breakthrough infection, with XBB.3 being the predominant variant identified in the study population. Interpretation: Our study indicates that the XBB variant is highly evasive from available vaccines and may be more transmissible, and potentially could emerge as the 'next' predominant variant, which likely could overwhelm the existing variants of SARS-CoV-2 omicron variants. Funding: National Health Mission (India), SIDASARC, VINNMER (Sweden), ORIP/NIH (USA).

Plasma CXCL8 and MCP-1 as surrogate plasma biomarkers of latent tuberculosis infection among household contacts-A cross-sectional study.

Early detection of latent tuberculosis infection (LTBI) is critical to TB elimination in the current WHO vision of End Tuberculosis Strategy. The study investigates whether detecting plasma cytokines could aid in diagnosing LTBI across household contacts (HHCs) positive for IGRA, HHCs negative for IGRA, and healthy controls. The plasma cytokines were measured using a commercial Bio-Plex Pro Human Cytokine 17-plex assay. Increased plasma CXCL8 and decreased MCP-1, TNF-α, and IFN-γ were associated with LTBI. Regression analysis showed that a combination of CXCL8 and MCP-1 increased the risk of LTBI among HHCs to 14-fold. Our study suggests that CXCL-8 and MCP-1 could serve as the surrogate biomarkers of LTBI, particularly in resource-limited settings. Further laboratory investigations are warranted before extrapolating CXCL8 and MCP-1 for their usefulness as surrogate biomarkers of LTBI in resource-limited settings.

Therapeutic Potential of Cannabis: A Comprehensive Review of Current and Future Applications.

Historically, cannabis has been valued for its pain-relieving, anti-inflammatory, and calming properties. Ancient civilizations like the Egyptians, Greeks, and Chinese medicines recognized their therapeutic potential. The discovery of the endocannabinoid system, which interacts with cannabis phytoconstituents, has scientifically explained how cannabis affects the human immune system, including the central nervous system (CNS). This review explores the evolving world of cannabis-based treatments, spotlighting its diverse applications. By researching current research and clinical studies, we probe into how cannabinoids like Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) help to manage conditions ranging from chronic pain, persistent inflammation, cancer, inflammatory bowel disease, and neurological disorders to even viral diseases such as Human Immunodeficiency virus (HIV), SARS-CoV-2. and the emerging monkeypox. The long-term recreational use of cannabis can develop into cannabis use disorder (CUD), and therefore, understanding the factors contributing to the development and maintenance of cannabis addiction, including genetic predisposition, neurobiological mechanisms, and environmental influences, will be timely. Shedding light on the adverse impacts of CUD underscores the importance of early intervention, effective treatment approaches, and public health initiatives to address this complex issue in an evolving landscape of cannabis policies and perceptions.

Efficient trapping and destruction of SARS-CoV-2 using PECO-assisted Molekule air purifiers in the laboratory and real-world settings.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is transmitted human-to-human via aerosols and air-borne droplets. Therefore, capturing and destroying viruses from indoor premises are essential to reduce the probability of human exposure and virus transmission. While the heating, ventilation, and air conditioning (HVAC) systems help in reducing the indoor viral load, a targeted approach is required to effectively remove SARS-CoV-2 from indoor air to address human exposure concerns. The present study demonstrates efficient trapping and destruction of SARS-CoV-2 via nano-enabled filter technology using the UV-A-stimulated photoelectrochemical oxidation (PECO) process. Aerosols containing SARS-CoV-2 were generated by nebulization inside an air-controlled test chamber where an air purifier (Air Mini+) was placed. The study demonstrated the efficient removal of SARS-CoV-2 (99.98 %) from the test chamber in less than two minutes and PECO-assisted destruction (over 99%) on the filtration media in 1 h. Furthermore, in a real-world scenario, the Molekule Air-Pro air purifier removed SARS-CoV-2 (a negative RT-qPCR result post-running the filter device) from the circulating air in a COVID-19 testing facility. Overall, the ability of two FDA-approved class II medical devices, Molekule Air-Mini+ and Air-Pro air purifiers, to remove and destroy SARS-CoV-2 in indoor settings was successfully demonstrated. The study indicates that as the "tripledemic" of COVID-19, influenza, and respiratory syncytial virus (RSV) overwhelm the healthcare facilities in the USA, the use of a portable air filtration device will help contain the spread of the viruses in close door facilities, such as in schools and daycare facilities.

Plasma CXCL8 and MCP-1 as biomarkers of latent tuberculosis infection.

Background: Early detection of latent tuberculosis infection (LTBI) is critical to TB elimination in the current WHO vision of End Tuberculosis Strategy. Methods: We investigated whether detecting plasma cytokines could aid in diagnosing LTBI across household contacts (HHCs) positive for IGRA, HHCs negative for IGRA, and healthy controls. We also measured the plasma cytokines using a commercial Bio-Plex Pro Human Cytokine 17-plex assay. Results: Increased plasma CXCL8 and decreased MCP-1, TNF-α, and IFN-γ were associated with LTBI. Regression analysis showed that a combination of CXCL8 and MCP-1 increased the risk of LTBI among HHCs to 14-fold. Conclusions: We postulated that CXCL8 and MCP-1 could be the surrogate biomarkers of LTBI, especially in resource-limited settings.

Proteomic landscape of astrocytes and pericytes infected with HIV/SARS-CoV-2 mono/co-infection, impacting on neurological complications.

Background: Although most individuals recover from coronavirus disease 2019 (COVID-19) within a few weeks, some people continue to experience a wide range of symptoms known as post-acute sequelae of SARS-CoV-2 (PASC) or long COVID. Majority of patients with PASC develop neurological disorders like brain fog, fatigue, mood swings, sleep disorders, loss of smell and test among others collectively called neuro-PASC. While the people living with HIV (PWH) do not have a higher risk of developing severe disease and mortality/morbidity due to COVID-19. As a large section of PWH suffered from HIV-associated neurocognitive disorders (HAND), it is essential to understand the impact of neuro-PASC on people with HAND. In pursuit of this, we infected HIV/SARS-CoV-2 alone or together in primary human astrocytes and pericytes and performed proteomics to understand the impact of co-infection in the central nervous system. Methods: Primary human astrocytes and pericytes were infected with SARS-CoV-2 or HIV or HIV + SARS-CoV-2. The concentration of HIV and SARS-CoV-2 genomic RNA in the culture supernatant was quantified using reverse transcriptase quantitative real time polymerase chain reaction (RT-qPCR). This was followed by a quantitative proteomics analysis of mock, HIV, SARS-CoV-2, and HIV + SARS-CoV-2 infected astrocytes and pericytes to understand the impact of the virus in CNS cell types. Results: Both healthy and HIV-infected astrocytes and pericytes support abortive/low level of SARS-CoV-2 replication. In both mono-infected and co-infected cells, we observe a modest increase in the expression of SARS-CoV-2 host cell entry factors (ACE2, TMPRSS2, NRP1, and TRIM28) and inflammatory mediators (IL-6, TNF-α, IL-1ß and IL-18). Quantitative proteomic analysis has identified uniquely regulated pathways in mock vs SARS-CoV-2, mock vs HIV + SARS-CoV-2, and HIV vs HIV + SARS-CoV-2 infected astrocytes and pericytes. The gene set enrichment analysis revealed that the top ten enriched pathways are linked to several neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Conclusions: Our study emphasizes the significance of long-term monitoring of patients co-infected with HIV and SARS-CoV-2 to detect and understand the development of neurological abnormalities. By unraveling the molecular mechanisms involved, we can identify potential targets for future therapeutic interventions.

Potential therapeutic targets for Mpox: the evidence to date.

INTRODUCTION: The global Mpox (MPX) disease outbreak caused by the Mpox virus (MPXV) in 2022 alarmed the World Health Organization (WHO) and health regulation agencies of individual countries leading to the declaration of MPX as a Public Health Emergency. Owing to the genetic similarities between smallpox-causing poxvirus and MPXV, vaccine JYNNEOS, and anti-smallpox drugs Brincidofovir and Tecovirimat were granted emergency use authorization by the United States Food and Drug Administration. The WHO also included cidofovir, NIOCH-14, and other vaccines as treatment options. AREAS COVERED: This article covers the historical development of EUA-granted antivirals, resistance to these antivirals, and the projected impact of signature mutations on the potency of antivirals against currently circulating MPXV. Since a high prevalence of MPXV infections in individuals coinfected with HIV and MPXV, the treatment results among these individuals have been included. EXPERT OPINION: All EUA-granted drugs have been approved for smallpox treatment. These antivirals show good potency against Mpox. However, conserved resistance mutation positions in MPXV and related poxviruses, and the signature mutations in the 2022 MPXV can potentially compromise the efficacy of the EUA-granted treatments. Therefore, MPXV-specific medications are required not only for the current but also for possible future outbreaks.

Engineering an ACE2-Derived Fragment as a Decoy for Novel SARS-CoV-2 Virus.

Entry inhibitors are an important resource in the response against emerging pathogens like the novel SARS-CoV-2, which enters human cells via interaction between the surface spike glycoprotein and the cellular membrane receptor angiotensin-converting enzyme 2 (ACE2). Using a combination of comparative structural analyses of the binding surface of the spike to ACE2, docking experiments, and molecular dynamics simulations, we identified a stable fragment of ACE2 that binds to the spike, is soluble, and is not predicted to bind to its physiological ligand angiotensin II. From this fragment we computationally designed and experimentally validated a smaller, stable peptide that disrupts ACE2-spike interaction at nanomolar concentrations, suggesting its potential use as a decoy that could interfere with viral binding by competition.

ACE-2, TMPRSS2, and Neuropilin-1 Receptor Expression on Human Brain Astrocytes and Pericytes and SARS-CoV-2 Infection Kinetics.

Angiotensin Converting Enzyme 2 (ACE-2), Transmembrane Serine Protease 2 (TMPRSS-2) and Neuropilin-1 cellular receptors support the entry of SARS-CoV-2 into susceptible human target cells and are characterized at the molecular level. Some evidence on the expression of entry receptors at mRNA and protein levels in brain cells is available, but co-expression of these receptors and confirmatory evidence on brain cells is lacking. SARS-CoV-2 infects some brain cell types, but infection susceptibility, multiple entry receptor density, and infection kinetics are rarely reported in specific brain cell types. Highly sensitive Taqman ddPCR, flow-cytometry and immunocytochemistry assays were used to quantitate the expression of ACE-2, TMPRSS-2 and Neuropilin-1 at mRNA and protein levels on human brain-extracted pericytes and astrocytes, which are an integral part of the Blood-Brain-Barrier (BBB). Astrocytes showed moderate ACE-2 (15.9 ± 1.3%, Mean ± SD, n = 2) and TMPRSS-2 (17.6%) positive cells, and in contrast show high Neuropilin-1 (56.4 ± 39.8%, n = 4) protein expression. Whereas pericytes showed variable ACE-2 (23.1 ± 20.7%, n = 2), Neuropilin-1 (30.3 ± 7.5%, n = 4) protein expression and higher TMPRSS-2 mRNA (667.2 ± 232.3, n = 3) expression. Co-expression of multiple entry receptors on astrocytes and pericytes allows entry of SARS-CoV-2 and progression of infection. Astrocytes showed roughly four-fold more virus in culture supernatants than pericytes. SARS-CoV-2 cellular entry receptor expression and "in vitro" viral kinetics in astrocytes and pericytes may improve our understanding of viral infection "in vivo". In addition, this study may facilitate the development of novel strategies to counter the effects of SARS-CoV-2 and inhibit viral infection in brain tissues to prevent the spread and interference in neuronal functions.

Cannabinoid enhancement of lncRNA MMP25-AS1/MMP25 interaction reduces neutrophil infiltration and intestinal epithelial injury in HIV/SIV infection.

Intestinal epithelial barrier dysfunction, a hallmark of HIV/SIV infection, persists despite viral suppression by combination antiretroviral therapy (cART). Emerging evidence suggests a critical role for long noncoding RNAs (lncRNAs) in maintaining epithelial homeostasis. We simultaneously profiled lncRNA/mRNA expression exclusively in colonic epithelium (CE) of SIV-infected rhesus macaques (RMs) administered vehicle (VEH) or Δ-9-tetrahydrocannabinol (THC). Relative to controls, fewer lncRNAs were up- or downregulated in CE of THC/SIV compared with VEH/SIV RMs. Importantly, reciprocal expression of the natural antisense lncRNA MMP25-AS1 (up 2.3-fold) and its associated protein-coding gene MMP25 (attracts neutrophils by inactivating alpha-1 anti-trypsin/SERPINA1) (down 2.2-fold) was detected in CE of THC/SIV RMs. Computational analysis verified 2 perfectly matched complementary regions and an energetically stable (normalized binding free energy = -0.2626) MMP25-AS1/MMP25 duplex structure. MMP25-AS1 overexpression blocked IFN-γ-induced MMP25 mRNA and protein expression in vitro. Elevated MMP25 protein expression in CE of VEH/SIV but not THC/SIV RMs was associated with increased infiltration by myeloperoxidase/CD11b++ neutrophils (transendothelial migration) and epithelial CD47 (transepithelial migration) expression. Interestingly, THC administered in combination with cART increased MMP25-AS1 and reduced MMP25 mRNA/protein expression in jejunal epithelium of SIV-infected RMs. Our findings demonstrate that MMP25-AS1 is a potentially unique epigenetic regulator of MMP25 and that low-dose THC can reduce neutrophil infiltration and intestinal epithelial injury potentially by downregulating MMP25 expression through modulation of MMP25-AS1.