Modulation of BRD4 in HIV epigenetic regulation: implications for finding an HIV cure.

Following reverse transcription, HIV viral DNA is integrated into host cell genomes and establishes a stable latent infection, which has posed a major obstacle for obtaining a cure for HIV. HIV proviral transcription is regulated in cellular reservoirs by complex host epigenetic and transcriptional machineries. The Bromodomain (BD) and Extra-Terminal Domain (ET) protein, BRD4, is an important epigenetic reader that interacts with acetyl-histones and a variety of chromatin and transcriptional regulators to control gene expression, including HIV. Modulation of BRD4 by a pan BET inhibitor (JQ1) has been shown to activate HIV transcription. Recent studies by my group and others indicate that the function of BRD4 is versatile and its effects on HIV transcription may depend on the partner proteins or pathways engaged by BRD4. Our studies have reported a novel class of small-molecule modulators that are distinct from JQ1 but induce HIV transcriptional suppression through BRD4. Herein, we reviewed recent research on the modulation of BRD4 in HIV epigenetic regulation and discussed their potential implications for finding an HIV cure.

Epigenetic Suppression of HIV in Myeloid Cells by the BRD4-Selective Small Molecule Modulator ZL0580.

Brain-resident microglia and myeloid cells (perivascular macrophages) are important HIV reservoirs in vivo, especially in the central nervous system (CNS). Despite antiretroviral therapy (ART), low-level persistent HIV replication in these reservoirs remains detectable, which contributes to neuroinflammation and neurological disorders in HIV-infected patients. New approaches complementary to ART to repress residual HIV replication in CNS reservoirs are needed. Our group has recently identified a BRD4-selective small molecule modulator (ZL0580) that induces the epigenetic suppression of HIV. Here, we examined the effects of this compound on HIV in human myeloid cells. We found that ZL0580 induces potent and durable suppression of both induced and basal HIV transcription in microglial cells (HC69) and monocytic cell lines (U1 and OM10.1). Pretreatment of microglia with ZL0580 renders them more refractory to latent HIV reactivation, indicating an epigenetic reprogramming effect of ZL0580 on HIV long terminal repeat (LTR) in microglia. We also demonstrate that ZL0580 induces repressive effect on HIV in human primary monocyte-derived macrophages (MDMs) by promoting HIV suppression during ART treatment. Mechanistically, ZL0580 inhibits Tat transactivation in microglia by disrupting binding of Tat to CDK9, a process key to HIV transcription elongation. High-resolution micrococcal nuclease mapping showed that ZL0580 induces a repressive chromatin structure at the HIV LTR. Taken together, our data suggest that ZL0580 represents a potential approach that could be used in combination with ART to suppress residual HIV replication and/or latent HIV reactivation in CNS reservoirs, thereby reducing HIV-associated neuroinflammation.IMPORTANCE Brain-resident microglia and perivascular macrophages are important HIV reservoirs in the CNS. Persistent viral replication and latent HIV reactivation in the CNS, even under ART, are believed to occur, causing neuroinflammation and neurological disorders in HIV-infected patients. It is critical to identify new approaches that can control residual HIV replication and/or latent HIV reactivation in these reservoirs. We here report that the BRD4-selective small molecule modulator, ZL0580, induces potent and durable suppression of HIV in human microglial and monocytic cell lines. Using an in vitro HIV-infected, ART-treated MDM model, we show that ZL0580 also induces suppressive effect on HIV in human primary macrophages. The significance of our research is that it suggests a potential new approach that has utility in combination with ART to suppress residual HIV replication and/or HIV reactivation in CNS reservoirs, thereby reducing neuroinflammation and neurological disorders in HIV-infected individuals.

IL-22 hinders antiviral T cell responses and exacerbates ZIKV encephalitis in immunocompetent neonatal mice.

BACKGROUND: The Zika virus (ZIKV) outbreak that occurred in multiple countries was linked to increased risk of nervous system injuries and congenital defects. However, host immunity- and immune-mediated pathogenesis in ZIKV infection are not well understood. Interleukin-22 (IL-22) is a crucial cytokine for regulating host immunity in infectious diseases. Whether IL-22 plays, a role in ZIKV infection is unknown. METHODS: The cellular source of IL-22 was identified in IFNAR-/- mice and wild-type (WT) neonatal mice during ZIKV infection. To determine the role of IL-22, we challenged 1-day-old WT and IL-22-/- mice with ZIKV and monitored clinical manifestations. Glial cell activation in the brain was assessed by confocal imaging. ZIKV-specific CD8+ T cell responses in both the spleen and brain were analyzed by flow cytometry. In addition, glial cells were cultured in vitro and infected with ZIKV in the presence of IL-22, followed by the evaluation of cell proliferation, cytokine expression, and viral loads. RESULTS: We found that γδ T cells were the main source of IL-22 during ZIKV infection in both the spleen and brain. WT mice began to exhibit weight loss, staggered steps, bilateral hind limb paralysis, and weakness at 10 days post-infection (dpi) and ultimately succumbed to infection at 16-19 dpi. IL-22 deficiency lessened weight loss, moderated the systemic inflammatory response, and greatly improved clinical signs of neurological disease and mortality. ZIKV infection also induced the activation of microglia and astrocytes in vitro. Additional analysis demonstrated that the absence of IL-22 resulted in reduced activation of microglia and astrocytes in the cortex. Although IL-22 displayed a negligible effect on glial cells in vitro, IL-22-/- mice mounted more vigorous ZIKV-specific CD8+ T cell responses, which led to a more effective control of ZIKV in the brain. CONCLUSIONS: Our data revealed a pathogenic role of IL-22 in ZIKV encephalitis.

Dissemination of non-typhoidal Salmonella during Plasmodium chabaudi infection affects anti-malarial immunity.

Malaria-associated bacteremia accounts for up to one-third of deaths from severe malaria, and non-typhoidal Salmonella (NTS) has been reported as a major complication of severe malarial infection. Patients who develop NTS bacteremia during Plasmodium infection show higher mortality rates than individuals with malaria alone. Systemic bacteremia can be caused by a wound or translocation from epithelial or endothelial sites. NTS is an intestinal pathogen, however the contribution of bacterial translocation from the intestinal tract during Plasmodium infection is not well studied. Here, we investigated the integrity of the intestinal barrier function of P. chabaudi-infected mice using large molecules and Salmonella infection. Intestinal histology and the adaptive immune response to malaria were also studied using light microscopy and flow cytometry. P. chabaudi infection compromised intestinal barrier function, which led to increased intestinal cellular infiltration. In addition, we observed increased serum lipopolysaccharide binding protein and leakage of soluble molecules from the intestine into the blood in infected mice. Plasmodium infection also increased intestinal translocation and dissemination of NTS to the liver. The adaptive immune response to P. chabaudi infection was also significantly impacted by NTS translocation. Reduced B and T cell activation were observed in co-infected animals, suggesting interference in the malaria-specific immune responses by bacteremia. These studies demonstrate that P. chabaudi infection induces failure of the barrier function of the intestinal wall and enhanced intestinal bacterial translocation, affecting anti-malarial immunity.

Bacterial Contamination of Mobile Phones Used by Healthcare Workers in Critical Care Units: A Cross-Sectional Study from Saudi Arabia.

BACKGROUND: Healthcare-associated infections (HAIs) present a formidable challenge for healthcare institutions, resulting in heightened mortality, morbidity, and economic burden. Within healthcare settings, various equipment and materials, including mobile phones, can potentially act as sources of infection. This study sought to examine the occurrence of bacterial contamination on mobile phones utilized by healthcare workers (HCWs) in intensive care units (ICUs), pediatric intensive care units (PICUs), neonatal intensive care units (NICUs), and cardiac care units (CCUs) within a central hospital (CH) and two peripheral hospitals (PHs) situated in the southwestern province of Saudi Arabia. MATERIALS AND METHODS: We collected a total of 157 samples from mobile phones utilized by HCWs across all ICUs in the CH and PHs. These samples underwent bacteriological analysis to evaluate the degree of bacterial contamination. RESULTS: We found that 45 out of 55 samples from physicians (81.81%) and 58 out of 77 samples from nurses (75.32%) showed bacterial contamination. Contamination rates on HCWs' mobile phones in the ICU, PICU, and NICU departments of the CH were observed at 69.56%, 80.95%, and 70.27%, respectively. Furthermore, the overall contamination rates in the ICUs, NICUs, and CCUs of the PHs were 78.26%, 88.88%, and 66.66%, respectively. The overall contamination rates of mobile phones in the CH and PHs were 72.11% and 81.13%, respectively. CONCLUSION: These findings underscore the necessity of routinely disinfecting the mobile phones of HCWs to mitigate the risk of cross-contamination. Implementing robust disinfection protocols can significantly contribute to curtailing the propagation of bacterial pathogens and reducing the incidence of HAIs in healthcare settings.

Low monocytic HLA-DR expression in critically ill patients of sepsis: An indicator for antimicrobial and/or immunomodulatory intervention.

BACKGROUND: Sepsis is a result of suppressed host immune response which leads to fatal multi-organ dysfunctionality. Low frequency of active monocytes or reduced expression of human leukocyte antigen (HLA)-DR on monocytes shows the suppressed immune response in sepsis patients. One of the well-studied markers in patients with sepsis is procalcitonin (PCT). The role of monocytic (m) HLA-DR expression has been monitored in sepsis and is being considered a marker of the severity of interim immuno-depression in these patients. The study describes the impact of HLA-DR expression on monocytes quantitatively using flow cytometry. METHODS: In this prospective study, we quantified monocytes and their HLA-DR expression in 20 patients of sepsis admitted to the Intensive Care Unit (ICU). Serum levels of PCT and interleukin (IL)-6 production were also measured in these patients, and the results were compared with those in healthy controls. RESULTS: Monocyte frequency calculated was higher in sepsis patients as compared to healthy controls, however, HLA-DR expressing monocytes were significantly reduced as was the mean fluorescence intensity (MFI) of HLA-DR. Contrastingly, IL-6 and PCT levels were significantly high in sepsis than controls. The results suggest that low HLA-DR expression, combined with PCT, is a better prognostic parameter in the early phase of sepsis. CONCLUSION: Poor recovery of mHLA-DR may serve as an early guide for clinicians to assess the prognosis of sepsis patients and consider immunomodulatory therapy in its management.

Evaluation of hematological parameters and thrombocytopenia following Pfizer-BioNTech (BNT162b2) SARS-CoV-2 vaccination.

OBJECTIVES: To evaluate hematological parameters and thrombotic profiles of healthy individuals who received Pfizer-BioNTech (BNT162b2) vaccines in Saudi Arabia. METHODS: Hematological parameters and the incidence of anti-platelet factor-4 (anti/PF-4) antibodies were evaluated in 40 participants who were eligible for COVID-19 vaccination in Saudi Arabia (above 18 years old) at Jazan University Hospital. These parameters were assessed at 2 different timepoints; at day 0 (the day of receiving the first dose of Pfizer- BioNTech (BNT162b2) and prior to vaccination) and 14-21 days after receiving the vaccine. RESULTS: Among the participants, 38 (80%) were men, while 12 (20%) were women, with a mean age of 27 years. A total of 15% of the participants reported previous infection with SARS-CoV-2 and 3 patients had a history of diabetes mellitus and hypertension. Hematological parameters results in those vaccines showed no significant changes between the 2 timepoints, such as, day 0 (just before receiving vaccination) and 14 to 21 days post vaccination. Further, anti/PF4 antibodies were negative for all participants following vaccination. CONCLUSION: Our data showed that the incidence of hematological abnormalities or induction of anti/PF4 antibodies following Pfizer-BioNTech (BNT162b2) vaccination is not common, which is consistent with several previous reports. However, larger studies with more participants evaluated at different timepoints following vaccination are warranted to exclude potential transient hematological abnormalities.

Bacterial Coinfections Increase Mortality of Severely Ill COVID-19 Patients in Saudi Arabia.

Coronavirus disease 19 (COVID-19) is an ongoing global pandemic that is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The severity and mortality rates of COVID-19 are affected by several factors, such as respiratory diseases, diabetes, and hypertension. Bacterial coinfections are another factor that could contribute to the severity of COVID-19. Limited studies have investigated morbidity and mortality due to microbial coinfections in COVID-19 patients. Here, we retrospectively studied the effects of bacterial coinfections on intensive care unit (ICU)-admitted patients with COVID-19 in Asir province, Saudi Arabia. We analyzed electronic medical records of hospitalized patients with COVID-19 at Asir Central Hospital. A total of 34 patients were included, and the clinical data of 16 patients infected with SARS-CoV-2 only and 18 patients coinfected with SARS-CoV-2 and bacterial infections were analyzed in our study. Our data showed that the length of stay at the hospital for patients infected with both SARS-CoV-2 and bacterial infection was 35.2 days, compared to 16.2 days for patients infected with only SARS-CoV-2 (p = 0.0001). In addition, higher mortality rates were associated with patients in the coinfection group compared to the SARS-CoV-2-only infected group (50% vs. 18.7%, respectively). The study also showed that gram-negative bacteria are the most commonly isolated bacteria in COVID-19 patients. To conclude, this study found that individuals with COVID-19 who presented with bacterial infections are at higher risk for a longer stay at the hospital and potentially death. Further studies with a larger population are warranted to better understand the clinical outcomes of COVID-19 with bacterial infections.

Awareness and Acceptance of Hematopoietic Stem Cell Transplantation for Sickle Cell Disease in Jazan Province, Saudi Arabia.

BACKGROUND: Sickle cell diseases (SCD) are a group of inherited disorders that lead to abnormal beta subunits of hemoglobin (Hb) and are characterized by several complications which can be life-threatening. The prevalence of this disease is high in Jazan province, Saudi Arabia. The current protocol for the treatment of SCD is mainly based on alleviating signs and symptoms to avoid severe complications. Hematopoietic stem cell transplant (HSCT) is considered a definitive therapy for SCD. However, there is a long patient waiting list for HSCT in Saudi Arabia. A lack of community awareness and incorrect information about the importance of HSCT in SCD treatment is believed to be contributing to the shortage in HSCT. Thus, this study aims to assess community awareness and attitudes toward HSCT as a cure for SCD in Jazan province, Saudi Arabia. METHODS: An observational cross-sectional retrospective study was conducted in Jazan province. General and demographic data were collected and pretested survey including questions about public knowledge and attitude toward HSCT for SCD were answered. Both t-test and chi-square tests were used for analysis. RESULTS: 1167 participants were included in this study with a mean age of 26 (SD: 8). About 50% of the study participants believed that SCD can be treated and 78% of the study participants already have heard about HSCT. About 57% of the participants defined HSCT correctly and 42% were willing to donate. Better knowledge and positive attitude toward HSCT were significantly reported among patients with SCD or their relatives as well as among people with higher education and healthcare workers (HCW). CONCLUSION: About 57% of the study participants were able to define HSCT and most related questions were answered correctly. A positive correlation was found between the knowledge about HSCT and people with higher education or those who were diagnosed with SCD or their relatives and friends. Further, only 42% of our study participants were willing to donate, a percent that is positively associated with better knowledge about HSCT. National education programs are needed to enhance the overall awareness of Jazan communities toward HSCT which could contribute to reducing the number of patients waiting for HSCT.

Investigation of Antistress and Antidepressant Activities of Synthetic Curcumin Analogues: Behavioral and Biomarker Approach.

Depression is a serious psychiatric disorder that affects millions of individuals all over the world, thus demanding special attention from researchers in order to investigate its effective remedies. Curcumin, along with its synthetic derivatives, is recognized for its incredible pharmacological activities. In this study, methyl, methoxy and chloro-substituent synthetic curcumin analogues C1-C3 were respectively tested for free radical-scavenging activity. Behavioral studies were performed using chemical-induced and swimming endurance tests as stress models, and forced swim tests (FSTs) and tail suspension tests (TSTs) as depression mice models. Biochemical examinations were performed after a scopolamine-induced stress model by decapitating the mice, and brain tissues were isolated for biochemical assessment of catalase (CAT), superoxide dismutase (SOD), glutathione (GSH), and malondialdehyde (MDA). The curcumin analogue C2 exhibited higher DPPH (2,2-diphenyl-1-picrylhydrazyl) and ABTS (2,2'-azinobis-3-ethylbenzothiazo-line-6-sulphonate) free radical-scavenging potential, having IC50 values of 45.18 µg/mL and 62.31 µg/mL, respectively, in comparison with reference curcumin and tocopherol. In the chemical-induced test, C2 (80.17%), C3 (72.79%) and C1 (51.85%) revealed higher antistress responses by significantly reducing the number of writhes, whereas the immobility time was significantly reduced by C2 and C3 in the swimming endurance test, indicating excellent antistress potential. Similarly, C2 and C3 significantly reduced the immobility times in FST and TST, demonstrating their antidepressant properties. The biomarkers study revealed that these compounds significantly enhanced hippocampus CAT, SOD and GSH, and reduced MDA levels in the scopolamine-induced stress mice model. These findings suggest the potential of curcumin analogues (C2 and C3) as antistress and antidepressant agents.

Synthetic Mono-Carbonyl Curcumin Analogues Attenuate Oxidative Stress in Mouse Models.

Alzheimer's disease is the commonest form of dementia associated with short-term memory loss and impaired cognition and, worldwide, it is a growing health issue. A number of therapeutic strategies have been studied to design and develop an effective anti-Alzheimer drug. Curcumin has a wide spectrum of biological properties. In this regard, the antioxidant potentials of mono-carbonyl curcumin analogues (h1−h5) were investigated using in vitro antioxidant assays and hippocampal-based in vivo mouse models such as light−dark box, hole board, and Y-maze tests. In the in vitro assay, mono-carbonyl curcumin analogues h2 and h3 with methoxy and chloro-substituents, respectively, showed promising 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2, 2'-azinobis-3-ethylbenzothiazo-line-6-sulfonate (ABTS) free radical scavenging activities. In the in vivo studies, scopolamine administration significantly (p < 0.001) induced oxidative stress and memory impairment in mice, in comparison to the normal control group. The pretreatment with mono-carbonyl curcumin analogues, specifically h2 and h3, significantly decreased (123.71 ± 15.23 s (p < 0.001), n = 8; 156.53 ± 14.13 s (p < 0.001), n = 8) the duration of time spent in the light chamber and significantly enhanced (253.95 ± 19.05 s (p < 0.001), n = 8, and 239.57 ± 9.98 s (p < 0.001), n = 8) the time spent in the dark compartment in the light−dark box arena. The numbers of hole pokings were significantly (p < 0.001, n = 8) enhanced in the hole board test and substantially increased the percent spontaneous alternation performance (SAP %) in the Y-maze mouse models in comparison to the stress control group. In the biomarker analysis, the significant reduction in the lipid peroxidation (MDA) level and enhanced catalase (CAT), superoxide dismutase (SOD), and glutathione (GSH) activities in the brain hippocampus reveal their antioxidant and memory enhancing potentials. However, further research is needed to find out the appropriate mechanism of reducing oxidative stress in pathological models.

Low clinical utility of testing for anti-platelet factor 4 in asymptomatic individuals after ChAdOx1 nCoV-19 vaccine.

INTRODUCTION: The development of anti-platelet factor 4 (PF4) antibodies is linked to a rare thrombotic complication described now as vaccine-induced immune thrombotic thrombocytopenia (VITT). This clinical syndrome with thrombosis and thrombocytopenia was reported after exposure to the Oxford-AstraZeneca COVID-19 vaccine, ChAdOx1 nCoV-19 vaccine (AZD1222), and Ad26.COV2.S vaccine (Janssen/Johnson & Johnson). In the absence of the clinical features, the incidence of positive anti-PF4 antibodies in asymptomatic individuals post-vaccination is unclear. METHODS: The aim of this study was to evaluate the development of anti-PF4 antibodies in asymptomatic individuals 14-21 days after receiving the first dose of ChAdOx1 nCoV-19 vaccine (AZD1222) and BNT162b2 vaccine. Prospectively, we collected serum from individuals before and after ChAdOx1 nCoV-19 vaccine and BNT162b2 vaccine and measured anti-PF4 antibodies using the Asserachrom HPIA IgG ELISA (Stago, Asnieres, France). RESULTS: We detected positive anti-PF4 antibodies in 5 of 94 asymptomatic individuals post-vaccine with a rate of 5.3% with low titers (OD 0.3-0.7). Four of 5 individuals who tested positive after the vaccine had also positive anti-PF4 antibodies before the vaccine, which indicates that a majority of the positive results are due to preexisting anti-PF4 antibodies. We did not find a relation between the development of anti-PF4 antibodies and the immune response to the vaccine, status of prior COVID-19 infection, and baseline characteristics of participants. None of the participants developed thrombosis nor thrombocytopenia. CONCLUSION: Our results provide new evidence to guide the diagnostic algorithm of suspected cases of VITT. In the absence of thrombosis and thrombocytopenia, there is a low utility of testing for anti-PF4 antibodies.

Evaluation of Side Effects Associated with COVID-19 Vaccines in Saudi Arabia.

BACKGROUND: Pfizer-BioNTech and Oxford-AstraZeneca are recently introduced vaccines to combat COVID-19 pandemic. During clinical trials, mild to moderate side effects have been associated with these vaccines. Thus, we aimed to evaluate short-term post-vaccination side effects. METHODS: Cross-sectional, retrospective study using an online questionnaire was conducted among COVID-19 vaccines recipients in Saudi Arabia. General and demographic data were collected, and vaccine-associated side effects after receiving at least one dose of each vaccine were evaluated. RESULTS: Our final sample consisted of 515 participants with a median age of 26 years. Most of the study participants were female (57%). Nearly 13% of the study subjects have reported previous infections with SARS-CoV-2. Oxford-AstraZeneca and Pfizer-BioNTech vaccines have been received by 75% and 25% of the study participants, respectively. Side effects associated with COVID-19 vaccines have been reported by 60% of the study subjects, and most of them reported fatigue (90%), pain at the site of the injections (85%). CONCLUSION: Side effects that are reported post Oxford-AstraZeneca and Pfizer-BioNTech vaccines among our study participants are not different from those that were reported in the clinical trials, indicating safe profiles for both vaccines. Further studies are needed to evaluate the effectiveness of the current vaccines in protection against SARS-CoV-2 reinfections.

Side Effects of COVID-19 Pfizer-BioNTech mRNA Vaccine in Children Aged 12-18 Years in Saudi Arabia.

Background: Massive vaccination campaigns have been undertaken globally to combat the spread of the Coronavirus Disease 2019 (COVID-19). While most COVID-19 vaccines have shown excellent efficacy and safety profiles in clinical studies, real-world monitoring of vaccine safety is still important. In this study, we aimed to investigate the early side effects of Pfizer-BioNTech (BNT162b2) mRNA vaccine in children between 12-18 years old in Saudi Arabia. Method: To investigate the side effects in children in this age range following the administration of either one or two doses of Pfizer-BioNTech (BNT162b2) mRNA vaccine, we conducted a retrospective, cross-sectional study using a self-administered online survey. General and demographic data were collected, and vaccine-associated side effects following vaccination were evaluated. Results: The study recruited a total of 965 eligible participants. Overall, 571 (60%) of the study participants reported at least one side effect following Pfizer-BioNTech (BNT162b2) mRNA vaccination. The most frequently reported side effects were pain or redness at the site of injection (90%), fatigue (67%), fever (59%), headache (55%), nausea or vomiting (21%), and chest pain and shortness of breath (20%). Joint or bone pain were reported less frequently among our participants (2%). Our data showed that more female participants reported side effects compared to male participants, with 52% and 48%, respectively. Side effects were more common after the second dose compared to the first dose in our study cohort. Conclusions: While 60% of the children (12-18 years old) who received Pfizer-BioNTech (BNT162b2) mRNA vaccine reported side effects, our data showed that these side effects were not different from those that were reported in the clinical trials which lasted only for a few days. Side effects were more common after the second dose. Larger epidemiological and molecular studies are needed to evaluate the safety and the effectiveness of COVID-19 vaccine in protection of children against SARS-CoV-2 reinfections.

Community-Based Seroprevalence of SARS-CoV-2 Antibodies following the First Wave of the COVID-19 Pandemic in Jazan Province, Saudi Arabia.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread globally, causing unprecedented effects on global health and economies. Community-based serological data are essential for understanding the true prevalence of infections, specifically the subclinical infections, as COVID-19 asymptomatic infections are common. Such data would also be important for decision making around choosing appropriate epidemiological control measures, as well as for the true estimation of mortality rates in the population. Further, determining the seroprevalence of anti-SARS-CoV-2 antibodies in the population would provide important information on herd immunity. In this study, we conducted a population-based age-stratified serological study to understand the prevalence of SARS-CoV-2 in Jazan Province, Saudi Arabia. Out of 594 participants who were recruited from 29 August to 30 December 2020, just before the vaccination rollout program in Saudi Arabia, about 157 were seropositive for SARS-CoV-2, indicating an estimated seropositivity rate of 26%. Although no significant difference in seropositivity was seen between male and female participants, we found that lower seroprevalence was associated with the younger (below 18 years old) and older populations (older than 56 years) compared with other age groups (19-55 years). These data indicate a high prevalence of SARS-CoV-2 antibodies following the peak of COVID-19 spread in Jazan province; however, most of the population (three-quarters) remains susceptible to SARS-CoV-2 infection.

Knowledge, Attitudes and Perception toward COVID-19 Vaccines among Adults in Jazan Province, Saudi Arabia.

BACKGROUND: Saudi Arabia is one of the countries that initiated early vaccination programs despite the global challenges concerning the availability of COVID-19 vaccines. Massive vaccination campaigns have been undertaken in the country; however, negative perception and hesitancy toward vaccines may exist which could reduce public response to vaccination. Further, studies evaluating the current perception and attitude toward COVID-19 vaccines are scarce. Thus, this study aims to assess the community attitudes and perceptions toward COVID-19 vaccines in Jazan Province, Saudi Arabia. METHODS: A cross-sectional, retrospective study using an online questionnaire was conducted among the public in Jazan, the southern region of Saudi Arabia. General and demographic data were collected, and perception and attitude toward COVID-19 vaccines were evaluated. RESULTS: Most participants in this study were female (67%) with a median age of 23 years. The majority held a bachelor's degree, and they trusted the Saudi healthcare system. Our survey showed that 67% of the study participants had positive perceptions toward COVID-19 vaccines, a finding that is significantly associated with receiving the influenza vaccine in the past, the existence of trust on the current healthcare system and holding positive beliefs toward the effectiveness of the current COVID-19 vaccines in reducing the risk of infection, complication, and mortality. CONCLUSIONS: The proportion of the public in Jazan who believed in the COVID-19 vaccine effectiveness is not inferior from similar international reports. Thus, national awareness programs toward the effectiveness of the vaccine could be enhanced to accelerate vaccination coverage. Further, nationwide surveys are warranted to include larger populations from different communities to assess the overall perception toward COVID-19 vaccines in the whole country.

Structure-guided drug design identifies a BRD4-selective small molecule that suppresses HIV.

HIV integrates its provirus into the host genome and establishes latent infection. Antiretroviral therapy (ART) can control HIV viremia, but cannot eradicate or cure the virus. Approaches targeting host epigenetic machinery to repress HIV, leading to an aviremic state free of ART, are needed. Bromodomain and extraterminal (BET) family protein BRD4 is an epigenetic reader involved in HIV transcriptional regulation. Using structure-guided drug design, we identified a small molecule (ZL0580) that induced epigenetic suppression of HIV via BRD4. We showed that ZL0580 induced HIV suppression in multiple in vitro and ex vivo cell models. Combination treatment of cells of aviremic HIV-infected individuals with ART and ZL0580 revealed that ZL0580 accelerated HIV suppression during ART and delayed viral rebound after ART cessation. Mechanistically different from the BET/BRD4 pan-inhibitor JQ1, which nonselectively binds to BD1 and BD2 domains of all BET proteins, ZL0580 selectively bound to BD1 domain of BRD4. We further demonstrate that ZL0580 induced HIV suppression by inhibiting Tat transactivation and transcription elongation as well as by inducing repressive chromatin structure at the HIV promoter. Our findings establish a proof of concept for modulation of BRD4 to epigenetically suppress HIV and provide a promising chemical scaffold for the development of probes and/or therapeutic agents for HIV epigenetic silencing.