Synthesis of Novel Triazine-Based Chalcones and 8,9-dihydro-7H-pyrimido[4,5-b][1,4]diazepines as Potential Leads in the Search of Anticancer, Antibacterial and Antifungal Agents.

This study presents the synthesis of four series of novel hybrid chalcones (20,21)a-g and (23,24)a-g and six series of 1,3,5-triazine-based pyrimido[4,5-b][1,4]diazepines (28-33)a-g and the evaluation of their anticancer, antibacterial, antifungal, and cytotoxic properties. Chalcones 20b,d, 21a,b,d, 23a,d-g, 24a-g and the pyrimido[4,5-b][1,4]diazepines 29e,g, 30g, 31a,b,e-g, 33a,b,e-g exhibited outstanding anticancer activity against a panel of 60 cancer cell lines with GI50 values between 0.01 and 100 µM and LC50 values in the range of 4.09 µM to >100 µM, several of such derivatives showing higher activity than the standard drug 5-fluorouracil (5-FU). On the other hand, among the synthesized compounds, the best antibacterial properties against N. gonorrhoeae, S. aureus (ATCC 43300), and M. tuberculosis were exhibited by the pyrimido[4,5-b][1,4]diazepines (MICs: 0.25-62.5 µg/mL). The antifungal activity studies showed that triazinylamino-chalcone 29e and triazinyloxy-chalcone 31g were the most active compounds against T. rubrum and T. mentagrophytes and A. fumigatus, respectively (MICs = 62.5 µg/mL). Hemolytic activity studies and in silico toxicity analysis demonstrated that most of the compounds are safe.

New pyridine-based chalcones and pyrazolines with anticancer, antibacterial, and antiplasmodial activities.

New pyridine-based chalcones 4a-h and pyrazolines 5a-h (N-acetyl), 6a-h (N-phenyl), and 7a-h (N-4-chlorophenyl) were synthesized and evaluated by the National Cancer Institute (NCI) against 60 different human cancer cell lines. Pyrazolines 6a, 6c-h, and 7a-h satisfied the pre-determined threshold inhibition criteria, obtaining that compounds 6c and 6f exhibited high antiproliferative activity, reaching submicromolar GI50 values from 0.38 to 0.45 µM, respectively. Moreover, compound 7g (4-CH3) exhibited the highest cytostatic activity of these series against different cancer cell lines from leukemia, nonsmall cell lung, colon, ovarian, renal, and prostate cancer, with LC50 values ranging from 5.41 to 8.35 µM, showing better cytotoxic activity than doxorubicin. Furthermore, the compounds were tested for antibacterial and antiplasmodial activities. Chalcone 4c was the most active with minimal inhibitory concentration (MIC) = 2 µg/mL against methicillin-resistant Staphylococcus aureus (MRSA), while the pyrazoline 6h showed a MIC = 8 µg/mL against Neisseria gonorrhoeae. For anti-Plasmodium falciparum activity, the chalcones display higher activity with EC50 values ranging from 10.26 to 10.94 µg/mL. Docking studies were conducted against relevant proteins from P. falciparum, exhibiting the minimum binding energy with plasmepsin II. In vivo toxicity assay in Galleria mellonella suggests that most compounds are low or nontoxic.

In silico prediction and in vitro assessment of novel heterocyclics with antimalarial activity.

The development of new antimalarials is paramount to keep the goals on reduction of malaria cases in endemic regions. The search for quality hits has been challenging as many inhibitory molecules may not progress to the next development stage. The aim of this work was to screen an in-house library of heterocyclic compounds (HCUV) for antimalarial activity combining computational predictions and phenotypic techniques to find quality hits. The physicochemical determinants, pharmacokinetic properties (ADME), and drug-likeness of HCUV were evaluated in silico, and compounds were selected for structure-based virtual screening and in vitro analysis. Seven Plasmodium target proteins were selected from the DrugBank Database, and ligands and receptors were processed using UCSF Chimera and Open Babel before being subjected to docking using Autodock Vina and Autodock 4. Growth inhibition of P. falciparum (3D7) cultures was tested by SYBR Green assays, and toxicity was assessed using hemolytic activity tests and the Galleria mellonella in vivo model. From a total of 792 compounds, 341 with good ADME properties, drug-likeness, and no interference structures were subjected to in vitro analysis. Eight compounds showed IC50 ranging from 0.175 to 0.990 µM, and active compounds included pyridyl-diaminopyrimido-diazepines, pyridyl-N-acetyl- and pyridyl-N-phenyl-pyrazoline derivatives. The most potent compound (UV802, IC50 0.178 µM) showed no toxicophoric and was predicted to interact with P. falciparum 1-cysperoxidredoxin (PfPrx1). For the remaining 7 hits (IC50 < 1 µM), 3 showed in silico binding to PfPrx1, one was predicted to bind the haloacid dehalogenase-like hydrolase and plasmepsin II, and one interacted with the plasmodial heat shock protein 90.

Non-canonical telomere protection role of FOXO3a of human skeletal muscle cells regulated by the TRF2-redox axis.

Telomeric repeat binding factor 2 (TRF2) binds to telomeres and protects chromosome ends against the DNA damage response and senescence. Although the expression of TRF2 is downregulated upon cellular senescence and in various aging tissues, including skeletal muscle tissues, very little is known about the contribution of this decline to aging. We previously showed that TRF2 loss in myofibers does not trigger telomere deprotection but mitochondrial dysfunction leading to an increased level of reactive oxygen species. We show here that this oxidative stress triggers the binding of FOXO3a to telomeres where it protects against ATM activation, revealing a previously unrecognized telomere protective function of FOXO3a, to the best of our knowledge. We further showed in transformed fibroblasts and myotubes that the telomere properties of FOXO3a are dependent on the C-terminal segment of its CR2 domain (CR2C) but independent of its Forkhead DNA binding domain and of its CR3 transactivation domain. We propose that these non-canonical properties of FOXO3a at telomeres play a role downstream of the mitochondrial signaling induced by TRF2 downregulation to regulate skeletal muscle homeostasis and aging.

Neutralizing activity to SARS-CoV-2 in 1.2 to 10.0 month convalescent plasma samples of COVID-19: A transversal surrogate in vitro study performed in Quito-Ecuador.

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, was first reported in Wuhan, China, in December 2019. Diagnostic methods for the detection of the virus and seroconversion of neutralizing antibodies (NAbs) in plasma have been developed specifically, but some of them require a BSL3 facility. In this study, we used the SARS-CoV-2 Surrogate Virus Neutralization Test Kit to determine the presence or absence of NAbs anti-receptor binding domain of the viral spike (S) glycoprotein in a BSL2 facility. The sample population was chosen in Quito, Ecuador, with a total of 88 COVID-19 positive convalescent patients. We determined that 97.7% of the analyzed convalescent sera maintained the presence of NAbs with neutralizing activity, and this activity remained until 10 months after the infection in some cases. In addition, the relationship between the presence of NAbs and immunoglobulin G was significant compared to immunoglobulin M, which tended to be absent over time.

The Power of Stress: The Telo-Hormesis Hypothesis.

Adaptative response to stress is a strategy conserved across evolution to promote survival. In this context, the groundbreaking findings of Miroslav Radman on the adaptative value of changing mutation rates opened new avenues in our understanding of stress response. Inspired by this work, we explore here the putative beneficial effects of changing the ends of eukaryotic chromosomes, the telomeres, in response to stress. We first summarize basic principles in telomere biology and then describe how various types of stress can alter telomere structure and functions. Finally, we discuss the hypothesis of stress-induced telomere signaling with hormetic effects.

A global analysis of the impact of COVID-19 stay-at-home restrictions on crime.

The stay-at-home restrictions to control the spread of COVID-19 led to unparalleled sudden change in daily life, but it is unclear how they affected urban crime globally. We collected data on daily counts of crime in 27 cities across 23 countries in the Americas, Europe, the Middle East and Asia. We conducted interrupted time series analyses to assess the impact of stay-at-home restrictions on different types of crime in each city. Our findings show that the stay-at-home policies were associated with a considerable drop in urban crime, but with substantial variation across cities and types of crime. Meta-regression results showed that more stringent restrictions over movement in public space were predictive of larger declines in crime.

Neutrophils: mediating TelOxidation and senescence.

Cellular senescence is considered to be a major driver of aging, yet the mechanisms explaining the accumulation of senescent cells during life time remain unclear. In this issue, Lagnado et al (2021) show that neutrophils can trigger the senescence of neighboring cells by transmitting reactive oxygen species (ROS), which they normally produce to fight pathogens. The main genomic targets of the neutrophil-mediated ROS damage are telomeres, supporting an intimate interplay between telomere homeostasis and oxidative stress in senescence and consequently aging.

Pathogenesis and in vivo interactions of human Streptococcus agalactiae isolates in the Galleria mellonella invertebrate model.

Group B Streptococcus (GBS) is a gram positive bacterium colonizing the gastrointestinal and urogenital tracts in humans. However under certain conditions GBS invades leading to severe infections in neonates, pregnant women, immunocompromised patients and the elderly people. The precise mechanisms involved in the transition from colonizer to pathogen remain to be elucidated, however it has been suggested that environmental determinants may regulate gene expression resulting in GBS invasion. We have assessed the potential of the moth Galleria mellonella as a model to study the in vivo virulence and GBS interactions of invasive and noninvasive human isolates from our population. Temperature, pH and bacterial competition effects were examined in the model as well as the response of Galleria hemocytes to GBS infection. GBS strains were able to effectively grow and infect G. mellonella in a dose dependent manner with a (half-lethal dose) LD50 1 × 107 CFU after 24 h. GBS infection induced larva melanization with hemocyte vacuolation and depletion. Larval killing increased with environmental conditions such as temperature (37 °C) and pH (≥5.5-7.2). Bacterial interference assays showed a remarkable antagonistic effect of Lactobacillus gasseri (cells and filtrates) on GBS infection and significantly improved Galleria survival. The protective effect of L. gasseri was observed even at ratios similar to those of GBS colonization suggesting that L. gasseri modulation by its metabolic products is relevant. Exposure to L. gasseri acidic filtrates induced growth inhibition and prevented larva killing after infection with the hypervirulent GBS clone (a multiresistant clinical ST 17 strain). We showed that mechanisms mediating these effects are mainly pH dependent, however other mechanisms may have a role depending on inocula. We also found that G. mellonella infected with invasive human GBS isolates showed differential killing curves with higher killing rates after 24 h when compared to those considered colonizers or noninvasive isolates. Overall it has been shown that G. mellonella may be a representative in vivo model for baseline GBS studies. Given the potential effects over the hypervirulent strain, our findings support the use of L. gasseri in the GBS control strategies based on Lactobacillus formulations.

Long-lived post-mitotic cell aging: is a telomere clock at play?

Senescence is a cellular response to stress for both dividing and post-mitotic cells. Noteworthy, long-lived post-mitotic cells (collectively named LLPMCs), which can live for decades in the organism, can exhibit a distinct type of cellular aging characterized by a progressive functional decline not associated to an overt senescence phenotype. The age-related drivers of senescence and aging in LLPMCs remain largely unknown. There is evidence that an increased production of reactive oxygen species (ROS) due to dysfunctional mitochondria, coupled with an inherent inability of cellular-degradation mechanisms to remove damaged molecules, is responsible for senescence and aging in LLPMC. Although telomeric DNA shortening, by nature linked to cell division, is generally not considered as a driver of LLPMC aging and senescence, we discuss recent reports revealing the existence of age-related telomere changes in LLPMC. These findings reveal unexpected roles for telomeres in LLPMC function and invite us to consider the hypothesis of a complex telomere clock involved in both dividing and non-dividing cell aging.

Mitochondrial function in skeletal myofibers is controlled by a TRF2-SIRT3 axis over lifetime.

Telomere shortening follows a developmentally regulated process that leads to replicative senescence of dividing cells. However, whether telomere changes are involved in postmitotic cell function and aging remains elusive. In this study, we discovered that the level of the TRF2 protein, a key telomere-capping protein, declines in human skeletal muscle over lifetime. In cultured human myotubes, TRF2 downregulation did not trigger telomere dysfunction, but suppressed expression of the mitochondrial Sirtuin 3 gene (SIRT3) leading to mitochondrial respiration dysfunction and increased levels of reactive oxygen species. Importantly, restoring the Sirt3 level in TRF2-compromised myotubes fully rescued mitochondrial functions. Finally, targeted ablation of the Terf2 gene in mouse skeletal muscle leads to mitochondrial dysfunction and sirt3 downregulation similarly to those of TRF2-compromised human myotubes. Altogether, these results reveal a TRF2-SIRT3 axis controlling muscle mitochondrial function. We propose that this axis connects developmentally regulated telomere changes to muscle redox metabolism.

Characterization of Cement Particles Found in Peri-implantitis-Affected Human Biopsy Specimens.

PURPOSE: Peri-implantitis is a disease characterized by soft tissue inflammation and continued loss of supporting bone, which can result in implant failure. Peri-implantitis is a multifactorial disease, and one of its triggering factors may be the presence of excess cement in the soft tissues surrounding an implant. This descriptive study evaluated the composition of foreign particles from 36 human biopsy specimens with 19 specimens selected for analysis. The biopsy specimens were obtained from soft tissues affected by peri-implantitis around cement-retained implant crowns and compared with the elemental composition of commercial luting cement. MATERIALS AND METHODS: Nineteen biopsy specimens were chosen for the comparison, and five test cements (TempBond, Telio, Premier Implant Cement, Intermediate Restorative Material, and Relyx) were analyzed using scanning electron microscopy equipped with energy dispersive x-ray spectroscopy. This enabled the identification of the chemical composition of foreign particles embedded in the tissue specimens and the composition of the five cements. Statistical analysis was conducted using classification trees to pair the particles present in each specimen with the known cements. RESULTS: The particles in each biopsy specimen could be associated with one of the commercial cements with a level of probability ranging between .79 and 1. TempBond particles were found in one biopsy specimen, Telio particles in seven, Premier Implant Cement particles in four, Relyx particles in four, and Intermediate Restorative Material particles in three. CONCLUSION: Particles found in human soft tissue biopsy specimens around implants affected by peri-implant disease were associated with five commercially available dental cements.

Foreign bodies associated with peri-implantitis human biopsies.

BACKGROUND: Peri-implantitis is an inflammatory condition that can lead to implant loss. The aim of this descriptive retrospective study is to describe the histopathologic findings in soft tissue biopsies of implants with peri-implantitis. METHODS: Thirty-six human peri-implantitis biopsies were analyzed using light microscopy (LM) and scanning electron microscopy (SEM). The composition of foreign materials found in the tissues was assessed using an energy dispersive x-ray spectrometer. RESULTS: At the LM level, the inflammatory lesion of peri-implantitis was in most cases a mixture of subacute and chronic inflammation dominated by plasma cells. At the SEM level, radiopaque foreign bodies were identified in 34 of the 36 biopsies. The predominant foreign bodies found were titanium and dental cement. These foreign materials were surrounded by inflammatory cells. CONCLUSIONS: At present, the exact mechanism for introduction of these materials and their role in peri-implantitis is unknown. Further research is warranted to determine their etiology and potential role in pathogenesis.

Gender differences in the association of hazardous alcohol use with hypertension in an urban cohort of people living with HIV in South Florida.

OBJECTIVE: Industrialized countries are currently experiencing an epidemic of high blood pressure (HBP) extending to people living with HIV (PLWH). Given the prevalence of hazardous alcohol use (HAU), this study examines the relationship between alcohol consumption and hypertension in PLWH. Including a gender analysis is critical, given the high rates of HAU and HIV among females. METHOD: We followed PLWH including both HAU and non-HAU (200 each). Participants were assessed twice for body weight, blood pressure, alcohol consumption, and other BP-associated lifestyle factors. High blood pressure (defined as systolic/diastolic blood pressure above 140/90 mmHg and/or treatment of HBP) was the primary outcome. RESULTS: Overall prevalence of hypertension was 38% and higher among HAU compared to non-HAU (42% vs. 34%, p = 0.02). Less than half with HBP (42%) were receiving treatment for hypertension. Overall, males had a 50% higher risk of HBP than women (odds ratio: 1.5, 95% CI: 1-2.6, p = 0.05). However among HAU, females were twice as likely to suffer HBP as their male counterparts (95% CI: 1-3.9, p = 0.02). Those HAU who preferred liquor, versus wine, had higher adjusted mean BP (132.6±18 vs. 122.3±14 mm Hg, p = 0.05). Additional analyses indicated that consumption of >1 standard drink of liquor or beer/day was associated with HBP. Risk of hypertension was noted in those with daily consumption of >3 glasses of wine. For those reporting <1 drink per day, the odds ratio of having HBP was 0.97 (CI: 0.6-0.99, p = 0.05). Factors associated with hypertension in the multivariate model included increased age, gender, BMI, HAU particularly of liquor, and smoking. CONCLUSIONS: Excessive hypertension burden in this population and its association with HAU and sub-optimal care indicate the need for preventive and educational intervention in PLWH. Analyses highlight the necessity of gender and type-of-beverage specific approaches.

Brain derived neurotrophic factor and cognitive status: the delicate balance among people living with HIV, with and without alcohol abuse.

INTRODUCTION: The advent of combination antiretroviral therapy(cART) has lead to a significant reduction in morbidity and mortality among people living with HIV(PLWH). However, HIV-associated neurocognitive disorders (HAND) still remain a significant problem. One possible mechanism for the persistence of these disorders is through the effect of HIV on brain-derived neurotrophic factor (BDNF). BDNF is influenced by various factors including hazardous alcohol use (HAU), which is prevalent among PLWH. This study attempts to elucidate the relationships between HAU, BDNF and HAND. METHODS: Cross-sectional analyses were conducted on a sample of 199 hazardous alcohol users and 198 non-HAU living with HIV. Members of each group were matched according to sociodemographic characteristics and CD4 count. Research procedures included validated questionnaires, neuropsychological assessments and a blood sample to obtain BDNF and immune measurements. RESULTS: Hazardous alcohol users showed either significantly lower or significantly higher BDNF levels compared to the Non-hazardous (OR=1,4; 95% CI: 1-2.1, p = 0.003). Therefore, for additional analyses, subjects were categorized based on BDNF values in: Group 1 < 4000, Group 2: 4001-7,999 (reference group), and Group 3 for those >8,000 pg/mL. Groups 1 and 3 performed significantly worse than those in Group 2 in the domains of processing speed, auditory-verbal and visuospatial learning and memory. Multivariate analyses confirmed that HAU and BDNF are significant contributors of HAND. CONCLUSION: Our findings offer novel insights into the relationships between BDNF, and alcohol use among PLWH. Our results also lend support to expanding clinical movement to use BDNF as an intervention target for PLWH, in those with evidence of deficiencies, and highlight the importance of including HAUat the inception of clinical trials.

Beyond the Brain: The Role of Brain-Derived Neurotrophic Factor in Viroimmune Responses to Antiretroviral Therapy among People Living with HIV with and without Alcohol Use.

OBJECTIVE: Given the emerging data suggesting the key role of brain-derived neurotrophic factor (BDNF) in the immune system, we assessed longitudinally whether BDNF depletions induced by hazardous alcohol use (HAU) would impact a response to antiretroviral therapy (ART). METHODS: In a prospective single-site cohort, virological and immunological responses to ART in 200 hazardous and 200 nonhazardous users were obtained, along with plasma BDNF levels. RESULTS: Hazardous drinkers were more likely to have BDNF levels <4000 pg/mL (odds ratio [OR] = 1.6, P = .01). Participants with BDNF <4000 pg/mL were less likely to have CD4 counts of more than 500 cells/mm(3) (P = .02) and to achieve viral suppression over the follow-up period (OR = 1.5, P = .03). Multivariate analysis confirmed the significant role of HAU and low BDNF in predicting viroimmune responses. CONCLUSION: Hazardous alcohol use was associated with BDNF alterations, which in turn were linked to a limited response to ART in terms of viral suppression and CD4 count improvements.

Menthol cigarettes and the cardiovascular risks of people living with HIV.

The possibility that menthol cigarettes add to the deleterious cardiovascular effects of smoking has been barely discussed. Although cardiovascular diseases (CVD) are at the forefront of medical concerns of people living with HIV (PLWH), an important, yet unknown, issue for clinicians and public health authorities is whether use of menthol-flavored cigarettes heightens CVD risk factors. Our study aims to assess traditional (10-year risk using the Framingham Risk Model) and nontraditional CVD risk factors and to contrast the effects of menthol-flavored versus non-menthol-flavored cigarettes on these risk factors. Compared to controls, menthol smokers were twice as likely to have hypertension. Users of menthol-flavored cigarettes had higher body mass index values, and increased risk of abdominal obesity. Multivariate analyses indicated that menthol smokers doubled the odds of having moderate to high CVD risk. This finding is highly significant given the widespread use of menthol-flavored cigarettes, particularly among women, minorities, and PLWH.

Are Serotonin Alterations the Link between Thrombocytopenia and Poor Immune Status among HIV Infected Individuals?

OBJECTIVE: Thrombocytopenia (TCP<150 × 103 cells/mm3) has emerged as a relevant factor in the clinical course of HIV. However, the mechanisms mediating such observations have not been well characterized, limiting the possibility of creating targeted interventions. Notably, platelets are the storage and transporter system for serotonin and Brain derived neurotrophic factor (BDNF), which recent laboratory studies associated with viral replication and lymphocyte survival. Thus, we posit that (1) TCP will be associated with reduced levels of BDNF and serotonin (2) That these alterations will lead to poor viro-immune responses to antiretroviral therapy. METHODS: To achieve this goal, a total of 400 people living with HIV were consecutively enrolled to characterize the frequency of thrombocytopenia in hazardous and non-hazardous alcohol user populations in the HAART era. Then, participants underwent immune and laboratory assessments, to determine if TCP was associated with alterations in serotonin (5-HT) and brain derived neurotrophic factor (BDNF). RESULTS: The prevalence of thrombocytopenia in this antiretroviral treated cohort was 14%. Rates were significantly higher in the heavy alcohol users, HAU versus the non HAU group (Heavy: 25% versus HAU: 15% versusnon-HAU: 10%). Multivariate model analyses indicated that having TCP, low BDNF levels (<5000 pg/ml), and number of drinks per day were predictors of serotonin levels. PLWH with TCP had about 2-fold lower PPP-BDNFlevels (5037.4 ± 381 vs. 9137.5 ± 7062 pg/ml p=0.0001). Other significant predictors of BDNF levels at the last visit included receiving selective serotonin reuptake inhibitors and PPP serotonin levels. Multivariate analyses also confirmed that altered serotonin levels were associated withhigh viral loadsboth low CD4 cell counts. CONCLUSIONS: Thrombocytopenia is a relatively frequent complication of HIV, andis particularly prevalent among hazardous alcohol users (HAU). These findings suggest that TCP is associated with altered levels of BDNF and serotonin, suggesting that they may be the bridge linking TCP and poor viro-immune responses observed in this group. These results could have important clinical and therapeutic implications.

Mood Disorders and BDNF Relationship with Alcohol Drinking Trajectories among PLWH Receiving Care.

BACKGROUND: Despite the excessive rates of Hazardous Alcohol Use (HAU) among people living with HIV (PLWH), although largely speculated, psychological and physiological components associated with HAU, has not been actively measured. Therefore, the present study was geared toward determining: 1) the rates of mood disorders and its relationship with HAU, and 2) to assess the impact of Brain Derived Neurotrophic Factor (BDNF), a well-known regulator of alcohol and mood disorders. METHODS: For this study, participants of the longitudinal PADS Study n=400, were followed over time. Alcohol use (Alcohol Use Disorders Identification Test -AUDIT- and the Alcohol Dependence Scale -ADS) and moods (depression, anxiety, and stress) were assessed repeatedly. RESULTS: A cluster analyses shows three distinctive trajectories. The first one, revealed a group with increased drinking (Cluster 1: n=140), constant alcohol intake (Cluster 2: n = 60), and one with decreased consumption (Cluster 3: n =120). Analyses discovered higher AUDIT scores across the clusters with Cluster 1 being followed by Clusters 2 and 3 (1: 14.5 ± 8 vs. 2=8.7 ± 7.5 vs. 3= 6.6 ± 4.2, p = 0.001). Women in Clusters 1 and 2 had higher levels of stress (1:21 ± 7.5; 2:19.3 ± 7) and lower BDNF levels (7904 ± 1248 pg/ml and 10405 ± 909 pg/mL) than their counterparts in Cluster 3 (PSS: 3: 16.6 ±5, p = 0.02 BDNF: 10828 ± 1127 pg/mL, p = 0.08). Men in Cluster 1 differed in terms of stress (19.8 ± 7 vs. 21 ± 7.5 score) and BDNF levels (Cluster 1: 5204 ± 818 vs. Cluster 2: 7656 ± 843 pg/ml, p = 0.002) but not in the number of years living with HIV. The proportion of subjects with multiple mood comorbidities was disturbingly higher (26%), and all were members of Cluster 1. Multiple logistic regression analyses indicated that participants reporting high relative to low levels of perceived stress, dual mood comorbidity, altered BDNF levels and low income increased the likelihood of being a member of Cluster 1. CONCLUSION: This study found that stress and overlaying psychiatric comorbidities are linked with persistent alcohol use. Findings suggest that BDNF and social support seems to be a logical target as it seems to be the bridge linking mood disorders and alcohol consumption.