Human immunodeficiency virus (HIV) has become a global pandemic over the past few decades, with new infections and related deaths in the millions each year. There is no cure in sight for HIV-1 infection, and there has been little progress in developing an efficacious vaccine. Heterosexual transmission of HIV-1 remains the principal mode of transmission throughout the world and thus measures, such as topical vaginal microbicides, to prevent infection of the female reproductive tract are actively being explored. Recent trials of topical vaginal microbicides have shown that their interaction with the mucosal surfaces of the female reproductive tract as well as semen can hinder microbicide effectiveness against HIV-1 infection. Therefore, understanding the role these fluids play in HIV transmission would be critical towards developing effective antiviral prophylaxes. A recent study from our group demonstrated that human cervicovaginal secretions contained numerous cationic antimicrobial peptides and proteins, which collectively inhibited HIV-1 infection of target cells and tissues. To ascertain if human seminal plasma (SP), the main vector responsible for transmitting HIV-1, exhibited antiviral activity we utilized several antiHIV assays in the presence or absence of minimally manipulated SP. The majority of the intrinsic anti-HIV-1 activity of SP resided in the cationic polypeptide fraction. Antiviral assays utilizing luciferase reporter cells and lymphocytic cells revealed the ability of whole SP to prevent HIV-1 infection, even when SP was diluted 3200-fold. Subsequent fractionation by continuous flow acid-urea (AU)-PAGE and antiviral testing revealed that cationic polypeptides within SP were responsible for the majority of anti-HIV-1 activity. A proteomic approach was utilized to resolve and identify 52 individual cationic polypeptides that contribute to the aggregate anti-HIV-1 activity of SP. One peptide fragment of semenogelin I, termed SG-1, was purified from SP by a multi-step chromatographic approach, protein sequenced, and determined to exhibit anti-HIV-1 activity against HIV-1. Anti-HIV-1 activity was transient, as whole SP incubated for prolonged time intervals exhibited a proportional decrease in anti-HIV-1 activity that was directly attributed to the degradation of semenogelin I peptides. Collectively, these results indicate that the cationic polypeptide fraction of SP is active against HIV-1, and that semenogelin-derived peptides contribute to the intrinsic anti-HIV-1 activity of SP. Conversely, naturally occurring peptidic fragments from the SP-derived prostatic acid phosphatase (PAP) have been reported to form amyloid fibrils called "SEVI" capable of enhancing HIV-1 infection in vitro. In order to understand the biological consequence of this proviral effect, we extended these studies in the presence of human SP. PAP-derived peptides were agitated to form SEVI and incubated in the presence or absence of SP. While PAP-derived peptides and SEVI alone were proviral, the presence of 1% SP ablated their proviral activity in several different anti-HIV-1 assays. The anti-HIV-1 activity of SP was concentration dependent and was reduced following filtration. Supraphysiological concentrations of PAP peptides and SEVI incubated with diluted SP were degraded within hours, with SP exhibiting proteolytic activity at dilutions as high as 1:200. Sub-physiological concentrations of two prominent proteases of SP, prostate-specific antigen (PSA) and matriptase, could degrade physiological and supraphysiological concentrations of PAP peptides and SEVI. While human SP is a complex biological fluid, containing both antiviral and proviral factors, our results suggest that PAP peptides and SEVI may be subject to naturally occurring proteolytic components capable of reducing their proviral activity. Our studies demonstrate the overall antiviral activity of human SP, but there is still a critical need for effective topical vaginal microbicides that can prevent HIV-1 transmission. The synthetic human retrocyclins are cyclic antimicrobial peptides that are remarkably active against HIV-1, and are being developed as topical vaginal microbicides. Herein, we assessed whether the putative proviral SEVI was able to adversely affect the anti-HIV-1 activity of the retrocyclin analog RC-101. While SEVI alone enhanced viral infection, this effect was completely negated in the presence of RC-101. Retrocyclins such as RC-101 are inhibitors of HIV-1 entry, by preventing gp41-mediated viral fusion. Interestingly, using an HIV-1 reverse transcriptase (RT) specific assay, we also determined that RC-101 directly inhibited the activity of RT in a dose dependent manner, suggesting a secondary mechanism of viral inhibition. Our group has determined that RC-101 induces only a modest level of resistance in HIV, which may be due in part to RC-101's dual mechanisms of viral inhibition.

Bakgrund: Humant immunbristvirus (HIV) är ett virus som bryter ner immunförsvaret, ökar mottagligheten för infektioner och klassificeras som en kronisk sjukdom. Till skillnad från många andra kroniska sjukdomar är HIV förknippat med ett djupt rotat stigma. Missförstånd om smittvägar har lett till stigmatisering, särskilt inom vården där kunskapsluckor om HIV försämrar bemötandet och upplevelser av vården för patienter som lever med viruset. Personcetrerad vård och sjuksköterskans professionella förhållningssätt kan förbättra omvårdnaden och upplevelsen av vården för personer som lever med HIV genom att skapa en trygg och respektfull miljö. Syfte: Syftet var att belysa erfarenheter av vården beskrivet av patienter med humant immunbristvirus. Metod: Studien genomfördes som en allmän litteraturstudie med en induktiv ansats. Resultat: Resultatet genererade sex kategorier som belyste erfarenheterna patienter med humant immunbristvirs har av vården; stigmatisering inom vården, bemötande med inverkan på den psykiska hälsan, bristande tystnadsplikt och sekretess, erfarenheter av vårdandet, positiva erfarenheter av omvårdnad och önskemål för en förbättrad HIV-vård. Underkategorierna genererades som samtal och stöd, samt fysisk omvårdnad. Konklusion: Erfarenheterna av vård för patienter med HIV avslöjar betydande brister såsom stigmatisering och integritetsbrott. Därmed indikerar studien behovet av utveckling för att frlämja en förbättrad omvårdnad för patienter med HIV. / Background: Human immunodeficiency virus (HIV) is a virus that breaksdown the immune system, increases the receptivity of infections, and isclassified as a chronic disease. Unlike other chronic diseases, HIV isassociated with a deeply rooted sense of stigma. Misconception of the routesof infection has led to stigmatization, especially in healthcare settings whereknowledge gaps deteriorate the treatment and experiences of patients livingwith the virus. Person-centered care and the nurse's professional approachcan enhance the experience of nursing and healthcare for individuals livingwith HIV by creating a safe and respectful environment. Aim: The aim wasto present the experiences of nursing care described by patients with humanimmunodeficiency virus. Method: This study is a general literature studywith an inductive approach. Results: The results generated six categoriesthat highlighted the experiences of healthcare: stigmatization in healthcare,treatment with the impact on mental health, lack of confidentiality andprivacy, experiences of healthcare, positive experiences of nursing care, anddesires for improved HIV care. The subcategories generated as support andcommunication, as well as physical care. Conclusion: The experiencespatients living with HIV have of healthcare reveals significant flaws such asstigmatization and breaches of privacy. Thus, the study highlights the needof development to promote improvement care for patients living with HIV.

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Bakgrund: Blodsmitta sprids mellan personer från blod eller slemhinna via kontaminerade injektioner, blodprodukter eller stickskador. Sjukdomar som humant immunbristvirus (HIV), acquired immunodeficiency syndrome (AIDS) och Hepatit A, B, C och D. HIV-infektion drabbar immunförsvaret och är en kronisk diagnos. HIV övergår senare till AIDS och AIDS är ett mer avancerat stadie av sjukdomen. Hepatit är leversjukdomar vilka kan vara såväl övergående som kroniska. Syfte: Kartlägga vilka faktorer som påverkar allmänsjuksköterskors stigmatiserade attityder vid omvårdnad av patienter med HIV/AIDS som vårdas i slutenvården. Metod: Litteraturöversikt som inkluderar 12 kvantitativa vetenskapliga artiklar vilka analyserades enligt Fribergs fyra-stegs analys. Resultat: Tre kategorier identifierades: Yrkeskompetens visade att sjuksköterskorna skattade minskad stigmatisering mot patienter med HIV/AIDS efter utbildning samt efter arbetserfarenhet. Säkerhetsåtgärder, visade att sjuksköterskorna skattade sig säkra i att skydda sig själva när de behandlade patienter med HIV/AIDS. Inställning till patienterna visade att de ansåg att patienterna själva bär ansvar över sjukdomen på grund av riskabla beteenden. Däremot ansåg de att patienter med HIV/AIDS skulle behandlas med respekt och lika värde. Slutsats: Det lyftes fram viktiga aspekter kring vårdande av patienter med HIV och att sjuksköterskor är delaktiga i stigmatiseringen av patienter med HIV vilket kan undvikas med utbildning om HIV/AIDS. Sjuksköterskor hade grundläggande kunskap i hur de skulle skydda sig mot HIV-infektionen däremot var det en bristfällande faktor som ledde till stigmatisering. När sjuksköterskor har mer kunskap om HIV-infektion bidrar det till en säker vård. / Background: Blood infections spreads between people from blood or mucous membranes via contaminated injections, blood products or puncture wounds. Diseases such as human immunodeficiency virus (HIV), acquired immunodeficiency syndrome (AIDS) and Hepatitis A, B, C and D. HIV infection affects the immune system and is a chronic diagnosis. HIV later turns into AIDS and AIDS is a more advanced stage of the disease. Hepatitis are liver diseases which can be transient as well as chronic. Aim: To map which factors influence general nurses' stigmatized attitudes when caring for patients with HIV/AIDS who are cared for in inpatient care. Method: Literature review that includes 12 quantitative scientific articles which were analyzed according to Friberg's four-step analysis. Results: Three categories were identified: Professional competence showed that the nurses estimated reduced stigma towards patients with HIV/AIDS after education and after work experience. Safety measures showed that the nurses felt confident in protecting themselves when treating patients with HIV/AIDS. Attitude towards the patients showed that they considered that the patients themselves bear responsibility for the disease due to risky behavior. However, they believed that patients with HIV/AIDS should be treated with respect and equal value. Conclusion: It highlights important aspects regarding the care of patients with HIV and that nurses are involved in the stigmatization of patients with HIV which can be avoided with education about HIV/AIDS. Nurses had basic knowledge of how to protect themselves against HIV infection, however, it was a deficient factor that led to stigmatization. When nurses have more knowledge about HIV infection, it contributes to safe care.

Mitochondria provide the main energy required for cardiac excitation-contraction coupling via aerobic oxidative phosphorylation (OXPHOS) process. Accumulation of reactive oxygen species (ROS), by-products of mitochondrial respiration, within dysfunctional mitochondria results in the activation of cardiac cell death pathways and has been associated with heart failure development. Therefore, maintaining mitochondrial homeostasis as a balance between mitochondrial biogenesis and degradation is of great importance toward cardiac proper functioning. In addition to the importance of mitochondrial energy supply, gap junctions, intercellular channels which connect plasma membrane of adjacent cardiomyocytes, by propagating action potential throughout the myocardium maintain cardiac synchronous beating and rhythm. Gap junctions have a rapid turnover and impair of gap junction quality control impacts cell-to-cell communication; resulting in electrical conduction abnormalities and arrhythmogenesis. Therefore, understanding the underlying mechanism the quality control of mitochondria and gap junctions profoundly contributes toward understating the genesis of cardiomyopathy. Furthermore, cardiovascular problems in HIV (Human immunodeficiency virus) positive patients whose viral load is controlled via antiretroviral therapy remains a problem while the underlying mechanism remains elusive. The current study has used an in vitro model of primary neonatal rat ventricular cardiomyocytes (NRVCs) to discover the molecular mechanisms of mitochondrial as well as gap junction quality control under normal and stress conditions. Furthermore, electrical activities of the primary cardiomyocytes were recorded using microelectrode array (MEA) system and important electrophysiological components such as impulse propagation pattern and conduction velocity were extracted from the complex signal recordings. Overall, we have pursued four main aims; Aim 1. Dysregulation of mitochondrial quality control machinery leads to cardiac death; Aim 2. HIV-1 Tat (transcriptional transactivator) dysregulates cardiac homeostasis via mitochondrial pathway; Aim 3. Impairment of protein quality control impacts the quality of gap junction; Aim 4. Inhibition of gap junction quality dysregulates electrical signal propagation within the culture. / Bioengineering

This descriptive research used the Health Belief Model (HBM) to assess HIV/AIDS knowledge, perceived severity, perceived susceptibility, and behavioral practices within the population throughout the State of Sonsonate, El Salvador. Geographic Information Systems (GIS) was also utilized to display the results of this population study. The study population was composed of 15-39 year olds consisting of a total sample size of 1,500 (250 participants from each of the six cities). The basis of this study was to evaluate where this population fit within the Health Belief Model (HBM) and also to practically represent the results pictorially. Also, this information was collected so that the government of El Salvador could see and understand where their educational deficits existed so that future programs could be established to alleviate these discrepancies. An instrument consisting of 65 items including demographics, knowledge, perceived severity, perceived susceptibility, and behavioral practices was used for the general population. The analysis of the data was two-fold using Geographic Information Systems (GIS) mapping and statistical analysis. GIS mapping was used to graphically pinpoint areas of knowledge deficit and misinformation about HIV/AIDS. Results were based on a general population of 1,454. Various indices were created to show the level of knowledge or frequency of safe behavioral practices. The Perceived Severity and Perceived Susceptibility sections were not aggregated into an index but rather treated as individual variables. An item analysis of the questionnaire found that on average the general population responded correctly to 78% of the knowledge questions. However, a total of 11 questions in the knowledge section had less 75% (n=385) of the general population answering correctly. Another 3 questions in the behavior section were also found to have less than 75% (n=385) indicating safe behavioral practices. Linear regression analyses were performed to explore correlations between the areas of demographics, knowledge level, perceived severity, and perceived susceptibility to safe behavior. GIS maps were created to pictorially show where this population's deficiencies were in regard to the HBM. This research helped to pinpoint where this population fits within the construct of the Health Belief Model so that future educational efforts can be targeted in geographic areas with the greatest need. This will help to move this sample toward behavioral change. / Ph. D.

Thesis advisor: Welkin Johnson / HIV-associated comorbidities including neurological disorders (HAND) and cardiovascular diseases (CVD) persist in people living with HIV (PLWH) regardless of adherence to antiretroviral therapies (ART). The development of these comorbidities correlates with increased monocyte/macrophages activation and accumulation. Studies report that the development of CVD and HAND are connected in PLWH, but few studies have examined the roles that monocyte/macrophages activation have in their co-development. We first asked how frequently CD8+ T lymphocyte depleted, SIV-infected rhesus macaques with AIDS co-developed cardiac pathology and SIV encephalitis (SIVE) compared to animals that developed CVD or SIVE alone, and animals with no significant cardiac pathology (NSF) and SIV with no encephalitis (SIVnoE) (Chapter 2). We sought to determine whether animals with concomitant CVD and SIVE had more monocyte activation, cardiac macrophages accumulation, and productively infected SIV-RNA+ and SIV- gp41+ cells in the heart and brain compared to animals with CVD or SIVE alone, and animals with NSF and SIVnoE. We found that animals with AIDS co-developed CVD and SIVE more frequently than animals developed CVD or SIVE alone, and NSF and SIVnoE. Animals with CVD and SIVE had increased biomarkers of monocyte activation, cardiac macrophages inflammation, and productively infected macrophages in the brain. We found that the quantity of SIV-RNA+ cells in the heart was sparse compared to the brain. When detected, cardiac SIV-RNA+ cells are CD68+ and CD206+ cardiac macrophages. Levels of plasma soluble CD163 (sCD163) correlated with plasma galectin-3 (Gal-3), galectin-9, and interleukin-18 (IL-18), more so than plasma viral load. We then assessed cardiac tissues from PWLH with HIV encephalitis (HIVE) and HIV no encephalitis (HIVnoE). We found that PLWH with HIVE had more cardiac inflammation and fibrosis than PLWH with HIVnoE. These findings indicate that CVD and HAND pathogenesis are connected, and that the level of myeloid cell activation correlates with the development and severity of concomitant CVD and HAND. The findings from this study emphasize the importance that macrophages accumulation has in developing AIDS-related comorbidities. Our findings highlight the importance of targeting monocyte/macrophages activation and accumulation in future HIV therapies. The persistence of CVD in the post-ART era suggests that ART successfully inhibits AIDS pathogenesis and HIV replication, but fails to block monocyte activation and macrophages accumulation correlated with CVD pathogenesis. We hypothesize that the optimal therapeutic approach for HIV-infection includes blocking AIDS pathogenesis and viral replication, and inhibiting monocyte/macrophages activation. Methylglyoxal-bis-guanylhydrazone (MGBG) is a polyamine biosynthesis inhibitor selectively taken up by monocytes and macrophages. MGBG treatment blocks monocyte/ macrophages activation in vitro, AIDS pathogenesis, and decreases inflammation in cardiac and brain tissues of SIV- infected rhesus macaques. We asked whether animals treated with ART and adjunct MGBG (ART+MGBG) had an additive decrease in monocyte activation and turnover, cardiac macrophages inflammation and collagen deposition compared to animals on ART, and untreated animals (Chapter 3). We found that animals on ART+MGBG had lower percentages of cardiac collagen deposition than animals on ART. Animals on ART, and ART+MGBG did not develop AIDS, and had decreased cardiac inflammation and collagen, and monocyte activation and turnover compared to untreated animals. Finally, we identified two populations of Gal-3 expressing (Gal-3+) cells in the heart, CD163+ Gal-3+ cardiac macrophages and CD163- Gal-3+ cells. Animals on ART, and ART+MGBG had decreased numbers of CD163+ Gal-3+ cardiac macrophages compared to untreated animals. All animals had similar numbers of CD163- Gal-3+ cells, and low frequencies of SIV-RNA+ cardiac macrophages regardless of treatment. These data suggests that blocking AIDS pathogenesis with ART, and ART+MGBG correlates with decreased monocyte activation and cardiac inflammation and collagen deposition. Overall, we did not find an additive effect in animals on ART+MGBG compared to animals on ART. Our findings show how targeting monocyte/macrophages activation with ART+MGBG blocks AIDS pathogenesis and decreases cardiac macrophages inflammation. This study demonstrates the advantages of therapeutic strategies blocking myeloid cell activation in conjunction with ART. / Thesis (MS) — Boston College, 2024. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Biology.

No / Medicinal plants used to treat infectious diseases in Bunda district, Tanzania, were screened for activity against Plasmodium falciparum and human Immunodeficiency Virus Type 1 (HIV-1, IIIB strain) and Type 2 (HIV-2, ROD strain). Antiplasmodial activity was observed for the 80% MeOH extract of Ormocarpum kirkii (root; MIC = =31.25 ¿g/mL). Combretum adenogonium (leaves), Euphorbia tirucalli (root), Harrisonia abyssinica (root), Rhyncosia sublobata (root), Sesbania sesban (root), Tithonia diversifolia (leaves), and Vernonia cinerascens (leaves; MIC value of 62.5 ¿g/mL). With regard to HIV, 80% MeOH extracts of Barleria eranthemooides (root), Cambretum adenogonium (leaves and stem bark), Elaeodedron schlechteranum (stem bark and root bark), Lannea schweinfurthii (stem bark), Terminalia mollis (stem bark and root bark), Acacia tortilis (stem bark), Ficus cycamorus (stem bark) and Indigofera colutea (shoot), as well as H2O extracts from Barleria eranthemoides (root), Combretum adenogonium (leaves and stem bark)and Terminalia mollis (stem bark and root bark) exhibited IC50 values below 10 ¿g/mL against HIV-1 (IIIB strain). The highest anti-HIV-1 activity value was obtained for the B. eranthemoides 80% MeOH root extract (IC50 value 2.1 ¿g/mL). Only a few extracts were active against HIV-2, such as the 80% MeOH extract from Lannea schweinfurthii (stem bark) and Elaeodedron schlechteranum (root bark), showing IC50 values < 10 ¿g/mL.

No / BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) is considered to be less transmissible due to the fitness cost associated with drug resistance-conferring mutations in essential genes. OBJECTIVE: To test the hypothesis that TB drug resistance-conferring mutations with fitness cost are more frequent among human immunodeficiency virus (HIV) positive than among HIV-negative patients. DESIGN: We analysed all strains from the two TB drug resistance surveys conducted in Uganda between 2008 and 2011. Strains phenotypically susceptible to rifampicin and/or isoniazid were assumed to be wild-type; in all other cases, we performed whole-genome sequencing. Mutations at the rpoB531 and katG315 codons were considered without fitness loss, whereas other rpoB codons and non-katG were considered with fitness loss. RESULTS: Of the 897 TB patients, 286 (32.1%) were HIV-positive. Mutations with fitness loss in HIV-positive and HIV-negative patients were respectively as follows: non-531 rpoB: 1.03% (n = 3), 0.71% (n = 4) (OR 1.46, 95%CI 0.58-3.68); non-katG: 0.40% (n = 1), 1.0% (n = 6) (OR 0.40, 95%CI 0.07-2.20); rpoB531: 1.49% (n = 4), 0.69% (n = 4) (OR 2.29, 95%CI 0.83-5.77); katG315: 3.86% (n = 11), 2.55% (n = 15) (OR 1.54, 95%CI 0.81-2.90). The odds of mutations with and without fitness cost were higher for patients with a history of previous anti-tuberculosis treatment. CONCLUSIONS: Our data do not support the hypothesis that resistance-conferring mutations with fitness cost are likely to be often present in HIV-positive individuals.