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HIV/AIDS is a global health problem of immense magnitude, with 33 million people living with HIV and 2 million AIDS-related deaths per year. As the development of drug resistance undermines treatment efficacy, the long-term success of anti-retroviral therapy depends upon the introduction of novel drugs aimed at additional targets essential for the viral life cycle. With a critical role in many viral diseases including the proteolytic maturation of the HIV-1 envelope glycoprotein gp160, the secretory pathway proprotein convertases (PCs) represent a potential anti-viral target. Our laboratory has reported the identification of Spn4A, a potent naturally occurring secretory pathway serine protease inhibitor directed at the prototype PC member, furin. Because of the requirement for the PCs in the production of infectious HIV-1, we hypothesized that strategic manipulation of PC activity by Spn4A and Spn4A-engineered variants would provide a means of effectively limiting HIV-1 infection. This thesis details the investigation of the anti-proteolytic activities and anti-HIV-1 properties of recombinant adenoviruses expressing Spn4A and Spn4A bio-engineered variants, including a secreted recombinant Spn4A (Spn4A S). Our data shows that the expression of Spn4A S in MAGI-CCR5 cells and furin-deficient LoVo cells inhibited the PC-dependent processing of the HIV-1 envelope precursor gp160. Furthermore, inhibition of processing resulted in a nearly complete reduction of productive HIV-1 infection as determined by HIV-1 Tat-driven β-galactosidase activity and multinuclear activation of a galactosidase indicator (MAGI) assays. Complementing the previously described anti-furin activity of Spn4A, our studies indicate that Spn4A S inhibits additional PCs involved in gp160 maturation, and that PC inhibition can serve as an effective means of limiting HIV-1 infection. With the central role of the PCs in the replication and pathogenesis of numerous infectious agents, the identification of Spn4A S as an efficacious HIV inhibitor establishes Spn4A as a prospective broad-based agent for the inhibition of PC-related diseases.

Background: A third of HIV-infected patients are co-infected with HCV in the developed world, and more of co-infected patients than ever before are dying because of liver related diseases today. Drug-related hepatotoxicity is a growing concern among human immunodeficiency virus (HIV) / hepatitis C virus (HCV) co-infected population. Nucleotide analogues containing HIV antiretroviral therapy, namely highly active anti-retroviral therapy (HAART), can induce mitochondrial toxicity. However, little is known about the effect of nucleotide analogues on the liver at the cellular and molecular level, and how it may affect treatment. Objective: To investigate whether liver tissue from HIV/HCV co-infected individuals will show greater liver mitochondrial toxicity if currently receiving antiviral HIV medication, compared to those who are not taking it. Methods: Liver biopsies were collected from 23 HIV/HCV co-infected males. Fourteen patients were on stable HAART (ON-HAART) and 9 were OFF-HAART, including 4 who stopped HAART >6 months prior and 5 who were HAART-nave. Liver mitochondrial toxicity was assessed by transmission electron microscopy-based quantitative stereological analyses of hepatocyte and mitochondrial morphometry, as well as by mitochondrial DNA (mtDNA) and mtRNA (COX1/(ß-actin) real-time-PCR quantification. Results: Hepatocytes tended to be larger in the ON-HAART group than in the OFF-HAART group (p=0.05), but they both showed similar mitochondrial volume fraction of the cell and mitochondrial crista density. Liver mtDNA and mtRNA levels were not significantly differentbetween ON-HAART and OFF-HAART. Hepatocyte lipid accumulation was significantly higher in HCV genotype 3 compared to genotype 1 infection ()=0.002), but was not associated with HAART status. Conclusions: We found no evidence or trend of increased mitochondrial toxicity in HIV/HCV co-infected individuals currently on HAART compared to those who are not. This finding could be relevant to the decision-making process with respect to initiating HCV therapy in this population.

Introduktion: HIV-infektion medför en kronisk och progressiv sjukdom som, i obehandlad form, leder till en successiv försämring av immunförsvaret och utvecklandet av AIDS. Syfte: Att vid två lärosäten undersöka sjuksköterskestudenters kunskaper om HIV och inställningen till behovet av HIV-testning. Metod: En empirisk tvärsnittsstudie med deskriptiv och komparativ design med kvantitativ ansats. Genomförd som enkätstudie bland studenter vid Högskolan i Gävle och Uppsala Universitet (N=95), som studerade på sjuksköterskeprogrammets tredje år. Resultat: Majoriteten (88,4 %) angav korrekt att samlag med fler än en partner ökar risken att smittas med HIV. Tre studenter (3,2 %) angav felaktigt att det finns ett vaccin mot HIV-infektion. Nästan hälften (42,1 %) saknade kunskap om att glidmedel, tillsammans med kondom, inte minskar risken för HIV-smitta. En majoritet (78,9 %) rekommenderade ett HIV-test till en kvinna som haft oskyddat sex med en man. I studenternas motiveringar till behovet av ett HIV-test, framkom fyra kategorier; ”risk”, ”sexualvanor”, ”patientens oro” och ”ovisshet”. Konklusion: Sjuksköterskestudenterna hade relativt goda kunskaper om HIV. Däremot fanns betydande brister i vissa frågor. Sjuksköterskestudenternas inställning till HIV-testning överensstämmer relativt väl med gällande riktlinjer. Däremot finns ett behov att förändra ett förlegat riskgruppstänkande för att kunna ge patienter rådgivning i enlighet med den senaste kunskapen. / Introduction: HIV-infection is a chronic and progressive disease that, left untreated, leads to a deterioration of the immune system and the development of AIDS.  Aim: To examine nursing students´, at two universities, knowledge about HIV and their attitude towards assessing the need for a HIV-test. Method: An empirical cross-sectional study using descriptive and comparative design with a quantitative approach. Data was collected by a questionnaire among third year nursing students at the University of Gavle and Uppsala University (N=95). Result: A majority (88,4 %) answered correctly that intercourse with more than one partner increases the risk for contracting HIV. Three students (3,2 %) answered incorrectly that there is a vaccine for HIV. Nearly half of the students did not know that lubricant, combined with a condom, does not reduce the risk for contracting HIV. A majority (78,9 %) recommended a HIV-test to a woman who have had unprotected sex with a man. In analyzing the students´ explanatory statements for the need for a HIV-test, four categories emerged; “risk”, “sexual behavior”, “patients´ concern” and “not knowing”.   Conclusion: The nursing students had relatively good knowledge about HIV. However, there was a significant lack of knowledge in some questions. The nursing students´ attitudes towards HIV-testing conforms relatively well with current guidelines. However, there is a need to change an outdated way of assessing the risk for HIV-infection to be able to provide counseling to patients based on current knowledge.

The present study investigated the longitudinal relationships between traditional, non-traditional, HIV and HAART-related risk factors and dyslipidemia in people who are living with HIV living in Nova Scotia. A total of 303 men and 39 women who were patients of the Halifax HIV clinic with at least two measurements of: total cholesterol, low density lipoprotein- cholesterol (LDL-C), high density lipoprotein- cholesterol (HDL-C) or triglyceride concentration, taken between 1997 and 2009 were included in this study. Univariate repeated measures linear mixed effects regression models were developed for men and women separately and multivariate models were developed for men. BMI, produced a significant independent effect on total cholesterol to HDL-C ratio in men living with HIV. Hepatitis C co-infection, a history of injection drug use, and viral load (copies HIV RNA/ ml blood), all found to produce significant independent effects on HDL-C concentration among men living with HIV.

Rates of female Human Immunodeficiency Virus (HIV) infection continue to rise despite the existence of effective methods of prevention. What is the fundamental variable acting as a barrier to women’s self-protection? Researchers have suggested that the oppression of women increases their vulnerability to HIV infection, and that the relationship between oppression and HIV infection must be examined to effectively address this public health issue. The purpose of this research was to gain greater insight into the life experiences of women with HIV, in order to clarify whether or not women with HIV have, indeed, experienced oppression. Answering this question was necessary prior to the study of the relationships between oppression and subsequent female HIV infection. Women, age 18 years of age or older, who live in Canada, are proficient at speaking English and HIV positive were recruited to this phenomenological study and each participant was asked to tell their “life story”. The findings of this study provide support for the ongoing use of both the oppression framework and feminist perspective in future research. Future studies may include replication of this study in partnership with women with HIV and other academic/community organizations, as well as further analysis of the use of both the Theory of Gendered Power and Social Dominance Theory/Four Bases of Gendered Power in addressing female vulnerability to HIV. / Thesis (Master, Nursing) -- Queen's University, 2010-08-31 10:23:53.052

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The great adaptability of the Human Immunodeficiency Virus type 1 (HIV-1) and the exclusive use of zidovudine (3$ sp prime$azido-3$ sp prime$deoxythymidine or AZT) in the treatment of AIDS has motivated our search for HIV-1 strains resistant to this drug. / Our first attempt at obtaining such strains was made by using an in vitro approach in which a lymphoid cell line, chronically infected with HIV-1, was exposed to various drug concentrations. Although this system has never generated such mutants, we found that the progeny virus population, present in the culture fluids of these chronically infected drug-treated cells lost infectivity. These results suggest a potential post-integrational role for zidovudine, possibly acting at the level of viral assembly or budding. / However, we were successful in isolating zidovudine-resistant HIV-1 strains from the blood of patients undergoing AZT treatment. Our work shows that a minimum of 27 weeks of treatment is necessary for the appearance of the resistant phenotype and that the majority (75%) of patients treated with AZT for more than one year will generate such resistant strains. No correlation between the clinical status of the patients and the occurrence of resistant variants can be drawn from our work. However, in vitro experiments have shown that the resistant isolates are more cytopathic, although less infectious, than the sensitive strains. Reverse transcriptase enzymes from both AZT-resistant and -sensitive strains were virtually identical when their respective enzymatic activities or their affinity for the substrate or the inhibitor were compared. Finally, some zidovudine-resistant isolates demonstrate cross-resistance to other nucleoside analogs with potential clinical applications.

A group of five HIV-positive gay men were compared with a group of five HIV-negative gay men. All participants were currently engaged in therapy. Participants completed the Session Evaluation Questionnaire (SEQ) and the Session Impacts Scale (SIS) in order to determine what these different groups of individuals felt was helpful or hindering in therapy. Results indicated that both groups of participants found therapy to be powerful, valuable, and helpful in that they: (a) learned something new about themselves or others, (b) changed their ways of thinking, (c) acquired insight into issues, (d) were more clear about their feelings, (e) were able to define their problems, and (f) were feeling understood, supported, and close to their counsellor. In comparison to the HIV-negative group, the HIV-positive group experienced many hindering aspects to counselling. Seropositive participants felt: (a) less understood, supported, and close to their counsellor, (b) more confused, or distracted in counselling, (c) more bothered by unpleasant thoughts in counselling, (d) more impatient or doubting of the value of therapy, and (e) felt more angry, more afraid, and less confident during and as a result of therapy. Implications for counselling are discussed.

Background. Numerous methods have been developed to model longitudinal data. In HIV/AIDS studies, HIV markers, CD4+ count and viral load are measured over time. Informative drop-out and the lower detection limit of viral load assays can bias the results and influence assumptions of the models. Objective The objective of this thesis is to describe the evolution of HIV markers in an HIV-1 subtype C acutely infected cohort of women from the CAPRISA 002: Acute Infection Study in Durban, South Africa. They were HIV treatment naive. Methods. Various linear mixed models were fitted to both CD4+ count and viral load, adjusting for repeated measurements, as well as including intercept and slope as random effects. The rate of change in each of the HIV markers was assessed using weeks post infection as both a linear effect and piecewise linear effects. Left-censoring of viral load was explored to account for missing data resulting from undetectable measurements falling below the lower detection limit of the assay. Informative drop- out was addressed by using a method of joint modelling in which a longitudinal and survival model were jointly linked using a latent Gaussian process. The progression of HIV markers were described and the effectiveness and usefulness of each modelling procedure was evaluated. Results. 62 women were followed for a median of 29 months post infection (IQR 20-39). Viral load increased sharply by 2.6 log copies/ml per week in the first 2 weeks of infection and decreased by 0.4 log copies/ml per week the next fortnight. It decreased at a slower rate thereafter. Similarly CD4+ count fell in the first 2 weeks by 4.4 square root cells/ul per week then recovered slightly only to decrease again. Left-censoring was unnecessary in this acute infection cohort as few viral load measures were below the detection limit and provided no improvement on model fit. Conclusion. Piecewise linear effects proved to be useful in quantifying the degree at which the HIV markers progress during the first few weeks of HIV infection, whereas modelling time as a linear effect was not very meaningful. Modelling HIV markers jointly with informative drop-out is shown to be necessary to account for the missing data incurred from participants leaving the study to initiate ARV treatment. In ignoring this drop-out, CD4+ count is estimated to be higher than what it actually is. / Thesis (M.Sc.)-University of KwaZulu-Natal, Pietermaritzburg, 2009.