Although, in the United States HIV infectivity has increased, survival rates have also improved due to highly active antiretroviral therapies (HAART). Adherence to HAART successfully prevents the progression of AIDS and AIDS-related morbidity for many living with HIV. Unfortunately, HAART’s permeability into the central nervous system (CNS) is limited; thus, the prevalence of HIV-associated neurocognitive disorders (HAND) still persists. The health belief model (HBM) is the theory often used to explain and predict behavior in relation to chronic illness. This model incorporates perceptions of susceptibility, vulnerability, and severity towards a particular illness, and beliefs regarding perceived efficacy and benefits of treatment. This study expands the existing model. Many who live with HIV have a long history of negative experiences, such as stigmatization, traumatic events, and discrimination. I examined supplementary psychosocial and physiological predictor variables, such as stigma, trauma, ethnicity, general medical conditions, HIV-opportunistic infections, and falls; all relevant to disease progression in HIV. Previous researchers found links between stigma and immune function, trauma and memory, ethnicity and neuropsychological impairment, and symptom load and CNS-related alterations. Therefore, this study examined how these different psychosocial predictor variables are associated with HIV-related neurocognitive impairment. My model explained 38.6% of the variance in the outcome variable, and I found that trauma (B = -.15, OR = .87; CI 95% = .75, 1.0, p = .05), ethnicity (B = 2.2, OR = 9.0, CI 95% = 1.68, 48.48, p =.01), general medical conditions (B = .30, OR = 1.34; CI 95% = 1.0, 1.81, p = .05), and falls (B = 2.0, OR = 7.2; CI 95% = 1.1, 47.0, p = .04), were all significant predictors of HIV-related neurocognitive impairment. However, contrary to my hypothesis, HIV-related opportunistic infections and HIV-related stigma were not significant predictors of HIV-related neurocognitive impairment. I hope that my results will contribute to revisions of older health models as well as suggest avenues for primary and secondary prevention and intervention to address those living with HIV/AIDS.

The prevalence of milder forms of HIV-associated neurocognitive disorders (HAND) is rising despite combination antiretroviral therapy (cART). Efavirenz (EFV) is among the most commonly used antiretroviral drugs globally, but causes neurological symptoms that may interfere with adherence and reduce tolerability, and may have central nervous system (CNS) effects that contribute in part to HAND in patients on cART. Thus we evaluated a commonly used EFV containing regimen: EFV/zidovudine (AZT)/lamivudine (3TC) in murine N2a cells transfected with the human “Swedish” mutant form of amyloid precursor protein (SweAPP N2a cells) to assess for promotion of amyloid-beta (Aβ) production (Chapter 3). Treatment with EFV or the EFV containing regimen generated significantly increased soluble Aβ, and promoted increased β-secretase-1 (BACE-1) expression while 3TC, AZT, or, vehicle control did not significantly alter these endpoints. Further, EFV or the EFV containing regimen promoted significantly more mitochondrial stress in SweAPP N2a cells as compared to 3TC, AZT, or vehicle control. We next tested the EFV containing regimen in Aβ - producing Tg2576 mice combined or singly using clinically relevant doses. EFV or the EFV containing regimen promoted significantly more BACE-1 expression and soluble Aβ generation while 3TC, AZT, or vehicle control did not. Finally, microglial Aβ phagocytosis was significantly reduced by EFV or the EFV containing regimen but not by AZT, 3TC, or vehicle control alone. These data suggest the majority of Aβ promoting effects of this cART regimen are dependent upon EFV as it promotes both increased production, and decreased clearance of Aβ peptide. Further (Chapter 4), there is evidence that neural stem cells (NSCs) can migrate to sites of brain injury such as those caused by inflammation and oxidative stress, which are pathological features of HAND. Thus, reductions in NSCs may contribute to HAND pathogenesis. Since the HIV non-nucleoside reverse transcriptase inhibitor EFV has previously been associated with cognitive deficits and promotion of oxidative stress pathways, we examined its effect on NSCs in vitro as well as in C57BL/6J mice. Here we report that EFV induced a decrease in NSC proliferation in vitro as indicated by MTT assay, as well as BrdU and nestin immunocytochemistry. In addition, EFV decreased intracellular NSC adenosine triphosphate (ATP) stores and NSC mitochondrial membrane potential (MMP). Further, we found that EFV promoted increased lactate dehydrogenase (LDH) release, activation of p38 mitogen-activated protein kinase (MAPK), and increased Bax expression in cultured NSCs. Moreover, EFV reduced the quantity of proliferating NSCs in the subventricular zone (SVZ) of C57BL/6 mice as suggested by BrdU, and increased apoptosis as measured by active caspase-3 immunohistochemistry. If these in vitro and in vivo models translate to the clinical syndrome, then a pharmacological or cell-based therapy aimed at opposing EFV-mediated reductions in NSC proliferation may be beneficial to prevent or treat HAND in patients receiving EFV. 1 Portions of this abstract have been previously published (Brown LAM, et al., 2014; Jin, J, et al, 2016) and are utilized with permission of the publisher.1

京都大学 / 0048 / 新制・論文博士 / 博士(医学) / 乙第13372号 / 論医博第2209号 / 新制||医||1047(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 花川 隆, 教授 髙橋 良輔, 教授 小柳 義夫 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Submitted by Claudia Cristina de Góes null (claudia_crgoes@hotmail.com) on 2016-10-25T00:07:10Z No. of bitstreams: 1 Dissertação versão final_claudia_c_goes.pdf: 2050683 bytes, checksum: 70e8dfcecbdd00db785d6e0d61886ba7 (MD5) / Approved for entry into archive by Juliano Benedito Ferreira (julianoferreira@reitoria.unesp.br) on 2016-10-31T13:53:47Z (GMT) No. of bitstreams: 1 goes_cc_me_bauru.pdf: 2050683 bytes, checksum: 70e8dfcecbdd00db785d6e0d61886ba7 (MD5) / Made available in DSpace on 2016-10-31T13:53:47Z (GMT). No. of bitstreams: 1 goes_cc_me_bauru.pdf: 2050683 bytes, checksum: 70e8dfcecbdd00db785d6e0d61886ba7 (MD5) Previous issue date: 2016-06-03 / A estimativa de pessoas vivendo com HIV/AIDS é de 734mil, a maior concentração de casos é na população com idade entre 25 e 39 anos desde 1980 até junho de 2014. Devido à supressão do sistema imune e queda do número de células de defesa CD4, o paciente pode ser acometido por alterações no funcionamento fisiológico e por doenças oportunistas, incluindo as manifestações neurológicas, como os transtornos neurocognitivos associados ao HIV (HAND; HIV-associated neurocognitive disorders). Pessoas com HAND geralmente apresentam comprometimento da aprendizagem e das habilidades motoras, alterações de humor e déficits nos domínios cognitivos, os quais são classificados conforme a gravidade como leve, moderada ou grave e podem comprometer a adesão ao tratamento com antirretrovirais e à qualidade de vida. Contudo, a relação entre estas variáveis, cruciais para a sobrevivência do paciente, não se encontra estabelecida, sendo o envelhecimento uma das variáveis a esclarecer. Objetivou-se traduzir e adaptar o instrumento Simplified Medication Adherence Questionnaire (SMAQ); avaliar e comparar diferenças do desempenho cognitivo entre dois grupos em função da idade e identificar relações entre Qualidade de Vida e adesão à Terapia Antirretroviral combinada. Foram avaliados 50 voluntários com idades entre 21 e 58 anos e divididos em dois grupos (jovens e maduros) que participaram do protocolo completo, composto por testes cognitivos (domínios cognitivos: atenção, memória, linguagem e inteligência) e escalas de rastreio de depressão, ansiedade, uso de drogas psicoativas, adesão ao tratamento e qualidade de vida e situação socioeconômica. Como resultados, foram encontradas diferenças significativas entre os grupos nos seguintes domínios cognitivos: memória episódica, memória operacional, linguagem, processamento visuoespacial e função sensório-motora, tornando possível observar a influência da idade sobre o comprometimento cognitivo em pessoas vivendo com HIV. / In Brazil, 734,000 people are currently estimated to live with HIV / AIDS, and most cases concentrate in the 25 to 39 year-old population born from 1980 to June 2014. Due to suppression of immune system and fall in the number of CD4 T immune cells, a patient may be affected by changes in physiologic functioning and opportunistic diseases, including neurological manifestations such as HIV-associated neurocognitive disorders (HAND). People with HAND usually present learning and motor skills impairments, mood changes, and deficits in cognitive domains, which are classified according to gravity as mild, moderate or severe and may compromise adherence to antiretroviral therapy and quality of life. However, the relation between those variables, which are critical to a patient’s survival, has not been established yet, and aging is a variable to be clarified. The objective of this study was to translate and to adapt the Simplified Medication Adherence Questionnaire (SMAQ) to Brazilian Portuguese; to evaluate and to compare differences in cognitive performance between two groups according to age; and to identify and to compare relations between quality of life and adherence to cART (Combination Antiretroviral Therapy) In this study, 50 volunteers, aged from 21 to 58 years old, were assessed and divided into two groups (young adults and mature). Both groups took part of the full protocol, composed by cognitive tests (cognitive domains: attention, memory, language, and intelligence) and screening scales for depression, anxiety, use of psychoactive drugs, treatment adherence and quality of life, and socioeconomic status. As a result, significant differences between the groups were found in the following cognitive domains: episodic memory, working memory, language, visuospatial processing and sensory-motor function, which made it possible to observe age influence on the cognitive impairment of people living with HIV.