Orientador: Pablo Agustin Vargas / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba / Made available in DSpace on 2018-08-22T04:22:01Z (GMT). No. of bitstreams: 1 Carvalho_MariannedeVasconcelos_D.pdf: 5637293 bytes, checksum: 2a8eb0432fb9178c3131d66c7baf68f0 (MD5) Previous issue date: 2013 / Resumo: A síndrome da imunodeficiência adquirida (AIDS) é causada pelo vírus da imunodeficiência humana (HIV). A infecção já acometeu mais de 60 milhões de pessoas em todo o mundo e 25 milhões de mortes. Apesar dos progressos que a comunidade internacional obteve, a AIDS ainda é uma epidemia global e constitui um dos principais problemas de saúde pública mundial. À luz dessa afirmação, este trabalho se fundamenta na abordagem das manifestações dos pacientes com AIDS, dando foco a dois tópicos relativamente distintos, porém de bastante relevância. O primeiro deles se baseia na descrição inédita da diversidade morfológica do sarcoma de Kaposi oral (SKO), o qual é umas das manifestações mais comuns associadas ao HIV, com frequente envolvimento oral. Realizamos um estudo retrospectivo de 135 casos de SKO presentes nos arquivos da Universidade de Pretoria, África do Sul. Após a revisão histológica, o SKO foi classificado em 7 categorias com base no padrão predominante de crescimento, tais como: sólido, limfangioma-like, telangiectásico, desmoplásico, linfangiectatico, equimótico e anaplásico. O significado prognóstico dessas variantes ainda precisará ser determinado, e o reconhecimento da diversidade morfológica do SKO é essencial para evitar erros diagnósticos. Em relação ao segundo capítulo, analisamos 100 tireoides obtidas de autópsias de pacientes com AIDS do Departamento de Patologia da Faculdade de Medicina da Universidade de São Paulo. Os casos foram analisados sistematicamente, a fim de determinar a frequência e as principais patologias presentes nesta glândula. Micobacteriose foi à infecção mais frequente, seguida por citomegalovírus (CMV) e criptococose. Envolvimento da glândula tiróide ocorreu geralmente como uma parte da disseminação da doença. Os médicos devem ter atenção especial para a detecção de sinais precoces de doenças na tireoide, que podem ser confundidos com sintomas gerais de manifestações da AIDS / Abstract: The acquired immunodeficiency syndrome (AIDS) is caused by the human immunodeficiency virus (HIV). The infection has affected more than 60 million people around the world and over 25 million deaths. Despite the progress of the international community, AIDS is still a global epidemic and is a considerable public health problem worldwide. Due to this, this work is based on the approach of the manifestations of AIDS patients, focusing to two relatively distinct topics, but too much relevant. The first description is based on the unpublished morphological diversity oral Kaposi's sarcoma (OKS), which is one of the most common HIV manifestations, with frequent oral involvement. We performed a retrospective study of 135 cases of OKS retrieved from the archives of the University Of Pretoria, South Africa. After histological review, the OKSs were classified into 7 categories based on the predominant pattern of growth, such as solid, lymphangioma-like, telangiectatic, desmoplastic, lymphangiectatic, ecchymotic, and anaplastic. Although the prognostic significance of these variants is yet to be determined, the appreciation and recognition of such morphologic diversity remains essential in distinguishing these lesions from possible mimickers. Regarding the second chapter, we analyzed 100 thyroid obtained from autopsies of patients with AIDS, Department of Pathology, Faculty of Medicine, University of São Paulo. The cases were systematically analyzed in order to determine the frequency and the main pathological features of the gland. Mycobacteriosis infection was the most frequent, followed by cytomegalovirus (CMV) and cryptococcosis. Involvement of the thyroid gland usually occurred as a part of dissemination of the disease. Physicians should pay special attention to the early signs of thyroid disease, which can be misdiagnosed with symptoms of general manifestations of AIDS / Doutorado / Patologia / Doutora em Estomatopatologia

A research report submitted to the School of Public Health, University of the Witwatersrand in partial fulfillment of the requirements for the degree of Master of Public Health. June 2018. / Introduction Southern Africa forms the epicentre of the HIV epidemic and young people commonly get diagnosed long after infection. Despite the evidence that HIV Counselling and Testing (HCT) can reduce risky sexual behaviors and prevent HIV, uptake of testing in young people remains limited and this is especially true in Southern Africa. In the last few years, effective interventions for HIV prevention have been implemented, including treatment as prevention and pre-exposure prophylaxis. In the context of very high prevalence of HIV among young people in Southern Africa, it is critical that countries attain higher levels of HCT. Demand creation is one of the means to increase uptake of HCT. This study investigated the relationship between exposure to a mass media campaign and uptake of HIV counselling and testing among young people in five countries of Southern Africa (Lesotho, Mozambique, South Africa, Swaziland and Zambia) for the period 2008 to 2012. A secondary data analysis from a multi-country study was undertaken. Methods: Secondary data on young people aged 15-24 years from a post-only cross-sectional observational multi-country study that was undertaken in 2012 to evaluate the One Love Campaign, a regional behavior change media campaign coordinated by Soul City Institute for Development Communication was undertaken. The exposure variable was exposure to One Love campaign (in the form of television film series; locally produced radio drama series, television public service announcements and a television series in South Africa. In other participating countries the programme also comprised talk shows broadcast by national- and community broadcasters; booklets, billboards used to trigger discussion during community dialogues and community outreach events) with the outcome of interest being HIV testing, with a number of covariates such as socio-demographic characteristics (e.g age, education level, nationality, sex, marital status, socio-economic status (defined as wealth quintile), whether respondent had children or not, and country of residence. Bivariate and multivariate analysis was conducted to establish the relationship between exposure to One Love campaign and HIV testing among the study population. Results: A total of eight-thousand-six-hundred and thirteen young people (n=8613) participated in the study. There was nearly equal distribution of respondents between those that had had an HIV test (52.0%) and those that had not (48.0%). Exposure to One Love through multiple media, was positively associated with HIV testing (aOR=2.34, 95% CI 1.94-2.81), and there was a dose response. Other factors associated with having an HIV test included being female (aOR= 1.95, 95% CI 1.75 - 2.18); having living child (aOR=4.23, 95% CI 3.57-5.01); being the aged 18-20 years (aOR=2.24, 95% CI 1.95 - 2.58) or group 20-24 years (aOR=4.14, 95% CI 3.57 - 4.81) and having secondary or tertiary education ( aOR= 2.67, 95% CI 1.92 - 3.68). Increased wealth until quintile 4 was negatively associated with having an HIV test, (aOR= 0.93, 95% CI 0.77 - 1.12). Conclusion: Overall the findings of this study show that exposure to more than one medium in the campaign has greater odds of testing. The results of this study provide important information on the relationship between exposure to a media campaign and HIV testing among young people. Social and behaviour change communication strategies that use multi-media are necessary to achieve improved HIV testing among young people. / LG2018

Thesis (Ph. D.)--University of Texas at Austin, 2007. / Vita. Includes bibliographical references.

Thesis (Ph. D.)--University of Washington, 1998. / Vita. Includes bibliographical references (leaves [135]-143).

Thesis (Ph. D.)--University of Hawaii at Manoa, 2005. / Includes bibliographical references (leaves 207-219).

Thesis (Ph. D.)--University of California, San Diego and San Diego State University, 1997. / Vita. Includes bibliographical references (leaves 116-132).

Thesis (M.S.)--University of Montana, 2006. / Mode of access: Internet. Title from title screen. Description based on contents viewed Dec. 6, 2006. Includes bibliographical references (p. 156-160).

HIV-2 is a contemporary human retrovirus with the majority of infections localised to West Africa. Both HIV-1 and HIV-2 are able to cause AIDS; however, in contrast to HIV-1 infection, a common outcome following HIV-2 infection (∼ 37% of patients in this study cohort) is long-term non-progression (LTNP), where patients remain aviraemic and asymptomatic in the absence of treatment, often for decades. HIV-1 and HIV-2 both arose following zoonotic transmission of SIVs from non-human primates at around the beginning of the 20^th century and when patients develop AIDS caused by HIV-2 infection, it is clinically indistinguishable from AIDS following HIV-1 infection. Whilst the estimated number of HIV-2 infections remains small in the context of the global HIV pandemic (HIV-2 ∼ 2 million, HIV-1 group M ∼75 million), the differences in pathogenicity between these two viruses has been a source of great interest, particularly the features of LTNPs that allow control of viral replication in the absence of anti-retroviral treatment. The studies described in this thesis were carried out using samples collected from a well-characterised longitudinal community cohort in Caió, Guinea-Bissau. Chapter 3 of this thesis presents an investigation into the variation and evolution present in the HIV-2 specific accessory gene vpx. The data showed significantly increased signals of positive selection pressure in vpx in viraemic when compared to non-viraemic patients and also allowed the identification of novel variations at high frequencies (up to 22%) in this cohort that were previously un-described. Chapters 4 and 5 present a novel application of shotgun RNA sequencing (RNA- Seq) to HIV ex vitro and ex vivo samples. Chapter 4 demonstrates the divergence seen in a cultured viral isolate at the level of the whole genome, in the absence of many of the biases typically involved in sequencing of RNA viruses. Chapter 5 further extends this method to show the applicability of using RNA-Seq on primary patient HIV samples for the first time. Analysis of diversity estimates over the whole genome in the context of a low bias sequencing method show a high level of diversity in HIV-2 pol and low diversity in vpx. The aim of this work was to combine traditional and novel sequencing methods to facilitate assessment of the variation and evolution acting on vpx and to generate an accurate picture of the genetic diversity over the whole genome of HIV-2.

The development of a safe, effective prophylactic HIV vaccine remains a major global health priority. Stabilized, soluble trimers that mimic the native functional HIV trimer have been developed that elicit strain-specific neutralizing HIV antibodies in animal models, and are currently being evaluated in several human clinical trials. Identifying whether multiple immunogens could be administered to facilitate the broadening of responses represents a pivotal challenge. In this thesis, we characterized the antibody response in individuals infected with multiple HIV strains to inform the development of polyvalent and sequential HIV vaccine regimens. We found that conventional approaches to detect HIV co- and superinfection are confounded by recombination. Therefore, we developed an automated, Bayesian approach to detect superinfection explicitly accounting for recombination. Using simulated and real sequence data, we demonstrated that this approach is sensitive, highly specific, and robust to recombination. Furthermore, analyzing previously published sequence datasets, we identified cases of superinfection that previously went undetected, indicating that superinfection occurs more frequently than previously estimated. We characterized the development of antibodies in five superinfected individuals identified in the CAPRISA 002 acute infection cohort. Specifically, we evaluated whether superinfection re-engaged cross-reactive memory B cells, promoting the development of cross-neutralizing antibodies. By comparing the breadth of the neutralizing antibody response in superinfected individuals to those that typically develop in singly infected individuals, we showed that HIV superinfection was not sufficient to broaden responses. By characterizing the kinetics and specificity of autologous neutralizing antibody responses, we show that responses to the superinfecting viruses failed to efficiently recruit neutralizing memory B cells. Instead, the secondary infection elicited strain-specific, de novo responses. This occurred even though the superinfecting viruses were relatively closely related (from the same subtype). To determine whether the co-exposure to diverse Env antigens favours the development of cross-neutralizing antibodies better than sequential exposure, we characterized the development of neutralizing antibodies in HIV co-infected individuals where several divergent viruses were transmitted prior to seroconversion. We identified three cases of co-infection that encompassed immunological exposure to: (i) two diverse, unlinked Envs, (ii) two related Envs with diversity uniformly distributed over the trimer, and (iii) two diverse but recombined Envs such that clusters of high homology were preserved in the presence of high diversity elsewhere. We found that, like superinfection, co-infection was not sufficient to broaden neutralizing antibody responses. Co-exposure to two HIV Env antigens did not necessarily produce additive or cross-neutralizing antibody responses, and in some cases was subject to immunological interference. This was most evident in the case of co-infection with two related Envs where diversity was uniformly distributed across the Env trimer; in this case neutralizing antibody responses to one variant arose to the near exclusion of responses to the other. However, in the case of co-exposure to diverse Envs but where the trimer apex was conserved in both variants through recombination, potent neutralization of both variants was evident. This was the co-infected participant who developed the broadest neutralizing antibody response, and we show that cross-neutralization was mediated, in part, by trimer apextargeting neutralizing antibodies. In conclusion, we find that HIV superinfection fails to efficiently recruit neutralizing memory B cells and, at best, results in additive nAb responses rather than a synergistic effect leading to cross-neutralization; a distinction that is highly relevant for vaccine design. While sequential immunizations with heterologous Env immunogens may be able to improve the potency of elicited responses, alone, they are unlikely to promote the development of bnAbs. Our observations from cases of co-infection suggests that cocktails of divergent stabilized Env trimers are unlikely to drive the development of cross-neutralizing antibodies, and may be subject to interference. However, the rational design of more similar immunogen cocktails where conserved epitopes are preserved across immunogens may be able to facilitate neutralizing antibodies to these targets, as seen in one individual. Thus, the use of related, stabilized Env trimers with diversity introduced in key regions together with strategies to reduce the immunogenicity of immunodominant, strain-specific epitopes may represent one path to a cross-neutralizing antibody response to multiple Envs within a cocktail.

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