archives@tulane.edu / The prevalence of HIV-associated neurocognitive disorders (HAND) has increased in the era of combination anti-retroviral therapy (cART). Despite this and documented neurocognitive impairment, there is a lack of pathology of HIV-encephalitis (HIVE), specifically multi-nucleated giant cells (MNGCs), in children and SIV-encephalitis (SIVE) in rhesus macaques infected pre-, peri-, and post-parturition. In this dissertation, we show that the lack of MNGCs seen is most likely due to innate differences in the blood-brain and blood-CSF barriers, and a robust pro- and anti-inflammatory response in neonatal rhesus macaques. Using a rhesus macaque model of HIV, we examined the plasma viral load, brain tissue viral load, and monocyte turnover, using PCR and flow cytometry, respectively. We also performed immunohistochemistry for monocyte, macrophage, tight junction, and aging markers of the choroid plexus. We sought to create a choroid plexus epithelial cell model to monitor the effects of inflammatory markers and virus on the tight junctions of the blood-CSF barrier in real-time. We demonstrated that neonates do not develop encephalitis, despite comparable viral load and monocyte turnover, previously established correlates of SIV-encephalitis (SIVE). However, we noted that uninfected adult rhesus macaques have an increase in virus susceptible cells in the brain, SIV-infected adults have a leakier blood-brain barrier than infected neonates, and adults with encephalitis have a greater viral burden in brain tissue compared to adults without encephalitis. In the choroid plexus, we discovered that despite the lack of encephalitis, neonates have an increase in monocytes and macrophages of the choroid plexus, indicating a strong immune response. While our choroid plexus epithelial cell model is still in preliminary stages, initial results are promising. Our work indicates a possible viral threshold needed for the development of encephalitis, and that the blood-brain barrier may play a role in this threshold due to lower levels of virus susceptible cells and a tighter blood brain barrier in neonates. In the choroid plexus, the strong pro- and anti-inflammatory macrophage response seen in neonates may offer an extra layer of protection development of SIVE. Our data also indicates that SIV causes a marked decrease in the expression of klotho, the anti-aging hormone that is produced in high levels in the choroid plexus in the brain. This could potentially explain the premature inflammaging phenotype seen in chronic infections. / 1 / Elizabeth Delery

Includes bibliographical references (p. 89-103). / This dissertation serves as a discursive exploration into the underdiscussed topic of heterosexual anal sex and pervading penile-vaginal heteronormativity. To understand the origins and character of the seemingly universal ambivalence towards heterosexual anal intercourse I attempt to situate it historically. There is general ignorance concerning the prevalence of this sexual behaviour, but there exist deep-seated taboos and undertones of immorality and abnormality associated with it. All these factors play a part in individual sexual decision making; an attempt is made at exploring the motivations and personal choices that culminate in an act of heterosexual anal intercourse.

Includes bibliographical references. / Do discourses of "hope" have real and practical consequences when it come to crucial issues such as policy, prevention, stigma, risk perception or funding? The following exploratory and treansdisciplinary study seeks to pull together a wide variety of the theoretical and analytical stances in order to examine the social construction of hope in the context of HIV/AIDS in South Africa. the theoretical framework is built from a base of cultural theory, discourse analysis and theology, and binds these together into a transdisciplinary argument.

abstract: Human Immunodeficiency Virus (HIV) remains a persistent problem around the world, even though antiretroviral therapy has shown to be effective in reducing viral load and limiting transmission of the virus. Due to HIV’s infectious nature, visibility, the populations at risk, and its connections to race, class, and sexuality, it is more stigmatized than any other illness. HIV stigma has been associated with increased depression, social isolation, and poor psychological adjustment. HIV stigma can influence disclosure and care-seeking behavior. Internet-based interventions have shown to be effective in increasing knowledge on STIs and HIV, however, researchers have tested strategies that include educating participants on HIV to reduce stigma and have found that informational approaches alone are not effective. There is evidence that emotional intelligence and empathy are associated with prosocial behavior and influence attitudes towards stigmatized groups. Thus, this thesis aims to test an online intervention using an informational video from the Center for Disease Control and Prevention (CDC) in combination with an empathy-generating component to reduce stigma. It was hypothesized that the online intervention would increase HIV knowledge scores (H1), but stigma will only be reduced in the group introduced to the empathy-inducing component (H2) and those with high emotional intelligence would show the greatest reduction in stigmatizing attitudes (H3). Results did not support these hypotheses, suggesting that the CDC’s video does not significantly increase HIV knowledge in the general public. Further, the video intended to generate empathy and reduce stigma was also ineffective. These findings stress the need for further research and questions the effectiveness of empathy-generating interventions (e.g., FACES OF HIV, HIV Justice Network) to increase knowledge and reduce stigma. Future researchers should test the effectiveness of personalized interventions to reduce HIV-related stigma. / Dissertation/Thesis / Masters Thesis Psychology 2020

The writing of this thesis is to investigate the role that the church play for the people living with HIV and AIDS and are poverty stricken. This investigation takes us both into the role of the Roman Catholic Church of Ndola Diocese and the Copperbelt Presbytery of the United Church of Zambia are doing in the fight against HIV and AIDS and poverty. The problem of HIV and AIDS in Zambia, as well as Africa in general, represents an economic, social, moral, and spiritual problem of great magnitude. Never before in the history of the world have we faced such a pandemic which results in creating poverty among Zambian people. It knows no boundaries, leaving a path of death and destruction to all that treat it lightly. HIV and AIDS have touched every community within the global village. There is not a person that has not pondered on this terrible disease. The researcher’s question through this thesis is to find out the role of the church as it seeks to care for those infected and affected by the HIV and AIDS pandemic. Can the church rise to embrace the enormous economic and social need that HIV and AIDS and poverty presents, can it make a difference in an environment of suffering as it seeks to become a healing community? This thesis is to enhance the response of churches in Zambia to the fight against HIV and AIDS and Poverty. Pastorally, churches have the duty and task to address issues of stigma, discrimination, judgmental tendencies and give pastoral care to people living with HIV and AIDS. This thesis has attempted to explore new theological perspectives and utilise the available ones, which have already been dealing with issues that address HIV and AIDS prevention and care. The study also seeks to encourage church ministers, pastors and lay leaders to provide the much needed leadership in the fight against HIV and AIDS and its accompanying social problems of poverty, injustices, culture and gender inequality. The church has a central role to play in the fight against poverty and impoverishment. As part of the civil society, it has the pastoral responsibility for ensuring that all citizens in Zambia enjoy their full rights. Far from being powerless victims of HIV and AIDS and poverty, the poor in Zambia must be treated with respect and dignity. Nevertheless effective therapy and pastoral care normally transcends all stigma and cultural barriers as it seeks to address the problems of people living with HIV and AIDS. Human beings respond to love, care and shelter, as basic needs. Ross reminds us that “It is only when the church becomes the leading symbol of healing in a situation of HIV and AIDS and poverty then it will be a blessing to all those who are living HIV negative lives and those who struggle to bring care, support, love and comfort to the orphans and widows and more especially to all those living with HIV and AIDS” (Ross 2002:vi). The church should not lag behind, but it should set the pace of showing the love and care for all people with HIV and AIDS and are living in poverty. / Dissertation (MA (Practical Theology))--University of Pretoria, 2006. / Practical Theology / MA / unrestricted

MPM / Oliver Tambo Institute of Governance and Policy Studies

archives@tulane.edu / 0 / Fayez

In order to achieve cure for HIV-1 infection in patients undergoing suppressive antiretroviral therapy, eradication of all latently infected reservoirs of the virus is required. The focus of HIV cure is predominantly centred on the elimination of latently infected memory T cells, while information on possible elimination of infected macrophages is lacking. Macrophages support continuous virus replication without succumbing to cytopathic effects of HIV-1. Recently, our laboratory has shown a protective role for cellular inhibitor of apoptosis proteins (IAPs) 1/2 in macrophages against Vpr-induced apoptosis. Depletion of cIAP1/2 by Smac mimetics (SM) reverse the IAP-mediated protection and sensitize macrophages to Vpr-induced cell death. My research aims to understand the role IAPs play in apoptotic resistance of HIV-infected macrophages. I hypothesized that ablation of cIAP1/2 by SM may induce apoptosis in HIV-infected macrophages. My results show that SM does not induce cell death in uninfected or healthy macrophages, but induces cell death in chronically infected U1 cells, in vitro infected monocyte-derived macrophages, and ex vivo derived HIV-infected macrophages from HIV-infected individuals. SM induce cell death of infected myeloid cells through apoptosis and not through necroptosis. Moreover, SM-induced apoptosis is independent of TNFα and other endogenously secreted cytokines. In vitro infection of monocyte-derived macrophages leads to the downregulation of RIPK1, RIPK3, and TRAF-1. Interestingly, necrostatin-1-mediated RIPK1- inhibition does not affect viability of healthy macrophages, but in combination with IAP degradation by SM leads to significant induction of apoptosis. This suggests a key role for RIPK1 in SM-induced apoptosis of HIV-infected macrophages. Altogether, the results from this project suggest that modulation of the IAP-associated signalling pathways by SM may be a potential strategy for selective killing of HIV-infected macrophages.

HIV/AIDS can affect individuals of any age. Efforts to educate those considered to be most at-risk, based on the age at which the most individuals are infected, are ongoing and public. Less work and mainstream education outreach, however, is being directed at an older population, who can be more likely to contract HIV, is more susceptible to the effects of HIV, and more likely to develop AIDS, than younger persons. Guided by the Health Belief Model theory, research was conducted to determine what, if any, relationship existed between age of an individual and the possibility that an HIV test will be sought. Factors of gender, education, ethnicity and marital status were included in analyses. the research indicated that as age increased, likelihood for getting an HIV test decreased. Overall, most individuals had not been tested for HIV. the implications of an aged and aging population with HIV include a need for coordinated service delivery, increased education and outreach.

Understanding the mechanisms used by HIV-1 to evade antibody neutralisation may contribute to the design of a high-coverage vaccine. This thesis explores the mechanism used by a Tier 3 virus leading to its high antibody neutralisation resistance phenotype. This thesis also describes how the glycans at the base of the V3 loop contribute to (i) breadth and potency in a cohort of unselected HIV-1-infected individuals and (ii) the selective pressures resulting from the V3/glycans shielding the virus from neutralisation and the glycans themselves being targets of broad antibody responses. HIV-1 isolates that are highly resistant to broadly neutralising antibodies could limit the efficacy of an antibody-based vaccine. For this reason, it is important to understand the mechanisms behind high HIV-1 resistance to neutralising antibodies. Chapter 2 and Chapter 3 of this thesis describe virus 253-11, a highly neutralisation resistant virus, which is particularly resistant to commonly-elicited, anti-membrane proximal external region (MPER) antibodies in sera. To further understand its resistance, mutations in the MPER were introduced that are known to delay fusion following CD4-binding and thus increase the time the virus spends in the open conformation. Interestingly, we found that these mutations affect the 253-11 Envelope (Env) spike before CD4-binding by destabilising the closed trimer structure. From these data, we hypothesized that the neutralisation resistance of 253-11 was due to an unusually tight, compact pre-fusion Env trimer that resists transient changes to the open conformation. The open conformation frequently exposes narrowly-neutralising antibody epitopes. Because the unliganded 253-11 Env presumably transitions infrequently into the open conformation, it would be able to evade these responses. 253-11 was sensitive to most but not all of the most potent broadly neutralising antibodies (bnAbs) tested, most likely because those broadly neutralising antibodies can access their epitopes in the pre-fusion Env conformation. To gain further information about the structure of the 253-11 Env, we designed a recombinant 253-11 SOSIP trimer and found it to be stable and predominantly adopt a closed conformation. The crystal structure of the SOSIP trimer revealed structural elements likely responsible for 253-11 Env compactness including the inward disposition of the heptad repeat helices and gp120 protomers towards the trimer axis. Taken together, the data from Chapter 2 and Chapter 3 highlight an underappreciated Env compactness mechanism of HIV-1 resistance to neutralising antibodies and these data may be useful in HIV-1 immunogen design research. Previous candidate HIV vaccines have failed to induce wide-coverage neutralising antibodies capable of substantially protecting vaccinees. A key approach in HIV immunogen development has been to define and model epitopes recognised by anti-HIV bnAbs. Candidate immunogen models identified by bnAbs include the V3/glycans, the V2/apex and the MPER epitopes. Autoreactivity and polyreactivity of anti-V3/glycan and anti-MPER antibodies are thought to pose both direct and indirect barriers to achieving neutralisation breadth. Chapter 4 of this thesis explored which of these bnAb epitopes were associated with breadth and potency in a South African cohort of chronically HIV-infected individuals. The study found that antibodies targeting the V3/glycans were associated with breadth and potency. In contrast, antibodies to the V2/apex were not associated with neutralisation breadth/potency. This suggests that auto/polyreactivity are not critical factors in the development of breadth and potency and that the V3/glycans should remain a high-priority vaccine candidate. Since targeting the V3/glycans was associated with breadth and potency in this cohort, the study continued to look at this epitope to investigate the role of these glycans in neutralisation resistance of Tier 2 viruses. The HIV-1 Env is surrounded by glycans that often prevent antibody neutralisation, leading to the term the "glycan shield", however some bnAbs have evolved to recognise these carbohydrates. Chapter 4 of this thesis describes how the N-linked glycan at position N301 is critical for maintaining neutralisation resistance of one subtype C virus (Du156.12), but not for another subtype-matched virus (CAP45.2.00.G3). Thus, the loss of the N301 glycan may have a substantial antibody-related fitness cost for some viruses but not others. The N301 glycan, as well as glycans at positions 332 and 334, are the primary targets of the anti-V3/glycan class of neutralising antibodies, which may select for loss of the targeted glycan. The evidence presented in Chapter 4 suggests that in some viruses, loss of the N301 glycan may result in evasion of anti-V3/glycan antibody responses while maintaining overall neutralisation resistance. This phenomenon may impair efficacy of passively-infused anti-V3/glycan bnAbs or a therapeutic vaccine.