Men who have sex with men (MSM) remain the group with the highest incidence of HIV in the UK, with a high concentration of infections in London. Multi-site safety and efficacy trials have demonstrated significant reductions in HIV acquisition among MSM when prescribed a daily pre-exposure prophylaxis (PrEP). Success translating these scientific developments into effective prevention interventions requires an understanding of how acceptable they are to individuals at risk of HIV acquisition. This thesis reports on the findings of twenty in-depth semi-structured qualitative interviews with MSM in London. To participate, men must have had at least one episode of sex without condoms with a known sero-discordant partner or a partner of unknown HIV status in the twelve months prior to interview. The acceptability of a range of PrEP methods were explored, including daily and intermittent oral; topical; and injectable formulations of PrEP and the potential impact of PrEP use upon men’s perceptions of risk and behaviours. Dimensions of acceptability draw on the personal (such as side effects; increased or diminished HIV vulnerability; adherence to drug/medical regimes); the inter-personal (such as negotiation of sex; stigma or discrimination); and community or social concepts of acceptability (such as financial burden and concepts of increased ‘community risk’). The thesis provides a framework for understanding PrEP acceptability, showing that concepts of acceptability are complex and that the different dimensions of acceptability are inter-related. The thesis concludes with recommendations for future policy and service delivery of PrEP to at-risk groups in the UK.

In the current scenario of decreasing aid, it is critical to develop mechanisms to guarantee the sustainability of programmes once donors exit a country. This study seeks to provide an indepth understanding of this process in Peru, an upper-middle income country and recipient of multiple HIV/AIDS Global Fund grants that, given recent economic growth, has allocated strategic funding for HIV/AIDS activities within the national budget. The aim of this study is to evaluate the transition of Peru from receiving Global Fund financing for HIV/AIDS to the increasing role of national institutions and capacity for policy development. For this, an original framework was employed, which allowed for the analysis of inputs (resources invested), actor motivations and incentives, HIV policies and plans, and their effects on programmatic sustainability; finally providing recommendations to inform decision-makers on priority areas that must be strengthened to ensure sustainable HIV/AIDS programming. To achieve these objectives, a case study (2004–2012) was conducted, employing a review of the literature and in-depth interviews among the main actors working in HIV in Peru, carried out between October–December of 2011. Findings demonstrate that Peru has made important progress towards ensuring a sustainable response for HIV/AIDS, primarily in the allocation of government funding and creation of spaces for actor discussion. Yet, this is not without challenges. The weak leadership and lack of coordination between the central and regional levels has exacerbated the already existing capacity issues in the regions, in this case related to HIV activity planning and implementation. Moreover, in order for HIV to remain a policy priority, mechanisms of accountability must be strengthened, as well as information systems to demonstrate need and key areas for action. Although findings are specific to the Peruvian context, this experience leaves important lessons learned in programmatic sustainability for other countries.

Public health strategies to tackle HIV-1 epidemics in a variety of national settings need to be aware of the factors involved in transmission of infections. There is support in the literature for the hypothesis that individuals with recent infection may contribute disproportionately to onward transmission due to the high viral load and lack of infection status associated with this stage. This thesis sets out to further explore this risk group, and to develop methods to monitor its impact on epidemics. Two epidemic settings, the United Kingdom and Kumasi, Ghana, were investigated using molecular epidemiological techniques to assess the role of individuals with recent infection in the formation of transmission clusters. A classifier of HIV-1 infection length was developed based upon the proportion of mixed nucleotides within consensus pol gene sequences and applied to phylogenies constructed using viral sequences obtained from each cohort. In the Ghanaian setting, the performance of the nucleotide ambiguity classifier was compared to an antibody avidity based measure of infection length, to gauge the usefulness of both approaches in a sub-Saharan setting. In order to more fully explore the complexity of intra-host HIV-1 quasi-species dynamics in the early phase of infection, a well defined cohort of UK-based individuals, some with multiple pre-treatment time points, had their virus deep-sequenced and analysed using a subpopulation reconstruction approach. The proportion of recent infections identified within the UK HIV-1 epidemic by the classifier agreed well with previous studies. Application of the classifier to UK-wide phylogenies revealed disproportionate linkage of recently infected individuals to clusters across subtypes. Phylogenetic analysis of the Kumasi cohort did not reveal a highly clustered epidemic. Transmitted drug resistance was present at a level consistent with reports elsewhere in West Africa. Comparison of the antibody avidity based measure of infection length with the nucleotide ambiguity classifier indicated both markers co-segregate together, but produced differing estimates of the proportion of recent infections in the cohort. Deep-sequencing of recently infected individuals revealed some individuals may have been infected with more than one viral subpopulation, whilst others appeared to have been infected with a single subpopulation. This work supports the utility of a consensus sequence based measure of infection length in assessing the role of recently infected individuals in driving epidemics on a large scale. Such a measure will need further refinement and validation depending on the setting used, but presents a potentially useful biomarker that could be used in conjunction with other clinical parameters. Deep-sequencing of HIV-1 in recently infected individuals points to the quasi-species complexity that exists between and within individuals, and the subpopulation reconstruction approach taken in this work reveals dynamics at play which have the potential to impact on vaccine design and molecular epidemiological monitoring of epidemics.

HIV severely affects children in sub-Saharan Africa. It is important to understand not only the effects of HIV on children, but also how to mitigate them and prevent future infections, with education as one possible avenue. This thesis investigates associations between HIV and education in youth participating in the Manicaland HIV/STD Prevention Project in eastern Zimbabwe from 1998 to 2011. In the first HIV prevalence survey from a general population sample of Zimbabwean children (aged 2-17 from 2009-2011), HIV prevalence was 2.1%, and was primarily due to mother-to-child transmission. Antiretroviral therapy coverage was low (< 25%) and driven by a lack of diagnosis. Therefore, increased testing and diagnosis should be a priority to improve the outlook of HIV-positive children in this population. Providing context for my detailed analyses of education, I show that although education has increased over time in Zimbabwe, it suffered during the economic turmoil of the 2000s, and females consistently achieve lower education levels than males. Increasing education is important because children with educated parents are more likely to be educated themselves, and education appears to be protective against HIV, particularly for females. Conversely, orphanhood is associated with poorer educational outcomes and substance use, which is associated with higher levels of sexual risk behaviours. School enrolment, however, mitigates these effects and is associated with lower levels of substance use and risky sex. Thus, I illustrate one pathway through which education may decrease HIV risk. Moving beyond problems to their solutions, I demonstrate that schools can impact on the education and wellbeing of vulnerable children: high quality schools were associated with better education outcomes and higher wellbeing, suggesting that schools are well placed to improve children's lives. The findings of this thesis suggest how education can support HIV-affected children and play a role in decreasing HIV in sub-Saharan Africa.

With the rapid scale up of testing and treatment for HIV, morbidity and mortality in sub-Saharan Africa have decreased dramatically. However, current treatment programmes providing ART are not maximally effective: they fail to identify infected individuals in a timely manner, resulting in millions of new infections and AIDS-related deaths per year. This thesis investigates why care programmes in sub-Saharan Africa do not succeed in achieving the full potential effects of ART - on both the risk of death and of onward transmission - and what can be done about it. I begin by exploring current treatment programmes using a framework known as the 'Cascade of Care', before detailing the development of an individual-based model that is able to track patients through care in western Kenya. I conclude that weaknesses exist throughout, attenuating the impact of individual interventions. However, a combination of interventions can improve patient outcomes more efficiently. I then find that through temporal and structural enhancements to the timing of home-based counselling and testing rounds, the UNAIDS 90-90-90 targets (90% of people with HIV diagnosed, 90% of those on treatment, and 90% of them virally suppressed) can be met by 2020. Finally, I explore the deficiencies in care across multiple countries utilising a simplified model encapsulating the concepts of the original but suitable for use with routinely available data. Overall, I conclude that current ART programmes in sub-Saharan Africa are not maximally effective due to deficiencies throughout care. However, I find that combinations of interventions targeting multiple aspects of care provide greater health outcomes (for a given cost) than 'wide-scale test and treat' without accompanying fixes to the cascade, or interventions acting independently. International guidance for countries implementing ART programmes should recommend strengthening care across the cascade to generate greater patient outcomes and achieve international targets.

Since the start of global HIV-1 pandemic about 30 years ago, great research resources and efforts devoted to this field have changed the picture of AIDS from a deadly disease to a manageable chronic illness sharing similar life span expectation as the normal population. However, despite achieving great clinical improvements, HIV infection is still far from a cure, therefore still more research is needed into the fundamental mechanisms of viral replication and to bring new treatment options to light. During my PhD project, I used a recently identified antiretroviral compound, Coumermycin A1 (CA1), as a tool to study early events in HIV-1 infection. I found that C-A1 inhibits HIV- 1 integration in a capsid-dependent way without affecting reverse transcription or nuclear import. Using molecular docking, we have identified an extended pocket in the N-terminal domain of capsid where C-A1 is predicted to bind. Isothermal titration calorimetry (ITC) confirmed that C-A1 binds to capsid. Time-of–uncoating assays in Jurkat CD4+ T cells expressing engineered human TRIM5-CypA showed that C-A1 causes faster and greater escape from TRIMCyp restriction of wild type but not A105S or N74D capsid mutant viruses. This suggests that C-A1 induces faster uncoating, yet it did not affect reverse transcription. Sub-cellular fractionation showed that small amounts of capsid accumulated in the nuclei of infected cells and C-A1 reduced the nuclear capsid. A105S and N74D mutant viruses did not accumulate capsid in the nucleus, irrespective of C-A1 treatment. Furthermore, depletion of Nup153, a nucleoporin located at the nuclear side of the nuclear pore that binds to HIV-1 capsid, made the virus less susceptible to TRIMCyp restriction, suggesting that Nup153 may help maintaining some integrity of the viral core. The results suggest that capsid may be required for a post-nuclear entry event that affects integration. I describe a novel step of the HIV-1 life cycle that can be targeted by a small molecule. I also tried to adapt the cyclosporin washout assay to a high throughput system to screen for CA targeting compounds from two small chemical libraries. Although I did not identify any specific hit, the assay will be useful for future larger screening.

Migrant workers are believed to act as a bridge population in the spread of HIV. However, migration patterns are highly variable, influenced by local historical and socio-economic contexts. In India, rural-to-urban, circular migrant workers are a priority group for HIV interventions. Their success requires an understanding of the processes influencing migrant vulnerability and how the migration-HIV relationship evolves over time. I conducted a systematic review examining the association between migration and HIV prevalence. I also analysed behavioural survey data from a study on migrant men to quantify and characterise those at greatest risk. For the case study, I carried out qualitative fieldwork in Allahabad district, an area of high rural-to-urban, circular migration and increasing HIV prevalence. I conducted interviews in two settings: clinical and rural village. I interviewed HIV-positive individuals at an HIV-treatment centre and migrant men and wives of migrants in two high out-migration villages. Published studies showed some association between circular migration and HIV, but migration was defined inconsistently across publications. According to survey data 20% of migrant men had non-spousal sexual partners at multiple locations; this was associated with self-perception of HIV risk, age and recent migrant status. The qualitative case study showed specific factors such as nature of social group and migration location affecting risk of infection. Following infection, migrant status delayed contact with HIV services, depleting household savings on private treatment for HIV-related conditions and facilitating onward transmission. After enrolment with HIV services, diminished health, a rigid ART regime and job insecurity hindered resumption of migration-based livelihoods. Increased HIV risk in migrants is due to the context of migration not mobility itself. Despite free testing and treatment services, migrant workers and their families are being diagnosed late. The risk to migrant livelihoods from HIV has strong implications for long-term ART adherence and prognoses.

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