Genomic and transcriptomic predictors of post-treatment HIV remission during primary HIV infection

Thesis

HIV control remains poorly understood, with only a small subset of individuals successfully suppressing the virus following treatment during primary HIV infection. One of the most promising strategies for HIV cure is broadly neutralising antibodies (bnAbs), which have shown to substantially prolong time to viral rebound in absence of antiretroviral medications. Understanding the mechanisms underlying this control is essential for improving clinical care. This thesis investigates the interplay between HIV and the host to uncover key determinants of HIV control, following antiretroviral treatment and treatment with two broadly neutralizing antibodies (bnAbs), 10-1074 and 3BNC117.

To assess the feasibility of bnAb-based interventions, this thesis first analyzes the prevalence of bnAb resistance-associated mutations at a population level throughout the pandemic, as well as in viral reservoirs of key populations with primary HIV infection. The goal is to determine whether screening for resistance prior to bnAb administration could improve treatment efficacy. Additionally, the origins of bnAb resistance-associated mutations are examined to identify factors associated with an increased risk of resistance emergence. The relationship between proviral and circulating viruses is also investigated to assess whether proviral sequencing can serve as a reliable proxy for resistance screening. Finally, the accuracy of bnAb sensitivity predictions is evaluated in individuals who received bnAbs as part of the RIO trial, correlating baseline sensitivity predictions with clinical outcomes post-treatment while accounting for other viral and host factors.

This work then shifts focus to the host immune response, exploring how transcriptomic changes may provide insights into mechanisms of post-treatment viral control, whether following antiretroviral or bnAb therapy. Bulk RNA sequencing of CD4+ T cells from post-treatment controllers and from early progressors is used to identify gene expression signatures that may predict time to viral rebound after treatment interruption. In a final chapter, single-cell transcriptomic profiling of PBMCs from RIO trial participants who experienced long-term viral control post-bnAb treatment is conducted. This analysis aims to elucidate bnAb-induced changes in immune cell gene expression and to investigate the potential vaccinal effects of bnAbs at a transcriptomic level.

Overall, this work highlights key challenges associated with bnAb treatment and contributes to the broader understanding of post-treatment HIV control. The findings may help inform the design of more effective treatment strategies incorporating bnAbs.

Authors: Zacharopoulou, P

• DOI: 10.5287/ora-4rxjepaje
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: RNA-seq; HIV immunology; 3BNC117; HIV; bNAb resistance; HIV envelope; bNAbs; 10-1074
• Subjects: HIV (Viruses); HIV antibodies; Viral genomes; Viral envelopes