The impact of HIV specific broadly neutralising antibodies on mucosal immunity and the HIV reservoir

HIV-specific broadly neutralising antibodies (bNAbs) have shown promise for maintaining prolonged antiretroviral therapy (ART)-free viral suppression in people living with HIV. However, it remains unclear if longer-acting variants of bNAbs (LS-bNAbs) achieve adequate levels in tissue to impact the gut-associated latent HIV reservoir.. This thesis explores the impact and safety of two LS-bNAbs amongst participants enrolled in the RIO trial, a double-blinded, placebo-randomised controlled trial. LS-bNAbs were associated with prolonged ART-free viral suppression after stopping ART compared with placebo. LS-bNAbs demonstrate an excellent safety profile. In my thesis I completed a meta-analysis of time to viral re-suppression after analytical treatment interruption (ATI) with or without trial interventions such as bNAbs and highlights the importance of reporting post-ATI viral suppression outcomes. The work in this thesis provides the first data on the pharmacokinetic profiles of two doses of LS-bNAbs in serum and rectal tissue. I demonstrated lower levels of rectal tissue LS-bNAb exposures compared to serum in people living with HIV. Modelling the pharmacokinetic-pharmacodynamics interactions provides mechanistic insights and estimates the time to loss of viral control following LS-bNAb administration. Despite the lower tissue LS-bNAbs, there was no substantial changes in the tissue-associated total HIV DNA reservoir or rectal mucosal immune cell populations at 12 weeks after dosing if participants who received LS-bNAbs remained suppressed. In summary, this thesis provides evidence that LS-bNAbs are safe and were associated with long-term viral suppression for people treated early in HIV. The extended viral control observed beyond the duration of LS-bNAbs is intriguing and is not explained by LS-bNAb persistence in tissue. However, despite the lower tissue exposures, LS-bNAbs appeared to be protective against early increases in the tissue HIV reservoir and HIV-associated mucosal immune injury. These findings will inform the development of improved immunotherapeutic strategies to better target the tissue-associated HIV reservoir.