Michael Keegan

Pathway 1+3

Cohort 2021

Pathway Journey

HIV-1 cell entry is mediated by the viral Env protein that binds CD4 and either CCR5 (R5) or CXCR4 (X4) coreceptors on host T-lymphocytes. Initial infection is typically mediated by R5 viruses while X4 viruses emerge later in infection through HIV-1 mutation and are associated with poor patient prognoses and AIDS development. However, what drives the R5-X4 coreceptor switch remains poorly understood. Recently, it has been proposed that HIV-1 coreceptor expansion is driven by selective pressure generated by the host adaptive immune response. Broadly neutralising antibodies (bnAbs) are generated by a subset of infected individuals and can recognise and neutralise a wide range of HIV-1 strains. Recently, several bnAb therapies, combining multiple bnAbs targeting different neutralising HIV-1 epitopes, have entered clinical trials, and have displayed promising results. However, antibody development in some individuals has been associated with HIV-1 coreceptor expansion and progression to AIDS. Preliminary data generated by the Doores group has characterised bnAbs isolated from HIV-1 infected donors and correlated these with viral strain divergence. We aim to build upon these preliminary results to confirm and determine the role of bnAbs in HIV-1 coreceptor expansion. We aim to examine how sequence changes within variable domains of HIV-1 Envelope protein, isolated from an infected donor, mediate both coreceptor switching and their impact upon neutralisation by autologously isolated bnAbs. Ultimately, our aims to build upon early evidence of adaptive immunity driven coreceptor expansion and subsequently the efficacy of HIV-1 bnAb therapies.

Biography

I completed a BSc in Genetics followed by an MSc in Virology with Specialism in Virology at the University of Glasgow. Through my undergraduate degree I developed an interest in the evolution of host-virus interactions through infection and further developed a specific interest in the progression of HIV-1.

Social Media

https://www.linkedin.com/in/michael-keegan-3805a3284/