HIV-1 infection and the central nervous system: investigating markers of neural activation and measures of HIV-1 reservoir

Abstract

Despite successful antiretroviral therapy (ART), mild cognitive impairments remain prevalent amongst people-living-with-HIV (PLWH). However, the underlying mechanisms driving this remain unclear. The persistence of an inaccessible HIV reservoir and low-level viral replication may be associated with immune activation and neuroinflammation, which can lead to neuronal injury and cognitive impairment. Furthermore, HIV-cure and ART-interruption strategies which disturb the HIV reservoir could result in detrimental central nervous system (CNS) sequelae. This thesis examines the following hypotheses: 1. Lower biomarker concentrations of HIV reservoir size are associated with lower biomarker concentrations of neural activation 2. Higher biomarker concentrations of HIV viral transcription are associated with higher biomarker concentrations of neural activation In cross-sectional analyses of virologically suppressed PLWH, associations were assessed between cerebrospinal fluid and plasma neurofilament light chain protein (NfL), and between surrogate measures of HIV reservoir size and neuroinflammation, measured in vivo using translocator protein (TSPO) binding on positron emission tomography neuroimaging (a marker of microglial activation). In longitudinal analyses, I assessed the impact of “shock-and-kill” using vorinostat + HIV-specific vaccination (a HIV-remission strategy) and ART interruption on measures of HIV reservoir size, HIV replication and plasma NfL, in individuals who initiated ART during primary HIV infection. My results demonstrated that cerebrospinal fluid and plasma NFL correlated moderately but I was unable to confirm an association between HIV reservoir size and neuroinflammation, as measured by TSPO binding. Using plasma NfL, the absence of associations between HIV reservoir size and replication with neuronal injury following this “shock-and-kill” strategy or ART interruption supports the presumption of CNS safety of these approaches and will inform the design of future HIV-cure studies. With the imminent introduction of novel therapeutics to control and cure HIV, continued CNS safety monitoring remains essential, and the implementation of CNS assessment using the aforementioned biomarkers was demonstrated to be feasible.