Unraveling HIV Reservoir Persistence and Dynamics in Peripheral Blood and the Central Nervous System during Antiretroviral Therapy

Abstract

Since the introduction of effective antiretroviral therapy (ART) in 1996, HIV has shifted from a fatal disease to a chronic infection. While ART suppresses viral replication, it does not remove the latent HIV reservoir from the cells, necessitating lifelong treatment. Most research focuses on the viral reservoir in the cells of the peripheral blood, but HIV also persists in cells of other tissues, including in the brain. This PhD thesis examines the dynamics of the HIV reservoir in both blood and brain tissue. We optimized a quantification technique capable of quantifying both HIV subtype B, prevalent in high-income countries, and subtype C, the most predominant subtype globally. Using this technique, we followed individuals on ART for 20 years and found that while the reservoir declines early in treatment, it stabilizes after a decade. In the brain, we identified the microglia cells as the primary HIV reservoir. This was studied using a newly developed microglia culture system and postmortem brain tissue from individuals with HIV. We demonstrated that viruses isolated from these could establish productive infection in these culture systems. Due to challenges in isolating intact cells from frozen brain tissue, we instead analyzed cell nuclei and found increased immune activation in individuals with HIV, even in those on ART. This persistent immune activation may contribute to cognitive impairments, known as HIV-associated neurocognitive disorder (HAND). These findings improve our understanding of the HIV reservoir in both blood and brain, as well as the potential harmful effects of HIV. Crucially, they highlight the need for innovative cure strategies and improvements in existing treatments to better address HAND.