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

Summary

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Since the introduction of effective antiretroviral therapy (ART) in 1996, HIV has shifted from a fatal disease to a chronic infection for many individuals. While ART suppresses viral replication, it does not eliminate the latent HIV reservoir, necessitating lifelong treatment. Understanding the persistence and dynamics of this reservoir is crucial for achieving the ultimate goal of HIV cure. Most research focuses on the viral reservoir in peripheral blood due to its easy accessibility. However, the virus also persists in other anatomical reservoirs, including the central nervous system. This PhD thesis explores the HIV reservoir not only in blood but also in the brains of people with HIV.

We optimized a quantification technique for the HIV reservoir capable of measuring not only HIV subtype B, the most prevalent subtype in high-income countries, but also subtype C, the most predominant subtype globally. Using this technique, we quantified the HIV reservoir in individuals on ART for 20 years and found that while the reservoir declines shortly after therapy initiation, it stabilizes after a decade of treatment. Furthermore, we identified microglia as the primary cellular HIV reservoir in the brain. This was studied using a newly developed microglia culture system, monocyte-derived microglia (MDMi), along with postmortem brain tissue from individuals with HIV. We demonstrated that viruses isolated from the brains of people with HIV could establish productive infection in these culture systems. Since isolating intact cells from frozen tissue is challenging, we instead isolated nuclei and found evidence of increased immune activation in the brains of people with HIV, even those receiving ART. This persistent immune activation may contribute to cognitive impairments associated with HIV, known as HIV-associated neurocognitive disorder (HAND).

These findings improve our understanding of the HIV reservoir in both peripheral blood and the central nervous system, as well as the potential harmful effects of HIV. Crucially, they highlight not only the need for innovative cure strategies but also for improvements in existing treatments to better address HAND. Especially in the current political climate, where funding and support for HIV research and treatment are increasingly under threat, ensuring continued progress in both therapeutic and curative approaches is more critical than ever.