Characterizing HIV-1 reservoir dynamics in Subtypes B and C to Advance Treatment and Cure Strategies

Summary

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HIV-1 continues to be a major global health issue. In 2022, approximately 39 million people were living with HIV-1, with 1.3 million new diagnoses and 630,000 deaths from AIDS-related illnesses. Despite the success of combination antiretroviral therapy (ART) since its introduction in 1996, which has significantly reduced HIV-1-related deaths and illnesses, ART cannot cure the infection.

The main challenge in curing HIV-1 lies in the viral reservoirs. These reservoirs form when HIV integrates its DNA into the host’s genome, where it can remain transcriptionally silent as a latent infection. This latent reservoir allows HIV-1 to persist despite ART, and hide from the immune system, making it difficult to eradicate. The reservoirs, primarily found in CD4+ T cells but also in other cell types and tissues, can survive for years. They consist of two types: intact viruses capable of infecting new cells, and defective ones with deletions and/or hypermutations. Understanding and accurately measuring these reservoirs is key to developing strategies that could eventually eliminate them.

However, the global variability of HIV-1 subtypes presents a challenge for universal quantification and cure strategies. Subtype B, common in high-income countries, accounts for only 12% of infections worldwide. In contrast, subtype C, the most widespread variant, represents about 47% of all infections, particularly dominating in Sub-Saharan Africa.

In this thesis, we enhanced the applicability of a specific HIV-1 quantification technique, the intact proviral DNA assay, by adapting it to accurately differentiate between intact and defective proviral reservoirs in both HIV-1 subtypes B and C. Using this quantification technique, we discovered that defective proviruses correlate with markers of reservoir activity and immune regulation.  Moreover, we found that defective proviruses are linked to ongoing viral production, contributing to persistent viremia. Our findings highlight the significant impact of defective proviruses and emphasize the need to eliminate the defective reservoir to halt HIV-1 associated disease progression.

Additionally, we investigated strategies to target HIV-1 reservoirs by reversing proviral latency as part of potential cure approaches. One approach we discussed in detail, also in relation to the central nervous system, is the "induce and reduce" strategy. This method aims to reactivate latent viruses using latency reversal agents (LRAs), allowing the immune system to recognize and eliminate the infected cells. Our findings highlight the potential of Panobinostat as a promising LRA for this purpose.

In summary, this thesis provides valuable insights into HIV-1 reservoir dynamics, focusing on global inclusivity by considering the most prevalent subtypes, and explores strategies for reactivating latent viruses to develop effective cures.