Immunological consequences of HIV reservoir activity in people on antiretroviral therapy

Current antiretroviral therapy (ART) is highly effective in suppressing viral replication in people with HIV (PWH). However, ART does not eradicate HIV, which persists in long-lived reservoirs from which the virus rebounds upon therapy interruption. A major knowledge gap for many years has been the question whether these reservoirs, aside from being a barrier to cure, can affect the immune system. Recent evidence suggests that HIV persistence spans a spectrum, ranging from deep latency to residual transcription and translation originating from integrated proviruses. Studying these active viral reservoirs (aVR) has been challenging due to a lack of suitable experimental approaches.

To study HIV reservoirs at the single-cell level, our lab has developed novel methods combining fluorescent in situ RNA hybridization for viral genes with detection of HIV proteins, cell phenotyping, and single-cell vDNA sequencing. Our findings reveal active HIV transcription in most PWH on ART. It positively correlates with HIV-specific T cell responses. Most of these aVR consist of defective proviruses. These findings raise questions about the interaction between aVR and the immune system.

Through these studies, we will shed led light onto: i) The interplay between reservoir activity and HIV-specific T cell immunity, as the efficacy of CD4 and CD8 T cell responses can dictate the potential for immunosurveillance in cure strategies; ii) The contribution of active reservoirs to sustained immune activation and suboptimal immune restoration. The knowledge gained may also help identify subpopulations of PWH that could benefit from adjuvant therapies.