“We question what makes HIV-1 transcriptionally silent”

HIV-1 DNA integration that enables the provirus to persist in a human reservoir for a long time is one of the critical characteristics of its life cycle. This biological phenomenon also highlights the unavoidable interaction between a provirus and the host genome. It has been known for many years that HIV-1 integration is not random; however, the purpose and the consequence of this selection of HIV-1 integration are presently not fully clear. One of the questions addressed by our team is to understand the consequence of this selection on HIV-1 pathogenesis. Specifically, we associate individual HIV-1 integration sites with corresponding sense- and antisense RNA transcription and investigate the role of single provirus transcriptomics in the establishment of HIV-1 latency.

Another question addressed here is to comprehend the evolution of the configuration of HIV-1 reservoirs. We have shown that different and unique immunologic signatures can be enriched by intact proviruses-targeted genes retrieved from HIV-1-infected individuals alongside infections associated with ART, suggesting that most likely the configuration of a HIV-1 reservoir remains dynamic after HIV-1 infections. We thus hypothesize that HIV-1 integration frequency might be used as a surrogate for gene sets, which may define specific immune cell types and proinflammatory soluble factors during HIV-1 infection. To verify this hypothesis, we use the in vivo model system to track and visualize the alteration of the landscapes of proviruses in different reservoir cells over time and elucidate the mechanistic interplay between gene sets targeted by wild-type HIV-1 and the functional genome property.

“We question what makes zoonotic viruses infect humans”

Nearly two-thirds of emerging infectious diseases that affect humans have their origins in animal reservoirs. To date, although evolutionary constraints, rendering some zoonotic viruses adaptive to humans remain unclear, genetic mutations that result in new variants of the viruses provide a window of opportunity for viral host jumps. In this respect, knowing when and how such mutations occur becomes essential to understand how constraints determine the fate of the virus, especially over an evolutionary timescale. In practice, we implement a high-throughput evolutionary strategy to probe constraints crucial for cross-species transmission in SARS-CoV-2 (Figure 2).