Innate immune regulation in HIV latency models

Area of Science:

• Immunology
• Virology
• Cell Biology

Background:

• Innate immunity and type 1 interferon (IFN) are crucial for controlling early HIV infection in CD4+ T cells.
• Latent HIV infection, established by some infected cells, persists despite antiretroviral therapy (ART), forming a major barrier to HIV cure.
• Understanding innate immune responses in HIV latency is vital for developing curative strategies.

Purpose of the Study:

• To evaluate innate immunity and IFN responses in various T cell models of HIV latency.
• To investigate the mechanisms underlying the failure of ISG induction in latent HIV infection.
• To identify potential latency restriction factors involved in mitigating HIV establishment.

Main Methods:

• Utilized established T cell lines, Jurkat cells with reporter virus, and primary CD4+ T cells to model HIV latency and virologic suppression.
• Assessed RNA sensing and IFN signaling pathways in latently infected cells.
• Employed bulk and single-cell RNA sequencing for a functional genomics approach to define ISG expression dynamics.

Main Results:

• Latently infected T cell lines possess functional RNA sensing and IFN signaling but exhibit defective induction of specific interferon-stimulated genes (ISGs).
• HIV-infected cells, including those with virologic suppression, show attenuated responses to type 1 IFN treatment.
• Functional genomics revealed specific ISG expression dynamics associated with latent HIV infection and viral suppression.

Conclusions:

• HIV latency and viral suppression are linked to cell-intrinsic defects in the induction of specific ISGs.
• These findings suggest that impaired ISG induction is a key feature of the persistent HIV reservoir.
• Identified a set of ISGs that may function as latency restriction factors, potentially inhibiting the establishment of latent HIV infection.