Active Infection & Immunity Genetics & Molecular Biology

Permissivity and reprogramming during HIV-1 infection of T cells

Funder Wellcome Charity-funded
Recipient organisation Queen Mary University of London
Funding £2.2M
Period Oct 2021 — Oct 2026

In plain English

AI plain-English summary

HIV-1 slips directly from one T-cell to another, bypassing the bloodstream, and this cell-to-cell spread makes resting T-cells—normally resistant to infection—suddenly vulnerable. This matters because current HIV treatments keep the virus suppressed but cannot eliminate it from the body. The virus persists in resting T-cells, which act as hidden reservoirs. Understanding how HIV-1 forces these cells to become permissive could reveal why the virus is so difficult to eradicate and how it rewires T-cell identity. The researcher has already found that HIV-1 reprograms infected T-cells into a tissue-residency-like state via the viral protein Vpr, a previously unknown consequence of infection. If this work succeeds, it will map the molecular steps HIV-1 uses to override a T-cell’s natural defences and reshape its fate. That knowledge could inform strategies to flush out or disable the latent reservoir—a critical step toward a cure. The project is fundamental science: it asks how a virus manipulates its primary target cell. Past discoveries in HIV cell biology have already transformed treatment from a death sentence to a manageable condition; deeper mechanistic understanding here could open routes to therapies that do not yet exist.

View original technical description
I aim to understand the molecular and cellular mechanisms regulating HIV-1 replication and spread in T-cells and how the virus manipulates cells to create a permissive niche. HIV-1 most efficiently disseminates between T-cells by cell-cell spread (CCS) that dominates infection. We have recently discovered CCS triggers target T-cells to become vastly more susceptible to infection, allowing HIV-1 to replicate in resting T-cells that are usually non-permissive for infection. By using CCS infection to bypass the need to mitogenically stimulate target T-cells (a process which drastically changes T-cell biology), we have discovered HIV-1 transcriptionally and phenotypically reprogrammes T-cells to induce a tissue-residency-like phenotype via Vpr, revealing new consequences of HIV-1 infection. Our key goals are now to: - Determine how CCS drives HIV-1 replication in resting T-cells, defining key viral and cellular factors and mechanisms. - Determine how HIV-1 navigates innate immune defences to infect resting T-cells, how this shapes permissivity, and how sensing operates in T-cells. - Dissect how HIV-1 reprogrammes T-cells, Vpr mechanism and the consequences for T-cell fate and function.Our work will advance mechanistic understanding of how HIV-1 manipulates its most important target cell to drive replication and persistence, uncover exciting new biology and inform future therapeutic innovation towards cure.

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Researchers

Clare Jolly (EPMC Awardee)

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Original classification

Investigator Award in Science

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