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Published on: May 30, 2013
Clonal Expansion of Infected CD4+ T Cells in People Living with HIV
John M Coffin1, Stephen H Hughes2
1Department of Molecular Biology and Microbiology, Tufts University, Boston, MA 02111, USA.
Insights
The human immunodeficiency virus (HIV) reservoir persists in patients on antiretroviral therapy (ART) due to clonal expansion of infected cells. Understanding this reservoir is key to developing a cure for HIV.
Area of Science:
- Immunology
- Virology
- Molecular Biology
Background:
- Current antiretroviral therapy (ART) cannot cure human immunodeficiency virus (HIV) infection.
- A persistent latent reservoir of infected CD4+ T cells, established before ART initiation, prevents complete viral eradication.
- Understanding the latent reservoir's nature and formation is crucial for developing curative HIV strategies.
Purpose of the Study:
- To investigate the clonal expansion of HIV-infected cells within the latent reservoir.
- To elucidate the mechanisms of HIV persistence in individuals undergoing suppressive ART.
- To identify factors contributing to viral reactivation from the latent reservoir.
Main Methods:
- Analysis of clonal structures within the HIV latent reservoir.
- Characterization of proviral DNA (intact vs. defective) in infected cell clones.
- Assessment of viral gene expression (RNA levels) in reservoir cells.
- Investigation of factors controlling proviral expression.
Main Results:
- A significant fraction of persistently HIV-infected cells on ART are large clones, challenging previous notions of resting cell infection.
- HIV persistence is largely driven by the expansion of infected cells, often due to antigen-driven activation.
- While most proviruses in clones are defective, intact infectious proviruses within these clones constitute the majority of the reservoir.
- Most proviruses are transcriptionally silent, but a small fraction expresses HIV RNA, with even fewer producing infectious virus capable of re-establishing infection upon ART cessation.
Conclusions:
- HIV persistence is primarily a result of clonal expansion of infected cells, not solely infection of resting cells.
- The latent reservoir comprises both defective and intact proviruses within expanded cell clones.
- Understanding the mechanisms controlling proviral expression in these clones is essential for developing strategies to purge the HIV reservoir and achieve a cure.
Abstract:
HIV infection is not curable with current antiretroviral therapy (ART) because a small fraction of CD4+ T cells infected prior to ART initiation persists. Understanding the nature of this latent reservoir and how it is created is essential to development of potentially curative strategies. The discovery that a large fraction of the persistently infected cells in individuals on suppressive ART are members of large clones greatly changed our view of the reservoir and how it arises. Rather than being the products of infection of resting cells, as was once thought, HIV persistence is largely or entirely a consequence of infection of cells that are either expanding or are destined to expand, primarily due to antigen-driven activation. Although most of the clones carry defective proviruses, some carry intact infectious proviruses; these clones comprise the majority of the reservoir. A large majority of both the defective and the intact infectious proviruses in clones of infected cells are transcriptionally silent; however, a small fraction expresses a few copies of unspliced HIV RNA. A much smaller fraction is responsible for production of low levels of infectious virus, which can rekindle infection when ART is stopped. Further understanding of the reservoir will be needed to clarify the mechanism(s) by which provirus expression is controlled in the clones of cells that constitute the reservoir.
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