Biology of the HIV-1 latent reservoir and implications for cure

  • Heather Mason
  • Medical News
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Antiretroviral therapy (ART) inhibits HIV, but it is not curative, and as only around 50% of the world’s HIV population receives effective ART, a cure is a priority. In this review article published in Cell Host & Microbe, the mechanisms behind persistence are described, highlighting findings from recent studies.  

With the emergence of advanced single-cell methodologies and next-generation sequencing capacities, it is clear that the latent reservoir is dynamic, with multiple factors such as gender and age contributing to its maintenance.

The persistence is ensured through massive and sustained clonal expansion of cells infected with intact and defective proviruses. Three mechanisms may contribute to this expansion: integration in or near genes associated with cell growth, homeostatic proliferation, and antigen-driven proliferation.

During ART, a minority of HIV-1 infected cells are transcriptionally active, producing elongated HIV-1 RNA, HIV-1 proteins, and intact virions. Thus, the reservoir is heterogeneous, with a continuum from ‘deep latency’ to active virion production. Using a method to quantify unspliced HIV-1 RNA production it was estimated that 10% of circulating infected cells express detectable levels of HIV-1 RNA. Simply transcribing HIV may not be sufficient to make a cell productive, the blocks to proximal elongation, polyadenylation, and splicing may be responsible for latency.

In one study, ART was started 4-5 days post-infection, revealing that a permanent latent reservoir was prevented, which may occur in patients receiving post-exposure prophylaxis (PrEP). A focus of ongoing research is the precise characterisation of cells harbouring latent infection.

Further study is required to uncover the contribution of infected cells in the periphery to viral rebound and a method to assess the whole-body virus burden in people living with HIV-1. Additional insight into immune control, by studying individuals who spontaneously control HIV-1 infection, will prove important.