Track A report by Renee van der Sluis
This symposium provided a comprehensive
overview of HIV-1 latency and reservoirs, including the latest information on
the ‘Mississippi child’, molecular mechanisms contributing to latency, current
approaches to target the reservoir, the complexity of T cell subsets and the
contribution of tissues, notably the CNS, as a reservoir.
Dr. Persaud (USA) offered a
late-breaker update on the ‘Mississippi Child’ who recently experienced HIV
rebound after 27 months of viral remission in the absence of therapy. Despite
this setback, Dr. Persaud was optimistic about the length of remission observed
and she underscored the importance of early therapy initiation, emphasizing
this case as strong in vivo evidence
supporting early establishment of the latent reservoir following infection.
Dr. van Lint (Belgium) followed with a
detailed description of the multifactorial molecular, epigenetic and
non-epigenetic mechanisms associated with viral latency. She discussed clinical
trials using HDAC inhibitors to reactivate latent HIV according to the ‘shock
and kill’ approach whilst patients remain on cART. This strategy aims to
reactivate HIV (shock) to produce viral proteins and/or virus particles that
will subsequently lead to the elimination of infected cells due to
virus-induced cytopathic effects or recognition of the infected cell by the
immune system (kill). These trials have indicated that the HDAC inhibitors will
likely need to be combined with other agents, such as vaccines, to effectively
eliminate latent HIV.
Dr. Verdin (USA) presented a study in
which an shRNA library targeting nearly 19,000 cellular proteins was used to
identify host proteins that contribute to reactivation of latent virus. This
work revealed several novel protein complexes that may regulate HIV latency,
including mTOR and TGF-beta. Notably, inhibitors of the mTOR pathway blocked
reactivation viral latency, providing a potential alternative to ‘shock and
‘kill’ where virus might be permanently silenced.
The last two speakers illustrated the
complexity of the latent reservoir and also highlighted the fact that multiple cell
types and cell subsets contribute to the latent pool. Dr. Chomont (USA) provided an overview
of T cell subsets, demonstrating that they showed
remarkable differences in terms of their contribution to the reservoir as well
as their susceptibility to reactivation. He also presented data suggesting that
early initiation of cART did not prevent latency establishment, however the size
of the reservoir in each T cell subset was reduced.
Finally, Dr. Churchill (Australia) gave
an excellent summary of the current knowledge on the CNS as an HIV sanctuary,
emphasizing that various anatomical sites display different features compared
to peripheral blood in terms of drug penetration and that neuronal cells
permissive for viral replication and latency, such as astrocytes, will require different
approaches since it would be unfavourable to induce cell death in the CNS
Altogether, this session provided an
excellent opportunity for participants to improve and update their
understanding of HIV latency.
Speakers presented the many remaining challenges to target latent HIV-1,
but also demonstrated what we already know a lot about the diversity of latent cells
and complexity of reservoirs. Take home messages: early start of ARV reduces
the size of the reservoir and we will likely need several approaches to target
all viral sanctuary sites due to its multifaceted nature.