The session gave an overview of viral reservoirs, factors affecting latency and the complexity of latency between and within tissue types.
Dr Persaud from the United States began the session with the unfortunate news and analysis of the re-emergence of HIV infection in the “Mississippi child”. The researchers detected HIV-1 plasma RNA 27 months after earlier assays showed no virus present. Phylogenetic analysis of the virus confirmed it to be a 98% similar to the virus isolated from the mother, strongly suggesting reemergence from “viral remission” rather than the child becoming newly infected via another source.
Dr Van Lint from Belgium then gave a brisk yet detailed overview of viral latency mechanisms. She referenced studies which showed HIV-1 preferentially integrates into transcriptionally active regions of the genome and areas associated with clonal expansion when infecting T-cells.
Dr Van Lint also gave an overview of existing “anti-latency” agents such as vorinostat (SAHA), and newer agents such as Romidepsin, which may be more potent – very much needed if the approach is to be effective in virally suppressed patients on ART.
The presentation was finished with a description of the many cell-associated and viral factors involved in latency and thus the multitude of potential targets for anti-latency therapeutics. However, as research emerges on the complexities of HIV viral latency, it also highlights the heterogeneity of the mechanisms involved in latency within different tissue and cell types and even between individual cells. Any future therapies will need to accommodate this if they are to have any lasting benefit.
Dr Verdin from the United States reiterated the complex nature of viral latency and then described an innovative system using Green Florescent Protein (GFP) and other reporter genes to visualise a profile of genes associated with viral latency (both promoting and suppressing).
This produced a milieu of genes and related protein complexes involved, some known previously, others completely new to the viral latency field. An unexpected outcome of the increased understanding of the breadth of cell-associated factors involved in latency was the closing suggestion of considering therapeutic agents to increase or promote viral latency rather than suppress it (unlike the current experimental agents being trialled which aim to reduce viral latency). By targeting the integrated proviral DNA and “locking it in place”, away from transcription and subsequent virus production, the outcome could be similar to ART, but perhaps more potent?
Dr Chomont from the United States followed on by describing the heterogeneity within latently infected CD4+ T cells and the proportion of subsets infected within different patient groups such as post-treatment controllers and long-term non-progressors.
Both have higher proportions of latently infected cells with a more differentiated phenotype (which have a shorter turn over period within the body). He then described the role of early treatment on latently infected CD4+ T cells with mixed results.
For example Buzon et al. 2014 showed that early ART initiation did not affect the proportion of the more naive (and longer lasting) cells being infected.
However, research discussed by Dr Jintanat Ananworanich earlier in the day suggested that very early initiation of ART (2/3 weeks after infection) was associated with a reduction in the size of the reservoir in all CD4+ T-cell subsets, including the longer lasting central memory cells.
Dr Chomont also remarked that this benefit could remain even if treatment is delayed until 4-8 weeks after infection - still very early initiation within a real world setting however.
The session was concluded by Dr Melissa Churchill, from the Burnet Institute, Melbourne who presented on the role of tissue reservoirs and in particular the CNS. She described the role of the CNS as a probable viral reservoir citing multiple indirect studies, but also acknowledging the lack of conclusive and direct evidence.
Latency in the CNS is likely and, just as was reported in earlier presentations, so is the heterogeneity in latency between the different cell types susceptible to HIV infection in the CNS; astrocytes, macrophages, and microglial cells.
Dr Churchill concluded by discussing the potential role of current curative strategies (such as using histone deacetylase [HDAC] inhibitors) on the CNS with some caution – cell death within the CNS even if targeted specifically to latently infected cells would likely have negative consequences for the tissue and therefore the patient.