Novel gene-sequencing probes to investigate ‘elite controllers’

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A study has used novel gene-sequencing probes to investigate exactly how the one in 200 people with HIV who are so-called “elite controllers” manage the feat. Aidsmap reports that the study, by Chenyang Jiang and colleagues from the Ragon Institute, a research consortium dedicated to finding vaccines and cures for HIV and other infectious diseases, suggests that a dynamic process happens whereby a strong anti-HIV response by the CD8 cells of the immune system preferentially kills off cells that are more likely to produce active HIV, but that in turn the low-level stimulus from the cells that are left – and which contain HIV genes that are much less likely to spring into action – is nonetheless enough to keep the anti-HIV CD8 response attuned to HIV.

In one individual among the 64 elite controllers studied, the investigators were unable to find any replication-competent HIV genetic material in over a billion T-cells, and were also unable to grow any HIV from her T-cells. Although the investigators say cautiously that “the logic of scientific discovery does not allow us to confirm that [this patient] has achieved a sterilising cure of HIV infection through natural immune-mediated mechanisms, it is notable that we have failed to falsify this hypothesis”.

In other words, the report says, this patient has managed to clear all intact viral material from her system in what could truly be called a self-cure.

Dr Xu Yu, the paper’s senior author, is quoted in the report as saying that since it was written they have found a couple more people that could qualify as cures. And the team is now contacting people who have been on stable ART for more than 20 years to find out if they too, have managed to exile their virus to a genetic version of Siberia.

Sustained, drug-free control of HIV-1 replication is naturally achieved in less than 0.5% of infected individuals (here termed ‘elite controllers’), despite the presence of a replication-competent viral reservoir1. Inducing such an ability to spontaneously maintain undetectable plasma viraemia is a major objective of HIV-1 cure research, but the characteristics of proviral reservoirs in elite controllers remain to be determined. Here, using next-generation sequencing of near-full-length single HIV-1 genomes and corresponding chromosomal integration sites, we show that the proviral reservoirs of elite controllers frequently consist of oligoclonal to near-monoclonal clusters of intact proviral sequences. In contrast to individuals treated with long-term antiretroviral therapy, intact proviral sequences from elite controllers were integrated at highly distinct sites in the human genome and were preferentially located in centromeric satellite DNA or in Krüppel-associated box domain-containing zinc finger genes on chromosome 19, both of which are associated with heterochromatin features. Moreover, the integration sites of intact proviral sequences from elite controllers showed an increased distance to transcriptional start sites and accessible chromatin of the host genome and were enriched in repressive chromatin marks. These data suggest that a distinct configuration of the proviral reservoir represents a structural correlate of natural viral control, and that the quality, rather than the quantity, of viral reservoirs can be an important distinguishing feature for a functional cure of HIV-1 infection. Moreover, in one elite controller, we were unable to detect intact proviral sequences despite analysing more than 1.5 billion peripheral blood mononuclear cells, which raises the possibility that a sterilizing cure of HIV-1 infection, which has previously been observed only following allogeneic haematopoietic stem cell transplantation2,3, may be feasible in rare instances.

Chenyang Jiang, Xiaodong Lian, Ce Gao, Xiaoming Sun, Kevin B Einkauf, Joshua M Chevalier, Samantha MY Chen, Stephane Hua, Ben Rhee, Kaylee Chang, Jane E Blackmer, Matthew Osborn, Michael J Peluso, Rebecca Hoh, Ma Somsouk, Jeffrey Milush, Lynn N Bertagnolli, Sarah E Sweet, Joseph A Varriale, Peter D Burbelo, Tae-Wook Chun, Gregory M Laird, Erik Serrao, Alan N Engelman, Mary Carrington, Robert F Siliciano, Janet M Siliciano, Steven G Deeks, Bruce D Walker, Mathias Lichterfeld, Xu G Yu


Full Aidsmap report


Nature abstract


Nature article

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