Researchers have reported that a third patient, referred to as an elite controller, has recovered from HIV-1 infection. Furthermore, this patient is the first known patient to recover without the use of drugs or surgery.
Durable HIV-1 control
Scientists consider elite controllers as untreated individuals that can durably control HIV-1 replication below detection thresholds of commercial viral assays. This to date represents the closest possible approximation to a natural cure of HIV-1 infection.
Previous research has linked elite control to specific variations within the human HLA class I gene locus. Research has also linked this to the presence of a highly functional cellular immune response. Scientists have well documented the presence of small, replication-competent proviral reservoirs in elite controllers. However, researchers have struggled to define the characteristics and distinguishing features of these cells in different individuals.
In this study, published in Nature, researchers used full-length individual provirus sequencing (FLIP-seq) to profile the proviral reservoir landscape at single-genome resolution of a cohort of elite controllers (n=1,385 from 64 elite controllers). This group maintained an undetectable HIV-1 plasma viral load for a median of 9 years. A cohort of 41 patients with HIV-1 infection who were treated with antiretroviral therapy (ART) was used as a comparison. Researchers also undertook a more in-depth analysis in the reservoirs of two elite controllers for whom they observed no genome-intact proviral sequences from their initial analysis.
Elite controller vs Long-term ART
The team found that in contrast to individuals treated with ART, elite controllers have intact proviral sequences integrated at high distinct sites within the human genome. Integration was preferentially located in centromeric satellite DNA or in Krüppel-associated box domain-containing zinc finger genes on chromosome 19. Researchers have shown that both of these regions associate with heterochromatin features. Furthermore, in elite controllers the sites of integration were further away from transcriptional start sites and accessible chromatin. These regions were enriched with repressive chromatin marks. These features are highly suggestive of deep latency.
The team found a single genome-intact proviral sequence in one of the elite controllers. They detected this sequence after analysing 1.02 billion peripheral blood mononuclear cells (PBMCs). For the other elite controller, despite analysing more than 1.5 billion PBMCs, they detected no single genome-intact proviral sequences.
Implications
The team highlight that quality rather than quantity of viral reservoirs may be a distinguishing feature for a functional cure of HIV-1 infection. The distinct configurations of the reservoirs represent a structural correlate of natural viral control.
To date, scientists believe that only two other individuals have recovered from HIV-1 infection. Timothy Ray Brown (‘The Berlin patient’) and Adam Castillejo (‘The London patient’) both undertook haematopoietic stem cell transplantations from donors who were homozygous for CCR5Δ32. Although the team cannot confirm that this current patient is cured of HIV-1 infection, they note that they failed to falsify this hypothesis despite analysing a large number of cells with sensitive detection techniques.
Image credit: Photo by Image Team – canva.com
