Our ability to keep HIV under control has been revolutionized by antiretroviral therapy (ART). But ART is not a cure — the HIV genome can integrate into host DNA and hide out in cells in a silent form, even after decades of successful therapy1–3. ART must be continued throughout life, to prevent the virus from rebounding from these viral reservoirs. Could ways to prevent this viral rebound be found by studying the small proportion (less than 0.5%) of people living with HIV who can control viral replication without the need for ART? Writing in Nature, Jiang et al.4 compared the viral reservoirs of these individuals, known as elite controllers, with those of people who are prescribed ART. Their findings suggest that elite control is associated with a small reservoir from which HIV is unlikely to be reactivated.
The authors began by using a sophisticated sequencing technique to compare viral genomes (proviruses) in millions of cells from the two groups of people. As expected, the comparison revealed fewer copies of the HIV genome in elite controllers than in people receiving ART. However, a higher proportion of the proviruses found in controllers were genetically intact — meaning that they have the potential to generate infectious viral particles when transcribed.
Jiang et al. frequently observed many identical copies of the viral genome in elite controllers. This observation confirms5 that infected cells have the ability to proliferate in controllers, as they do in people receiving ART6–8. Elite controllers are known9 to mount a potent immune response against HIV-infected cells, and the authors found that the proviral sequences persisting in elite controllers were predicted to generate viral proteins that could be targeted by this response.
How, then, do these proviruses escape the immune response? To answer this question, the authors made use of a recently developed approach10 to analyse the sites at which viruses have integrated into the host genome, in conjunction with corresponding proviral sequences. The analysis revealed several characteristics that suggest that the proviruses found in elite controllers are in a deeper state of latency (dormancy) than are the proviruses in people treated with ART.
First, proviruses in elite controllers are more likely to be integrated in non-protein-coding regions of the genome. Second, viral genomes from controllers are frequently positioned in, or surrounded by, repetitive stretches of DNA at chromosomal structures called centromeres. The host genome is packaged into a DNA–protein complex called chromatin — at centromeres, this packaging is unusually dense, which strongly represses transcription. Third, a substantial portion of HIV genomes in elite controllers are integrated in genes that encode members of the zinc-finger protein family, at which chromatin notoriously carries many molecular modifications that are associated with transcriptional repression11….
