Infectious disease: Insights into how rare individuals control HIV replication

In certain individuals with HIV-1 who are able to control virus replication without antiretroviral therapy (ART), the virus is frequently integrated into specific regions of the human genome in which viral transcription is suppressed. These findings are published online in Nature this week.

Less than 0.5% of individuals infected with HIV-1 are able to maintain drug-free control of HIV. Although viral reservoirs that are capable of replication have been identified in these individuals, it is unclear how this control takes place.

Xu Yu and colleagues compared proviruses (viral genomes that have been integrated into the DNA of a host cell) from cells of 64 people who maintain drug-free control of HIV-1 to those of 41 individuals who are receiving ART. The authors found that the median number of proviruses in cells from the drug-free ‘elite controllers’ was significantly lower than those in cells from individuals receiving ART. However, a larger proportion of the proviral sequences in the cells of these drug-free elite controllers were genetically intact. Using chromosomal integration site analysis, they observed that in drug-free elite controllers the virus was integrated into non-protein-coding regions of the DNA or in KRAB-ZNF genes on chromosome 19. These areas consist of tightly packed DNA (called heterochromatin) and are typically disfavoured for HIV-1 integration. They also found that the integration sites tended to be further away from host transcriptional start sites. The authors suggest that such deep viral dormancy, or latency, has a role in maintaining drug-free control of HIV-1, but note that this process is not completely permanent or irreversible.

In one individual, Yu and co-authors were unable to detect any intact proviral sequences in more than 1.5 billion peripheral blood mononuclear cells analysed. The authors cautiously suggest that this individual may have achieved a sterilizing cure of HIV, an effect previously only observed after hematopoietic bone marrow transplantation.