Drug-free remission of HIV seen in ‘elite controllers’

Elite HIV controllers—those who can control viral replication without medications—have fewer proviral sequences, a recent study has found. These viral genomes appear to be more concentrated in inaccessible and transcriptionally repressed areas of the genome.

“[I]t is likely that deep viral latency in elite controllers is a dynamic process, and that occasional bursts of viral transcription may occur despite genomic and epigenetic features of integration sites restricting viral gene expression,” researchers said.

In order to profile viral genomes with great resolution, researchers performed full-length individual provirus sequencing on a cohort of elite controllers who had maintained undetectable HIV-1 levels for a median of 9 years. The same was done for a reference cohort of HIV-1 patients who had been on antiretroviral treatment (ART) for a similar duration.

Proviral genome analysis in 64 elite controllers and 41 ART-treated comparators showed that the per-person median count of proviral amplification products was significantly lower in elite controllers (p<0.001). This was true for both total and near-full-length intact HIV-1 DNA sequences. Notably, elite controllers had a higher proportion of intact proviral genomes than ART-treated references. [Nature 2020;doi:10.1038/s41586-020-2651-8]

To evaluate the landscape of the viral reservoir, the researchers focused on 11 elite controllers who had a sufficient number of cells for analysis. They found that intact proviral sequences integrated themselves into a total of 92 sites. Compared with ART-treated individuals, a significantly larger proportion of intact viral genomes were inserted in nongenic or pseudogenic regions (45 percent vs 17.8 percent; p=00051).

Moreover, sequences in elite controllers located in nongenic sites were often in the vicinity of centromeric satellite or microsatellite DNA, which are noncoding regions of the genome, consisting of stretches of densely packed heterochromatin devoid of protein-coding genes.

In cases were viral genomes were integrated at genic sites, elite controllers saw that insertion happened almost exclusively at introns that were transcriptionally weak, or in genes that are typically modified to be transcriptionally weak.

“[T]his work identifies a markedly distinct reservoir landscape of intact proviral sequences in peripheral blood mononuclear cells from individuals with durable natural control of HIV-1, characterized by features of integration sites that are highly suggestive of deep latency,” the researchers said.

In an in vitro experiment, they infected CD4⁺ T-cells from 12 elite controllers and nine healthy controls with an HIV-1 construct that also encoded for a fluorescent protein. They found no statistical evidence for the preferential insertion of proviral sequences in non-genic or transcriptionally repressed sites in elite controllers.

“We propose that the distinct reservoir configuration in elite controllers is not related to altered preferences for integration site locations during acute HIV-1 infection in elite controllers, but instead represents the result of cell-mediated immune selection forces that preferentially eliminate proviral sequences that are more permissive to viral transcription,” the researchers explained.

“[I]t is hoped that future longitudinal evaluations will be informative for designing strategies to induce long-term drug-free remission of HIV-1 infection in larger populations of individuals,” they added.