Harvard: Investigators from Harvard Medical School, Massachusetts General Hospital, and the Ragon Institute of MGH, MIT and Harvard have added another piece to the puzzle of how a small group of individuals known as elite controllers are able to control HIV infection without drug treatment. In their paper published in the journal PLOS Pathogens, the research team reports finding that dendritic cells of elite controllers are better able to detect the presence of HIV—paradoxically through a greater susceptibility to HIV infection—which enables them to stimulate the generation of T cells specifically targeting the virus.
“It’s been recognized for a while that these individuals have
stronger T-cell immune responses against HIV than other patients, but
the reason for that has been unknown,” said Xu Yu,
HMS associate professor of medicine at Mass General and corresponding
author of the paper. “We have shown that dendritic cells, which play a
critical role in generating virus-specific T cells, have an improved
ability to recognize HIV and build effective immune responses in elite
Part of the innate immune system that is the body’s first line
defense against infection, dendritic cells sense the presence of
pathogens in the blood or other tissues, ingest infecting organisms and
then display fragments of the invaders on their surface, which alerts
and activates both killer and helper T cells (CD4 and CD8 cells),
essentially teaching them to target the specific pathogen.
Because of this critical role of dendritic cells, the investigators
explored the hypothesis that dendritic cells of elite controllers were
better able to sense HIV and, as a result, better able to generate
virus-specific T-cell responses.
When HIV infects a cell, it first injects its genetic material—RNA in
this case—into the cell along with the reverse transcriptase enzyme
that transcribes the single-strand RNA molecule into a double-stranded
DNA molecule. After HIV DNA enters the nucleus of an infected cell, it
becomes integrated into the cellular DNA, turning it into an HIV factory
that generates more virus particles.
In experiments using dendritic cells from elite controllers, from
patients with progressing HIV infection, and cells from uninfected
individuals, the investigators found a surprising difference. In most
people, HIV infection of dendritic cells appears to be blocked at an
early stage, resulting in a lack of HIV DNA and limited viral
replication within those cells. While this may seem beneficial, it
actually works more to the benefit of the virus than the infected
individual by allowing HIV to escape recognition by dendritic cells.
The dendritic cells of elite controllers, however, were found to
contain higher levels of HIV DNA, probably because of limited expression
of a protein called SAMDH1 that usually blocks reverse transcription in
several types of immune cells. The dendritic cells of elite controllers
also appear to produce higher levels of a DNA-sensing protein called
cGAS that recognizes the presence of HIV and induces rapid expression of
type 1 interferons. This contributes to the generation of the more
powerful T-cell responses against HIV that are typically observed in
“We are now focusing on fully understanding all the components
required to trigger appropriate activation of dendritic cells in HIV
infection, which may help to induce an elite-controller-like, drug-free
remission of HIV in a broader patient population,” Yu explained.