AUTHOR: Nick Kolev

Antiretroviral therapy can hold HIV in check for a lifetime, but it cannot clear it. A small number of infected cells carry a complete, working copy of the virus in their DNA and can survive for decades. If treatment stops, those cells restart the infection. These cells, known as the HIV reservoir, are functionally the main reason HIV has no cure.

The field has long assumed these cells go unnoticed. Because they produce little or no virus, there is nothing for the immune system to recognize. That assumption shaped two decades of cure research, including the “shock and kill” strategy, which tries to wake the hidden virus so the immune system can find and destroy it.

Research from the Lichterfeld Lab and Yu Lab at the Ragon Institute of Mass General Brigham, MIT, and Harvard, published in Nature Immunology, suggests otherwise. The paper, titled “Innate immune imprints shape HIV-1 reservoir cell persistence during long-term
antiretroviral therapy,” shows that even after 20 years of treatment, the reservoir is under steady immune pressure from natural killer (NK) cells. 

NK cells work differently from T cells which are the other main component of the immune response. Instead of hunting a specific target, they check whether a cell is displaying proper identification on its surface. Healthy cells carry proteins called HLA molecules that signal they belong. Viruses often strip those proteins away to hide from T cells, and NK cells are built to catch exactly that. A cell missing its HLA molecules gets flagged and killed.

The team sequenced more than 6,000 copies of viral DNA from 104 people living with HIV who had been on treatment for a median of 21 years, then compared the size of each person’s reservoir to their genetics. People carrying a version of the HLA-C protein called C2, which trains a specific group of NK cells to respond more strongly, had markedly fewer intact viruses. The same pattern held for a second group of NK cells trained on a different HLA protein.

That advantage was absent in a separate group of 4,007 people who were not on antiviral treatment, which suggests that NK cells can specifically target infected cells that persist during ART, rather than an effect carried over from before therapy began. 

Supporting evidence came from the virus itself. HIV carries a protein called Vpu that strips HLA-C from the cell surface. In people with C2, viruses whose Vpu did this efficiently were linked to smaller reservoirs, consistent with those infected cells being easier for NK cells to spot. Meanwhile, the few infected cells that survived two decades of treatment carried unusually high levels of HLA-C, a sign they had been selected for keeping their identification firmly in place.

Taken together, the most and least favorable combinations of human and viral genetics differed in reservoir size by more than sevenfold, roughly what a decade of continuous treatment achieves on its own.

Overall, this study shows that the human immune system is not powerless against the rare HIV-infected cells that persist despite current antiviral treatment. If appropriately programmed and directed, NK cell-based immune therapies could represent promising approaches for targeting and eliminating such virally-infected cells, and may ultimately allow for interventions that lead to a cure of HIV infection.