In prior updates, we’ve focused on CCR5, the primary receptor enabling HIV to infect cells. CCR5 is known for its role in the cure of the “Berlin patient” following a bone marrow transplant with donor cells bearing a mutated, thus non-functional, CCR5 protein.
Reporting in the online journal eLIFE, Dr. Steven Deeks of the University of California, San Francisco, and colleagues, found another way that CCR5 is connected to the ability to control HIV without antiretroviral therapy (ART). Interestingly, they also found evidence that this ability is heritable.
Deeks and colleagues sought to define genetic factors enabling a small population of HIV-infected individuals called elite and viremic controllers to maintain viral loads less than 50 or 2000 copies, respectively, without ART. These are considered “functional cures” since the virus is not eradicated—the usual definition of “cure”—but the person does not develop immune problems over time.
The researchers studied 131 such individuals, about half elite and half viremic controllers, some of whom have been infected since 1980. Some had HLA types—cell protein markers—associated with elite control, but those protective genes account for only about 20% of the viral effect.
They discovered that control was related to a natural and partial resistance to infection in controllers and noncontrollers. Further analysis showed that controllers had less CCR5 present on their cells than noncontrollers, and their cells were less permissive to HIV infection. Furthermore, natural resistance to HIV was shown to be inherited, as multiple generations of family members, male and female, from one of the viremic controllers had a similar profile of lowered CCR5.
There have now been at least two instances related to CCR5 in which researchers identified partial or full resistance to HIV. The first is a rare mutation, CCR5-delta32—a defunct CCR5 protein—leading to the cures of the Berlin and London patients after stem cell transplants with cells containing this mutation. The second, in this new study by Deeks and colleagues, is the natural decrease in some elite and viremic controllers who make a normal CCR5 protein, but at much lower levels than people who cannot control HIV.
Studying how and under what circumstances these controllers make lower levels of CCR5 may lead to new discoveries that could inform interventions for a functional cure.