For HIV Reservoirs, One Size Does Not Fit All

Taking effective medications daily allows people living with HIV to suppress the virus in their body, lead longer and healthier lives and prevent transmission to sexual partners. However, therapies for HIV have not yet been able to eliminate latently infected cells—collectively known as the HIV reservoir—that hide from the immune system and reestablish infection when someone stops therapy.

Scientists have previously recognized that the HIV reservoir varies in size between individuals. Now, NIAID researchers and their collaborators have discovered that variations in an important viral gene may play a role in the size of one’s HIV reservoir. Their findings, reported online last week in the Journal of Virology, expand scientists’ understanding of how specific attributes of the virus a person acquires can affect the course and nature of their HIV infection.

The authors analyzed viral samples and HIV reservoir data from 30 Canadian volunteers who recently acquired HIV. In Canada and elsewhere in the Americas, people are more likely to acquire a subtype of HIV known as clade B HIV. NIAID researchers previously found that people living with clade B HIV in Baltimore had, on average, larger HIV reservoirs—measured by the number of cells latently infected with HIV—than Ugandans living with clade A or D HIV. In the new study, investigators hypothesized that this may be in part because clade B viruses have a more functional version of an HIV gene called nef. This gene encodes the Nef protein, which helps the virus skirt our immune systems’ defenses during early infection to access T cells and establish latent infection. Researchers wondered, could more functional nef genes lead to larger HIV reservoirs?

Among the 30 study participants, 25 had clade B HIV, while five had another subtype of the virus. As expected, after a year of consistent therapy with anti-HIV medications, researchers found that volunteers without clade B HIV had smaller reservoirs. Viral nef genes for these individuals were indeed less active than their clade B counterparts, and researchers observed that the less active they were, the smaller the HIV reservoir. Even in the participants who were infected with subtype B HIV, those with more functional nef genes had larger reservoirs. However, nef activity did not fully explain the gap in reservoir size between clade B and non-clade-B viruses, suggesting that further research is needed to better understand the many factors—including other viral genes and proteins—that may play a role in this discrepancy.

Understanding how differences in viral genes and protein function impact the size of the HIV reservoir may inform research efforts towards eliminating HIV in the body, an approach to an HIV cure also known as viral eradication. However, researchers emphasize that, most of all, this small study helps underscore the significance of the genetic diversity of human immunodeficiency viruses that circulate in people around the globe.

Reference:
F Omondi et al. HIV subtype and Nef-mediated immune evasion function correlate with viral reservoir size in early-treated individuals. Journal of Virology DOI: 10.1128/JVI.01832-18 (2019).