IL-21 May Play Key Role in Limiting Early HIV Infection

By triggering CD4 cells to pump out more of a small RNA molecule called microRNA-29, interleukin-21 (IL-21) limits HIV replication soon after infection, according to results of tissue and mouse studies conducted by U.S. researchers. The investigators believe their findings, which were published June 25 in Nature Communications, offer insight into the first steps of HIV infection and could inform strategies that limit the magnitude of early HIV infection.

Scientists have long appreciated the role IL-21 plays in activating CD4 cells to produce antibodies in response to HIV. Much less is known about how IL-21 triggers an immune response immediately after HIV infection. To address that question, scientists from Weill Cornell Medical College, the Ragon Institute of MGH, MIT and Harvard, and Massachusetts General Hospital conducted two sets of experiments.

First they made human lymphoid organ tissue cultures -- mainly from spleen and lymph nodes. They doused some cultures with IL-21 and left others unexposed. Three days after infecting the cultures with HIV-1, the investigators found that those treated with IL-21 harbored about two-thirds less virus than untreated cultures.

A second set of experiments assessed the impact of IL-21 in mice transplanted with human bone marrow, fetal liver, and thymus stem cells to create a human-like immune system. After exposing these fully reconstituted humanized mice to HIV-1, the researchers verified severe depletion of CD4 cells from gut and lamina propria, which was reflected in a loss of IL-21-producing CD4 cells. Next the researchers injected the mice with either inert plasmid (these were the control mice) or IL-21-encoding plasmid aimed at inducing IL-21 expression. Compared with control mice, those injected with IL-21 plasmid had higher IL-21 levels 72 hours after injection.

Then the investigators infected both groups of mice with HIV-1.

Two weeks later, nine of 12 control mice (75%) had a plasma viral load above 100,000 copies/mL, compared with only two of 14 IL-21-treated mice (14%). Eight of 14 IL-21-treated mice (57%) had a plasma viral load below 100 copies/mL.

In addition, viral load correlated inversely with IL-21 level in plasma. Lower viral load also correlated with higher levels of spleen CD4 cells expressing microRNA-29, an antiviral factor induced by IL-21.

The researchers stressed that IL-21 suppressed initial HIV infection in CD4 cells independently of cytotoxic CD8 cells or natural killer cells, which reached equivalent levels in control mice.

Because of these findings, the authors "speculate that local concentrations of IL-21 produced by ... CD4 T cells in mucosal tissues would contribute to limiting the magnitude of HIV-1 replication and initial dissemination" in the first week of HIV infection. They proposed that "endogenous IL-21 and strategies that exogenously augment IL-21 or induce pre-existing cellular sources of IL-21" could both promote adaptive antiviral immunity and help limit the scope of the early HIV infection.

Mark Mascolini is a freelance writer focused on HIV infection.