Why Doesn't the Immune System Clear HIV?

Research may lead to new drugs that boost the immune response to HIV.

The host protein NLRX1 was found to weaken the immune response to HIV in humans and could help in the development of future treatments.

An early and potent innate immune response is necessary for the control of HIV and could help improve the efficacy of viral vaccines, a study published in Cell Host & Microbe found.

“Our study provides critical insight on a paramount issue in HIV research: Why is the body unable to mount an efficient immune response to HIV to prevent transmission?” said co-senior study author Sumit Chanda, PhD. “This research shows that the host protein NLRX1 is responsible — it’s required for HIV infection and works by repressing the innate immune response.”

The study provided evidence that NLRX1 deficiencies reduce HIV replication. The results suggest that by developing small molecules that modulate the innate immune response, it could inhibit viral transmission and promote infection immunity.

“We anticipate expanding our research to identify NLRX1 inhibitors,” Chanda said.

Once HIV infects an immune cell, it’s rapidly reverse transcribed into DNA, increasing the level of DNA found in the cytosol.

When cytosolic DNA is elevated, it triggers a stimulator of interferon genes (STING), a sensor that turns on the innate immune response.

“Until now, the mechanism by which NLRX1 promoted HIV infection was unexplored,” said researcher Haitao Guo, PhD. “We have shown that NLRX1 interacts directly with STING, essentially blocking its ability to interact with an enzyme called TANK-binding kinase 1 (TBK1). The STING-TBK1 interaction is a critical step for interferon production in response to elevated cytosolic DNA, and initiates the innate immune response.”

This discovery is similar to host immune checkpoints, PD-L1 and CTLA-1 that control the immune response to cancer.

Immune checkpoints are immunological “brakes” that prevent over-activation of the immune system on health cells. Tumor cells will use these checkpoints to evade detection from the immune system.

Currently, there are several FDA-approved checkpoint inhibitors available for the treatment of certain cancers.

“Checkpoint inhibitors have made a huge impact on cancer treatment, and significant investment by the biotech/pharmaceutical sector is being made to identify STING inhibitors as the next generation of immune-oncology therapeutics,” said lead study author Jenny Ting, PhD. “This study, showing that NLRX1 is a checkpoint of STING, sheds more light on the topic and will help advance those efforts.”