Improved HIV antiviral therapies in the offing

Scientists, including one of Indian-origin, have identified a human protein that weakens the immune response to HIV and other viruses, an advance that may help improve antiviral therapies, create viral vaccines and lead to new cancer treatments.
"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 Sumit Chanda, from Sanford-Burnham Prebys Medical Discovery Institute (SBP) in US.
"This research shows that the host protein NLRX1 is responsible - it's required for HIV infection and works by repressing the innate immune response," said Chanda.

The innate immune response works by producing a cascade of signalling chemicals (interferons and cytokines) that trigger cytotoxic T cells to kill pathogens.
Increasing evidence suggests that mounting an early, potent innate immune response is essential for the control of HIV infection, and may improve the effectiveness of vaccines.
"Importantly, we were able to show that deficiencies in NLRX1 reduce HIV replication, suggesting that the development of small molecules to modulate the innate immune response may inhibit viral transmission and promote immunity to infection," said Chanda.

"We anticipate expanding our research to identify NLRX1 inhibitors," he said.
Although HIV is a single-stranded RNA virus, after it infects an immune cell it is rapidly reverse transcribed into DNA, increasing the level of DNA found in the fluid portion of a cell (cytosol).

Elevated cytosolic DNA triggers a sensor called STING (stimulator of interferon genes) that turns on the innate immune response.
"Until now, the mechanism by which NLRX1 promoted HIV infection was unexplored. We have shown that NLRX1 interacts directly with STING, essentially blocking its ability to interact with an enzyme called TANK-binding kinase 1 (TBK1)," said Haitao Guo from the University of North Carolina (UNC) School of Medicine and lead author of the study.
"The STING-TBK1 interaction is a critical step for interferon production in response to elevated cytosolic DNA, and initiates the innate immune response," said Guo.
"This research expands our understanding of the role of host proteins in viral replication and the innate immune response to HIV infection, and can be extended to DNA viruses such as HSV and vaccinia," added Guo.

The findings were published in the journal Cell Host and Microbe.