How HIV adapted for pandemic spread

Image - How HIV adapted for pandemic spread

Pandemic-causing HIV strain sneaks past cellular sensors that activate immune destruction of viruses.

The human immunodeficiency virus, or HIV, is a retrovirus originally transmitted from animals to humans. It has been reported that thirteen different strains of HIV have emerged from such transmissions, known as zoonotic events. But only one of these strains is readily transmitted from human to human and responsible for the HIV and AIDS pandemic.

Research teams led by Professor Greg Towers of University College London and UNSW Sydney’s School of Biomedical Sciences researcher Dr David Jacques set out to determine what gives the pandemic strain of HIV – named HIV-1(M) – the fitness advantage over other strains.

Innate immune cells have specialised sensors for HIV that, once set off, trigger production of potent anti-viral agents that quickly destroy the virus. The researchers report in Nature Microbiology that pandemic HIV has evolved mechanisms to evade these sensors in macrophages, cells among the first to respond to invading pathogens. In stealth mode, the virus can establish infection, make enough copies of its genetic material to infect more cells, and spread rampantly between humans.

“We believe that it’s the ability to evade the innate immune system that grants the virus pandemic potential. And only the pandemic HIV strain is able to establish infection in macrophages. The other strains are stopped by macrophages before infection can establish,” said Dr Jacques, head of the Structural Virology Group in the Department of Molecular Medicine.

By comparing the immune responses elicited by infection with pandemic and non-pandemic HIV strains, and examining the viral structures of the different strains, the interdisciplinary team discovered small mutations in HIV-1(M) that enable the virus to evade host immune defences.

Macrophages have two protein sensors to let them know when HIV is present: TRIM5 recognises retroviral capsids which shields the viral genome, while cGAS is triggered when DNA is detected in the cell cytoplasm – where there is usually no DNA in uninfected cells. These surveillance systems are somehow tricked by the pandemic HIV strain.  

“We found that the structure of the capsid is different between the pandemic and non-pandemic strains of HIV, but only slightly. Two mutations in the capsid of pandemic HIV appears to be enough for it to escape detection by TRIM5. The sensor cannot recognise the capsid anymore because the surface structure is more dynamic,” Dr Jacques said.

“And it looks like the pandemic virus no longer exposes its DNA. This is something we still don’t understand much about.”

These new observations show how HIV has adapted to evade immune defences in humans, leading to wide-spread transmission globally. Dr Jacques believes that it also provides new insight into viruses more broadly.  

“This discovery helps us to understand fundamental virology. It tells us more about the capsid, its role in infection and how it interacts with the immune system. Retroviruses are useful tools for genetic manipulation in the laboratory, and their capsids are therapeutic targets. So, we need to understand them better for research and clinical purposes.”

This research was enabled in part by the Structural Biology Facility in the Mark Wainwright Analytical Centre at UNSW.

Date Published: 
Friday, 13 January 2023