Defective Proviruses Hinder Search For HIV Cure

Defective HIV proviruses cause more harm than previously believed, a recent study found. Prior research suggests that these defective proviruses are harmless. But in a study published in Cell Host and Microbe, investigators found that hypermutated HIV proviruses create proteins that cytotoxic T cells recognize as HIV.

“The virus has a lot of ways, even in its defective forms, to distract our immune systems, and understanding how they do this is essential in finding a cure,” lead investigator Ya Chi Ho, MD said in a press release about the study.

HIV proviruses can outnumber functional HIV by approximately 1000 copies to 1. The faulty proteins can make it more challenging to accurately measure a patient’s viral load. Furthermore, it can also exhaust immune systems, shield functional HIV from attack by natural means or drugs, and complicate the development of a cure.

Scientists believe they could exploit the hypermutated HIV proviruses to eliminate defective HIV proviruses and develop an HIV cure. For the study, investigators collected 9 different defective HIV proviruses from 6 patients with HIV, and transfected cultures of human immune cells with the defective proviruses in the laboratory.

The transfected cells were grown and tested for potential markers of HIV proliferation. The results showed that all of them could create these components despite their mutations.

“The fact that defective proviruses can contribute to viral RNA and protein production is concerning, because it means that the measurements of HIV load in infected patients may not be as accurate as we thought. Part of the count is coming from defective viruses,” Ho said. Once the investigators verified that the defective proviruses create HIV proteins, they tested whether human immune system cells could biologically recognize and interact with the proteins.

Cells were transfected in the lab with 6 different types of defective HIV proviruses obtained from patients. The investigators then matched the cytotoxic T lymphocytes from the corresponding patient in the infected cells. The results of the study showed that the cells containing hypermutated HIV could be recognized by cytotoxic T cells of a patient with HIV.

“If we identify and find a way to use the right protein, perhaps one of those expressed by the ‘hypermutated’ HIV we found in this study, we could create a potent vaccine which could boost the immune system enough to eliminate HIV altogether,” Ho said.

Unfortunately, defective HIV proviruses can also distract immune cells from attacking infectious HIV. “The cytotoxic T lymphocytes’ ability to identify and target the real threat appears to be greatly impaired, because a they may attack proteins from defective proviruses instead of the real thing,” Ho said. The authors hope their findings will fuel research to gain more information about the mutant proviruses, and to create a cure for HIV.

Reference

Pollack RA, Jones BR,Pertea M et al. Defective HIV-1 proviruses are expressed and can be recognized by cytotoxic T lymphocytes, which shape the proviral landscape. Cell Host Microbe. 2017;21 (4), 494-506.e4.