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Despite the development of effective therapeutics, HIV, the virus that causes AIDS, remains a major threat to humans worldwide. 37.9 million people are currently living with HIV, with 770,000 people dying of AIDS each year.  A cure for HIV is essential, but has not been made.  To better combat HIV, and to inform the development of new and better antiviral drugs to treat infection, an international group of scientists, led by Dr. Michael Gale, Jr., at the University of Washington, and Drs. Fredrik Barrenas and Jan Komorowski of the University of Uppsala, Sweden, and of the Institute of Computer Science, Polish Academy of Sciences, have evaluated the immune system in the early stages of infection in nonhuman primates exposed to the Simian immunodeficiency virus (SIV), a virus closely related to HIV that serves to model HIV infection.  The study, which is to be published November 8, 2019 in Nature Communications, found that the biological events involved in wound healing are important in creating an immune environment that is protective against SIV. This finding reveals components of the body’s wound healing immune response as novel targets for therapeutic development to protect against disease and AIDS in people with HIV infection.

The study involved the application of “Systems Biology” to examine gene expression in cells and tissues across the body and immune system, and by applying computational analyses known as “Bioinformatics”. The group used a combination of data from their experiments and from other published studies to generate their findings. From the combined data sets the team created a new Systems Biology approach to evaluate the virus-host interactions and immune response of SIV infection as well as HIV infection humans. The group found that the activation of a specialized wound healing program following infection decreased the chance of progressing to AIDS.  “The use of public datasets were a key component of this research, and highlight the importance of the scientific community sharing their data in public forums,” said Dr. Barrenas, the lead author of the paper and senior scientist at Uppsala University.

Upon HIV or SIV infection, the virus infects an essential immune cell called a T helper cell, which is found in large numbers within the intestine and in specialized tissue elsewhere in the body. HIV infection causes an immune response that injures the tissue surrounding the intestine and allows the bacteria that normally reside in the intestine to penetrate the tissue and invade other sites of the body to cause further inflammation and damage. In HIV infection this process is known to attract more immune cells, some of which get infected with HIV, with others undergoing a program of spontaneous cell death in an overall process leading to AIDS. However, when wound healing is activated, the team found, this progression of cell death to AIDS onset is interrupted.

“We think that regenerative wound healing process likely preserves the tissue integrity and could prevent the inflammatory insults that underlie immune exhaustion, cell death, and AIDS that happens due to SIV or HIV infection“, explained Dr. Gale, Jr., Professor of Immunology, Director of the Center for Innate Immunity and Immune Disease at the University of Washington, and senior corresponding author on the study.  “This maintenance of tissue integrity could be a valuable therapeutic strategy to avoid systemic immune activation that underlies HIV disease and progression to AIDS. Our findings indicate that the use of therapies that stimulate the wound healing response early during virus infection could have a protective effect against disease in HIV infection.”

This work was supported by the National Institutes of Health, Office of the Director P51OD010425, R24OD011157, and R24OD011172; University of Washington Center for Innate Immunity and Immune Disease; NIAID contract no. HHSN272201300010C; an NIAID Simian Vaccine Evaluation Unit contract with the University of Washington (contract no. N01- AI-60006); NIDDK, NCRR and NHLBI, NIH (R01 DK087625, R24-OD010445, RR025781, DK108837, R01HL117715, R01HL123096, R01DK113919, R01AI119346); the Preclinical Research & Development Branch, VRP, DAIDS, NIAID, NIH (task order under N01-AI-30018); the DAIDS Reagent Resource Support Program for AIDS Vaccine Development, Quality Biological, Gaithersburg, MD, Division of AIDS (contract no. N01-A30018); National Institutes of Health Training Grant T32 AI065380-08 and AI065380-09 and the Swedish Research Council (D0045701), Institute of Computer Science, Polish Academy of Sciences and the eSSENCE program.

PhotoThe group measured changed gene expression during SIV infection (upper panel) and found that the activation of gene groups involved in the wound healing process (bottom panel) decreased the chance of progressing to AIDS.

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Nature Communication paper