Lyle McKinnon: Blocking the Route of HIV Infection (2017 Basic Sciences Winner)

Microbiologist Lyle McKinnon is helping untangle the mystery as to why certain people exposed to HIV don’t become infected–a key to future HIV prevention.

In 2002, fresh from an undergraduate science degree and dreaming about what he’d do next, Lyle McKinnon sent an e-mail cold query to famed University of Manitoba virologist Dr. Francis Plummer.

The e-mail changed McKinnon’s career. Dr. Plummer was trying to understand why some Kenyan sex workers with repeated HIV exposure didn’t become infected.

“At the time I started my PhD people didn’t know what kind of immune response could protect someone from becoming infected and this was thought to be important for prevention,” says McKinnon, a 2017 CAHR-CANFAR Excellence in Research Award winner in Basic Sciences, and researcher at the University of Manitoba.

For 15-years he’s conducted research and increasingly taught in Canada, Kenya and South Africa helping lead the way in teasing apart how the body’s immune defenses, particularly immune cells in the mucosal lining of the vagina and rectum, can either block or facilitate HIV infection–and how they might be further harnessed to prevent it.

During this time, McKinnon has ridden the roller-coaster of efforts to develop a vaccine against HIV.

His PhD research focused on the hope that an immune cell, the CD8 T-cell, could be retrofitted into a vaccine that induced immunity to HIV. However, a major clinical trial, the STEP trial, found that this type of vaccine could actually increase infection rates in some groups.

“The trial was a bit of a disappointment,” says McKinnon, whose thesis identified in part how the HIV virus escapes from immune T-cell responses. “But it introduced me to working in Nairobi, Kenya.” From 2009 to 2013, he shuttled between Nairobi and the University of Toronto conducting post-doctoral research.

For the Gimli, Manitoba native, working in Nairobi, grounded his immunological research–often focused on in-vitro research–in a natural history approach, “what happens in actual people,” says McKinnon.

For the past decade, this has meant working to understand mucosal immunology in the context of how people become HIV-infected, particularly with female sex workers in Kenya, and women in South Africa.

“A lot of exposures to HIV don’t lead to transmission probably because the mucosal defenses are often quite good,” says McKinnon, an honorary lecturer at the University of Nairobi.

His research is revealing that when this mucosal-barrier fails, it’s in part because some of the front line immune T-cells, are more susceptible to HIV than others–a potential key insight for developing ways to prevent HIV infection.

McKinnon has identified a subset of mucosal immune cells that express the cell surface integrin alpha 4 beta 7 that have a high level of HIV-infection susceptibility. These immune cells also travel to the gut, a key site of HIV replication.

“It’s interesting that this is a very important site for HIV to get to, and the virus also seems to be able to use a molecule to target these cells that will take it to that site,” says McKinnon. The research was conducted with the postdoctoral supervisors Rupert Kaul at the University of Toronto and Joshua Kimani at the Kenya AIDS Control Project at the University of Nairobi.

Based on his Kenyan experience, McKinnon was hired by the Centre for AIDS Programme of Research (CAPRISA) in South Africa to retrospectively analyze a group of biobanked samples from a clinical trial in which a subset of women acquired HIV.

“We found that women with more alpha-4 beta 7 are more likely to get infected and also have faster disease progression,” says McKinnon.

Recently, in a multi-author study published in the journal Science, McKinnon and co-authors reported that they’d infected monkeys with SIV while simultaneously administering anti-retrovirals and an alpha-4 beta 7-blocking drug. The result: fewer monkeys than expected developed an SIV infection.

“It seems that blocking alpha-4 beta 7 is clinically beneficial for them,” says McKinnon.

The finding is a bright light on the journey McKinnon began with a single e-mail.

There’s already an FDA and Health Canada approved alpha-4 beta 7 antibody on the market to treat inflammatory bowel disease.

“It could be used off-label in an HIV-infected person,” says McKinnon, noting that there’s already one human clinical trial underway trying to replicate the monkey results in humans, and other trials planned.

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Each year, the CAHR – CANFAR Excellence in Research Awards are awarded to highlight and celebrate the contributions of Canadian researchers in HIV/AIDS research. Dr. McKinnon was awarded the prize at the 2017 CAHR Conference for using “cutting edge basic science immunology techniques to identify the key cells that HIV infects (and placing this) knowledge in the context of behavioural and epidemiological factors.”