Giving HIV a free ride: Immature red blood cells increase HIV progression

UAlberta researchers identify a new role immature red blood cells play in HIV-1.

Jessalyn King - 10 December 2019

A team led by Shokrollah Elahi, immunologist with the University of Alberta's Department of Dentistry, has identified a new role played by immature red blood cells in HIV-1.

Immature red blood cells-also known as erythroid precursors or CD71+ erythroid cells (CECs)-are now shown to have multiple effects on HIV. They make HIV target cells more susceptible to HIV infection, carry the virus to new places in the body, possibly facilitate mother-to-child infection, and even harbour the virus, hindering treatment.

Allowing more rapid progression of HIV-1

After three years of study, Elahi and his team have determined that these cells release a chemical called reactive oxygen species (ROS) that makes HIV target cells more susceptible to HIV infection.

"If we place immature red blood cells in a tissue culture plate with HIV and HIV target cells, the HIV goes crazy," Elahi says. "HIV replication increases in some cases up to twentyfold."

This is not the only role CECs play in progressing the spread of HIV in the body. Elahi explains the virus binds to a protein (called CD235a) on the surface of the immature red blood cells and travels to new parts of the body. "The HIV basically hitchhikes or gets a free ride on these cells, which travel all over the body and brain. This discovery is novel. No one has yet shown that HIV interacts with CD235a."

Combined, the increased susceptibility and the "hitchhiking" may cause HIV to progress very fast in individuals with high levels of immature red blood cells.

In a healthy adult, these cells remain in the bone marrow, where they are produced. "Every second, our bodies produce 2.5 million red blood cells," says Elahi. "These cells eventually mature and leave the marrow and do their main job as oxygen transporters. However, in anemia and some other chronic infections, the bone marrow is unable to produce enough red blood cells for the body. Therefore, red blood cell production may occur in other organs such as the spleen and liver to meet the body's oxygen supply. This seems to cause the immature red blood cells to leave these organs early and appear in blood circulation."

Alarmingly, Elahi and his team have also discovered that the virus can enter the immature red blood cells and remain inside for at least 72 hours, even in the presence of antiretroviral drugs used to treat HIV. "We retested the samples after 72 hours and the HIV had come out of the immature red blood cells and infected the target cells."

Adults with anemia or any condition that results in the abundance of CECs in the blood are therefore highly susceptible to HIV-1, and for the usual HIV treatment to be effective, doctors will need to get the anemia under control first.

"For people who have HIV and are anemic, doctors need to treat their anemia first. If they don't, it can negatively impact the HIV disease outcome," says Elahi.

He also calls for anemia to be treated as an immunological disorder. "We have shown that CECs have immunosuppressive properties. It means they suppress your immune system, making you more prone to disease and infection. With more of these cells, your response to vaccines will be compromised, too. It's more serious than we thought."

Mother-to-child HIV transmission

CECs are also naturally abundant in fetuses and newborns. This has huge implications for mother-to-child transmission of HIV. "Immature red blood cells become abundant during pregnancy-especially in the third trimester-and are also abundant in the cord blood and placenta," Elahi explains. "If the mother has HIV during pregnancy, the presence of immature red blood cells first accelerates the infection in the mother, then transports the virus into the placenta, where it spreads rapidly throughout the fetus."

Mounting evidence-much of it by Elahi and his team-shows that immature red blood cells suppress the immune system.

Healthy pregnancies require the immunosuppressive function of the immature red blood cells. This protects the fetus from the mother's immune system, which otherwise would attack it as a half-foreign object. Therefore, while this discovery could explain the rapid progression of HIV infection in newborns (and why they usually die within two years), Elahi calls for further study to come up with a solution.

The study can be read in full here.

The Northern Alberta HIV Program, led by medical program director and U of A Department of Medicine professor Stan Houston, contributed HIV patient recruitment for this study. Funding was provided by CIHRand in part by the Stollery Children's Hospital Foundation through the Women and Children's Health Research Institute.