Investigators Build List of Cells Most Susceptible to HIV Infection

Not all CD4+ T cells are equally susceptible to infection in vivo, which could suggest that the most susceptible cells could eventually become targets of preventive interventions.

Despite a growing body of knowledge on HIV and ways to treat it, investigators have struggled to understand which exact cells are most susceptible to the virus. However, researchers at the Gladstone Institutes have begun creating an atlas of these cells using blood samples from donors with HIV at various stages of infection.

According to a press release, this knowledge is important in order to target susceptible cells and potentially protect the millions of people who first encounter HIV each year, or infected people in whom the infection is likely to rebound if they go off of therapy. Scientists have long known that the virus lives in so-called memory CD4+ T cells, which help the body build lasting immunity against pathogens. These CD4+ T cells, however, are too broad a category to target for therapy, according to the study.

“CD4+ T cells orchestrate the immune response against all kinds of pathogens, so you can’t just eliminate them to prevent HIV infections,” said associate investigator Nadia Roan, PhD, in the press release. “But if you can find the more specific subsets of CD4+ T cells that are highly susceptible to HIV infection, you may be able to specifically target those cells without detrimental side effects.”

A lot of knowledge about HIV comes from in vitro experiments in which scientists expose CD4+ T cells cultured in the lab to the virus. However, these cultures are not a perfect model for the human body’s complex ecosystems, so investigators hypothesized that in vitro infection might yield a skewed view of the virus’s preference.

Roan and her team compared CD4+ T cells in vitro to the CD4+ T cells circulating in the blood of 11 individuals at various stages of infection. Some blood samples were taken before the donors had started treatment with antiretroviral therapy (ART) while some were taken after, and others came from individuals who had stopped treatment and were experiencing a new round of infection. The investigators used these samples to establish a detailed atlas of the CD4+ T cells on individuals not on ART.

“Our work affords novel insight into the basics of how HIV behaves in the human body, rather than just in a lab dish,” Roan said in the press release. “It informs our understanding of what really happens during an active infection, which is interesting in its own right. Moreover, we know that some infected cells become reservoirs of latent virus, so our work could help us better understand how the reservoir forms during an infection.”

The technology used by the team, called CyTOF/PP-SLIDE, can precisely distinguish cells based on the proteins they contain or carry on their surface. With this information, the scientists can classify CD4+ T cells into many subsets, and then determine whether some subsets are more susceptible to infection than others. Importantly, the researchers said this technology can also trace infected cells back to their original state prior to infection.

“This is important,” said first author Guori Xie, PhD, a postdoctoral researcher in Roan’s lab, in the press release. “We know that when HIV infects cells, it remodels the cells such that they no longer contain the exact same levels of proteins as they did before infection. With CyTOF/PP-SLIDE, we can identify the uninfected cells that most closely match the infected ones in the same patient.”

The team found that remodeling was extensive in blood CD4+ T cells infected in vivo as well as in vitro. In the process, they were surprised to also find that Tfh cells—a subtype of CD4+ T cells, are susceptible to HIV. However, they also found that the virus can infect non-Tfh cells and remodel them to adopt features of Tfh cells.

“This result strikes a cautionary note in our field,” Roan said in the press release. “You really can’t tell which cells HIV prefers to target simply by looking at infected cells. You need to know what the cells looked like before remodeling.”

They found that remodeling causes infected blood cells to alter their surface in ways that can change how the cells move through the body. Roan speculated that this might help the virus steer infected cells toward sites in which it can infect even more cells.

The profile of HIV’s favorite cells differed somewhat between in vivo and in vitro infections, although the researchers found one subset of cells that was preferentially infected in both cases and could become a useful model for further lab studies. They also confirmed that not all CD4+ T cells are equally susceptible to infection in vivo, which could suggest that the most susceptible cells could eventually become targets of preventive interventions.

“There is still much to discover in this atlas that may help uncover new insights into HIV infection and how it develops, and perhaps lead to the identification of new approaches for HIV/AIDS prevention,” Roan concluded in the press release.


At Atlas of HIV’s Favorite Targets in the Blood of Infected Individuals [news release]. Gladstone Institutes; April 27, 2021. Accessed April 30, 2021.