Study: Scientists Identify Potential Cell Reservoir That Supports Latent HIV Reactivation

When patients with HIV are treated with antiretroviral therapy, the HIV virus continues to exist in small reservoirs of cells in the immune system. Most studies that have looked into targeting these cells for elimination have looked at the cells in the blood, due to the ease of testing blood samples from volunteers.¹

Yet HIV targets immune cells, known as T cells, which reside primarily in lymphoid tissues, such as lymph nodes and tonsils. A recent study published in PLOS Pathogens analyzed this class of cells that preferentially support latent infection by HIV and are characterized by a surface protein called CD127.¹

“Our findings suggest that CD127 cells from tissues may be an important population to target for an HIV cure,” said Nadia Roan, PhD, associate professor of urology at UC San Francisco and Gladstone Visiting Scientist, in a press release.²

Additionally, researchers may be able to isolate reservoir cells from patients using the CD127 protein, which would make it possible to study what allows the cells to silence the virus and then reactivate it.¹

In prior research, the scientists from this study used tonsil cells to test their exposure to HIV in the lab, in order to understand which cells were most vulnerable to infection. Ultimately, the results demonstrated that tonsil cells with the surface protein CD127 supported HIV infection, yet these cells did not frequently replicate the virus. However, tonsil cells carrying CD57 readily supported virus infection that replicated.²

These results seemed to demonstrate that CD127 cells were not necessarily reservoir cells.

Feng Hsiao, a former research associate in Roan's lab and co-author of the present study, explained in a press release that this may be because cells have ways of escaping infection after HIV enters them.²

Since the virus initially makes DNA copies of HIV’s RNA genome upon entering a cell, the researchers believed that one way to prevent infection is to stop the virus from copying its genome in the cell.¹

By activating an enzyme called SAMHD1, which decreases the stores of the building blocks needed to copy the virus’s genome, cells may be able to hamper this step. This possibility was supported from the results of prior research on blood cells as well.¹

However, in this study, the researchers observed that through the elimination of SAMHD1 by genetic manipulation, CD127 cells did not replicate the virus, but it did support viral production by CD57 cells.¹

“This suggested to us that CD127 cells blocked the virus at a later step in its life cycle,” said Julie Frouard, PhD, a postdoctoral scholar in Roan's lab and co-author of the study, in a press release.²

This may mean that CD127 tissue cells do act as a reservoir in the body, although instead of replicating the virus regularly like CD57 cells, they keep the virus dormant and occasionally activate it, which would then support a new round of infection.¹

“The ability of a specific type of tissue T cell to preferentially support latent infection is very intriguing and can teach us much about how the tissue reservoir becomes established initially,” Roan said in a press release.²

The researchers explained that follow-up studies of multiple tissue sites will be needed to assess whether CD127 cells are a significant component of the reservoir in patients with HIV. Yet, the results from this study are encouraging in that they demonstrate that the CD127 marker on the cells' surface may be usable for further analyses.²

“CD127 tonsil cells exposed to HIV in vitro provide a novel model to study viral latency in tissues,” Roan said.²

A new study has already begun that will assess what makes CD127 cells prone to silent infections. So far, after comparing the genes expressed in CD127 and CD57 tonsil cells, the researchers found evidence that CD127 cells are in a quiescent state which may stop any expression of the virus's genes. Furthermore, the researchers also observed that the virus's RNAs did not allow for the processing that would support the production of viral proteins.²

“Ultimately, our hope is that the mechanisms we uncover can be harnessed to control the latent reservoir and move us closer to achieving a cure for HIV,” Roan said.²

REFERENCES

• Hsiao F, Frouard J, Gramatica A, et al. Tissue memory CD4 T cells expressing IL-7 receptor-alpha (CD127) preferentially support latent HIV-1 infection. PLOS Pathogens. 2020;16(4):e1008450. doi: 10.1371/journal.ppat.1008450.
• Scientists identify a new potential reservoir of latent HIV: New study identifies a type of T cells in tissues that preferentially supports latent infection by HIV [news release]. ScienceDaily; April 30, 2020. sciencedaily.com/releases/2020/04/200430150202.htm. Accessed May 4, 2020.