Antiretroviral therapy can keep HIV at undetectable levels in the blood, but it does not clear the virus from the body. A major reason is that HIV persists in lymph nodes, particularly inside structures called germinal centers, where infected cells can escape both treatment and the body’s own defenses.

A new study from the lab of Zaza Ndhlovu, PhD, at the Ragon Institute and the Africa Health Research Institute in Durban, South Africa shows that natural killer (NK) cells, immune cells that can destroy virus-infected cells, are largely kept out of these reservoir sites.

The findings were published Sept. 22 in The Journal of Infectious Diseases and selected as an Editor’s Choice article under the title ‘Spatial Constraints Limit Natural Killer Cell Access to Germinal Center HIV Reservoirs in Lymph Nodes.’

Earlier research found that CD8+ T cells, the immune system’s main virus-killing cells, have trouble entering germinal centers. NK cells have drawn interest as a possible alternative because they can recognize and kill infected cells without first being trained on a specific target, which makes them less vulnerable to the mutations HIV uses to evade T cells. Until now, however, little was known about where NK cells actually sit inside human lymph nodes during HIV infection.

To find out, the team analyzed paired lymph node and blood samples from 50 young women in South Africa, including women living with HIV and women without HIV. Many of the women with HIV had started treatment during the earliest stage of infection. The researchers combined tissue imaging, flow cytometry and spatial analysis to map where NK cells were located and what they were equipped to do.

They found that NK cells in lymph nodes were mostly positioned in the zones surrounding germinal centers rather than inside them, regardless of HIV status. Very few NK cells carried CXCR5, a receptor that works like a homing signal to guide immune cells into the follicles where germinal centers form. Women with HIV did not have more of these cells than women without HIV.

In women with uncontrolled HIV, lymph node NK cells produced higher levels of granzyme B, a molecule used to kill infected cells. But those armed cells were found almost entirely outside the follicles. Spatial mapping confirmed a clear separation between NK cells and the germinal center regions where HIV protein was detected.

The results reveal a disconnect between NK cells’ ability to kill infected cells and where the virus is actually hiding. They suggest that future cure strategies could focus on helping NK cells travel into follicles and boost their cytotoxicity, for example by increasing CXCR5 on their surface, infusing them with cytokines, or by engineering them with chimeric antigen receptors.