How HIV Weakens and Uses Lung Immune Cells in Tuberculosis

Tuberculosis (TB) remains a leading global killer, causing an estimated 1.25 million deaths each year and standing as the leading cause of death in people with HIV (PWH). The immune system’s CD4 + T helper (Th) populations are central to controlling Mycobacterium tuberculosis (Mtb), but they are also prime targets for HIV. Emerging evidence from blood and gastrointestinal mucosa of PWH suggests that two Th subsets — Th17 and Th22 — may be preferentially lost during HIV infection. That selective targeting could undermine the body’s ability to contain Mtb and might also feed HIV persistence. To investigate these risks, Janice J. Endsley and colleagues used a humanized mouse model to study how infection with HIV, Mtb, or both together changes the frequency and function of Th17 and Th22 cells in the lung and other tissues. By focusing on these specific Th populations in a controlled co-infection setting, the team set out to learn whether HIV simply weakens these responses or actively exploits them in ways that affect both diseases.

The researchers infected humanized mice with HIV, Mtb, or both and then measured Th17 and Th22 cells, viral load, cytokine production, and gene expression in infected tissues. They found that Th17 cells were the predominant host for HIV in the spleen and were a source of HIV replication within pulmonary TB granulomas. In the lung, Th17 cells were increased in animals with TB or TB-HIV co-infection, while Th22 cells were reduced in mice with HIV alone or TB-HIV co-infection. Mtb infection raised the viral load in the lungs of co-infected mice. At the same time, HIV suppressed the pulmonary Th17-family cytokine response to Mtb, including IL-6, IL-22, IL-23, and IL-1β. A differential transcriptome assessment showed that HIV co-infection disrupted Th17 pathways that would normally be activated by Mtb in the lung. Together these results document both depletion and functional alteration of key Th responses during co-infection.

Taken together, the findings suggest a double danger in TB-HIV co-infection: HIV appears to compromise Th22 immunity while exploiting Th17 cells as hosts for viral replication and spread. This interaction could both weaken the immune mechanisms needed to control Mtb and promote HIV proliferation and persistence, creating a vicious cycle in co-infected individuals. Because TB already kills many people with HIV, understanding how HIV shifts Th17 and Th22 balance and function in the lung may explain part of that vulnerability. The work by Janice J. Endsley and colleagues points to specific cytokines and pathways — IL-6, IL-22, IL-23, IL-1β and Th17-associated transcriptional programs — as places where HIV undermines anti-Mtb responses and where future research could focus to better protect people with HIV from tuberculosis.