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. 2025;8(1):25012.
doi: 10.31083/JMCM25012. Epub 2025 Feb 5.

Regulatory T Cells Kinetics in Immune Reconstitution Inflammatory Syndrome in HIV-Tuberculosis Co-Infected Individuals

Nicolas Barros  1   2 , Cesar A Sanchez  1 , A Clinton White Jr  1   3 , Allison Bauer  4 , Fernando Woll  1 , Edward A Graviss  5 , Carlos Seas  1 , Eduardo Gotuzzo  1 , Martin Montes  1   3
Affiliations

Regulatory T Cells Kinetics in Immune Reconstitution Inflammatory Syndrome in HIV-Tuberculosis Co-Infected Individuals

Nicolas Barros et al. J Mol Clin Med. 2025.

Abstract

Background: Combination antiretroviral therapy (cART) can suppress human immunodeficiency virus (HIV-1) replication, but some patients develop worsening of co-infections, termed immune reconstitution inflammatory syndrome. Regulatory T cells (Tregs) are a population of CD4+ T cells that modulate immune responses. We hypothesized that immune reconstitution inflammatory syndrome (IRIS) is associated with Tregs dysfunction.

Methods: We prospectively enrolled antiretroviral naive HIV patients with co-infection with Mycobacterium tuberculosis (MTB; N = 26) or controls with no prior opportunistic infection (N = 10). We prospectively measured HIV viral load, CD4+ T cell count, regulatory T cell (CD4high, CD127low-neg, Foxp3+) proportion, and Interferon-γ (IFN-γ) response to MTB peptides before and after initiation of combination antiretroviral therapy.

Results: Eleven of the MTB patients developed IRIS; 15 did not. IRIS patients had a lower proportion of Tregs at baseline compared to no-IRIS patients (HIV/no-OI and HIV/MTB no-IRIS), but the difference did not reach statistical significance (IRIS: 9.6 [5.3-11.2]; no-IRIS: 13.9 [7.6-22.5] p = 0.066). After 2 weeks of cART the proportion of Tregs was significantly lower in HIV/MTB IRIS patients (HIV/MTB IRIS: 9.8 [6.6-13.6], HIV/MTB no-IRIS: 15.8 [11.1-18.8]. The antigen-specific IFN-γ production was greater in the patients who developed IRIS compared with those who did not develop IRIS.

Conclusion: IRIS patients had a lower proportion of Tregs and more marked IFN-γ production, suggesting that Tregs may be responsible for suppressing the antigen-specific inflammatory response.

Keywords: HIV; IFN-γ; immune reconstitution inflammatory syndrome; immune recovery; regulatory T cells; tuberculosis.

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Conflict of interest statement

Conflict of Interest The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.. CD4+ T cell dynamics during cART.
(a) During cART treatment all the patients increased their absolute numbers of circulating CD4+ T cells. No differences were found between HIV and MTB co-infected individual and HIV patients with no signs of opportunistic infections. (b) No differences were found when comparing the HIV patients that developed IRIS with those who did not. The gray area represents the time frame when most of the patients developed IRIS. The dots and lines represent means with the standard error of the mean in bars. HIV/MTB: HIV and MTB coinfected individuals that did not developed IRIS. HIV/MTB IRIS: HIV and MTB coinfected individuals that developed IRIS. HIV/no-OI: HIV infected patients with no signs or active or previous opportunistic infections. cART, Combination Antiretroviral Therapy; HIV, Human Immunodeficiency Virus; MTB, Mycobacterium tuberculosis; IRIS, Immune Reconstitution Inflammatory Syndrome; HIV/no-OI, HIV with no Opportunistic Infections.
Fig. 2.
Fig. 2.. Regulatory T cell dynamics during cART.
The proportion of circulating Tregs after 2 weeks of cART was diminished in the patients who developed IRIS when compared to those who did not (p = 0.0099). The gray area represents the time frame when most of the patients developed IRIS. The dashed line represents the median proportion of circulating Tregs in the healthy controls. The dots and lines represent means with the standard error of the mean in bars. no IRIS: HIV and MTB coinfected individuals that did not develop IRIS. IRIS: HIV and MTB coinfected individuals that developed IRIS.
Fig. 3.
Fig. 3.. Antigen-specific Interferon-γ (IFN-γ) responses during cART.
(a) HIV and Mycobacterium tuberculosis coinfected patients that developed IRIS presented with detectable antigen-specific IFN-γ responses throughout the treatment. In addition, they presented a larger expression of antigen specific IFN-γ responses between 8–16 weeks after cART when compared with the HIV and MTB coinfected individuals that did not developed IRIS (p = 0.01). (b) Similar results were found when comparing the expression of antigen specific IFN-γ responses per CD4+ T cells (p = 0.01). The dots and lines represent means with the standard error of the mean in bars. TB, tuberculosis.
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