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Three-Month cART Initiated During Primary HIV Does Not Correct the Structural, Immune, and Microbial Abnormalities
Camilla Tincati1, Valeria Bono1, Silvia Nozza2
1Clinic of Infectious Diseases, Department of Health Sciences, ASST Santi Paolo e Carlo, University of Milan, Italy.
Insights
Early combination antiretroviral therapy (cART) for primary HIV infection (PHI) did not reverse HIV-related gut damage or inflammation. This suggests limited efficacy of early cART in addressing the pro-inflammatory signature that drives comorbidities.
Area of Science:
- Gastroenterology
- Immunology
- Virology
- Microbiome Research
Background:
- HIV infection severely impacts gut structure, immunity, and microbiome, causing immune activation and inflammation.
- These gut alterations contribute to non-infectious comorbidities in people living with HIV (PLWH).
- The efficacy of combination antiretroviral therapy (cART) initiated during primary HIV infection (PHI) on gastrointestinal health is largely unknown.
Purpose of the Study:
- To investigate the effects of 12-week cART on gastrointestinal structure, immunity, and mucosal microbiome in PLWH with PHI.
- To assess whether early viro-suppressive treatment can reverse HIV-associated gut abnormalities.
Main Methods:
- Eleven participants with PHI underwent colonoscopy with biopsies, peripheral blood mononuclear cell (PBMC), and plasma collection before and after 12 weeks of cART.
- Gut biopsies were analyzed for structural changes (E-cadherin, collagen) and immune cell populations (macrophages, T cells).
- PBMCs and gut tissue microbiome composition were analyzed.
Main Results:
- Despite 12-week cART, gut barrier damage (E-cadherin loss, collagen deposition) progressed in PHI participants.
- CD4+ and γδ T-cell frequencies remained stable, with decreased activation in the colon, but no changes in Th17 and Treg cells.
- Peripheral inflammation and gut barrier integrity markers showed no significant changes; however, the gut microbiome composition evolved.
Conclusions:
- Early initiation of 12-week cART does not correct HIV-mediated gut damage or fully revert the pro-inflammatory signature.
- Continued gut injury despite early treatment suggests a limited efficacy of cART in preventing long-term complications.
- These findings highlight the pathogenetic link between persistent gut injury and the development of non-communicable comorbidities in PLWH.
Background:
HIV infection leads to profound alterations of gut structure, immunity, and microbiome, resulting in immune activation and inflammation, which drive the development of non-infectious comorbidities. The introduction of combination antiretroviral therapy (cART) in the chronic stages of disease does not correct such abnormalities; however, the effect of viro-suppressive treatment in the gastrointestinal tract during primary HIV infection (PHI) is largely unknown. We studied the effects of 12-week cART on gastrointestinal (GI) structure, immunity, and mucosal microbiome in people living with HIV (PLWH) with PHI.
Methods:
Eleven participants with PHI enrolled in the INACTION trial underwent colonoscopy with ileum and colon biopsies, as well as peripheral blood mononuclear cell (PBMC) and plasma collection, prior to and at 12 weeks of cART. Gut biopsies were stained with CD14, CD68, CD163, and E-cadherin antibodies and Masson trichrome. Flow cytometry was performed on lamina propria and PBMCs to characterize CD4, γδ T, Treg, and Th17 cells. Gut tissue-associated microbiome analysis was conducted on colon and ileum biopsies. Ten untreated individuals with chronic HIV infection (CHI) were also studied for comparative analysis.
Results:
Despite treatment of PHI, gut barrier damage (E-cadherin loss, collagen deposition) progressed, with a partially preserved distribution of intestinal macrophages. Treated PHI showed stable CD4+ and γδ T-cell frequencies and decreased activation of these subsets in the colon, with no effect on intestinal Th17 and Treg cells. No major changes in peripheral inflammation and intestinal barrier integrity markers were observed. Gut tissue-associated microbiome composition evolved during cART treatment in PHI.
Conclusion:
Despite early initiation, 12-week cART is unable to correct the HIV-mediated gut damage. Since gut injury drives systemic inflammation, which in turn fosters the pathogenesis of non-communicable comorbidities, our findings provide pathogenetic evidence of limited efficacy of early cART in reverting the HIV-associated pro-inflammatory signature and clinical risk.
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