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[Preprint]. 2025 Feb 7:2025.02.05.25321757.
doi: 10.1101/2025.02.05.25321757.

Senescence-related cytokine levels are associated with HIV-1 serostatus and persistence

Yijia Li  1 , Zoamy N Soto-Ramirez  1   2 , Jenny Roscher  1 , Tom Medvec  1 , Mounia Alaoui-El-Azher  1 , Paolo Piazza  3 , Yue Chen  1 , Nicolas Sluis-Cremer  1 , Charles Rinaldo  1 , Bernard Jc Macatangay  1
Affiliations

Senescence-related cytokine levels are associated with HIV-1 serostatus and persistence

Yijia Li et al. medRxiv. .

Update in

Abstract

Background: HIV-1 is associated with accelerated aging. The senescence-associated secretory phenotype (SASP) includes biological and cytokine profiles that induce cellular senescence and inflammaging. In this study, we leveraged the Multicenter AIDS Cohort Study (MACS) to evaluate the role of SASP in aging, HIV-1 reservoir, and inflammation in people with HIV-1 (PWH) on long-term suppressive antiretroviral therapy (ART).

Methods: In this retrospective study we included plasma and serum samples from 27 virally-suppressed PWH and 10 people without HIV-1 (PWoH) collected in 2019 and 2023. SASP markers were quantified in the 2019 and 2023 samples. Plasma residual viremia, intact and defective proviral DNA were quantified in the 2019 samples. Correlations between SASP markers and HIV-1 reservoir were performed using the Spearman test, and the sparse partial least squares discrimination analysis was used to identify variables that distinguish HIV-1 serostatus.

Results: All study participants were male with a median age of 59 years. SASP markers did not show significant changes longitudinally in either group. We identified a set of markers that had moderate performance in distinguishing PWH and PWoH, including CMV serum antibody titer, matrix metalloproteinase 9 (MMP-9), Growth/differentiation factor-15, Stanniocalcin-1 and SerpinE1. Among all the SASP markers, MMP-9 was significantly associated with intact HIV-1 proviral levels (rho=0.60, P=0.002).

Conclusion: In this cohort study, we revealed the relationship between SASP markers and HIV-1 persistence. Future interventions targeting the senescence pathways may impact HIV-1 persistence.

Keywords: CMV; HIV-1; Inflammaging; Reservoir; Senescence-associated secretory phenotype.

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Figures

Figure 1.
Figure 1.
Partial least squares discriminant analysis (PLS-DA) to evaluate the association between SASP markers, CMV Ab, and HIV-1 serostatus. (A) SASP markers and CMV Ab from 2019; (B) Variable importance in projection (VIP) of selected SASP markers from 2019 that can distinguish HIV-1 serostatus. (C) SASP markers and CMV Ab from 2019; (D) Variable importance in projection (VIP) of selected SASP markers from 2019 that can distinguish HIV-1 serostatus.
Figure 2.
Figure 2.
Correlations among SASP markers, CMV Ab, chronological age, and HIV-1-related parameters in all participants. (A) Heatmap showing Spearman correlations among variables. ****, P<0.0001; ***, P<0.001; **, P<0.01; *, P<0.05. (B) Spearman correlation between intact HIV-1–1 proviral levels and MMP-9. (C) Spearman correlation between total HIV-1–1 proviral levels and geometric mean (logarithmic 10) of SASP markers from 2019. (D) Spearman correlation between 5’ Defective HIV-1–1 proviral levels and geometric mean (logarithmic 10) of SASP markers from 2019.
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