Inflammaging and anti-inflammaging cytokines in the HIV-seropositive geriatric population in Uganda

Abstract

Background: Although the life expectancy of people living with HIV (PLWH) has increased significantly, HIV infection seems to be associated with accelerated ageing processes compared to uninfected individuals. Longevity is characterized by a balance between pro-inflammatory and anti-inflammatory agents, which act as key players. A pro-inflammatory state can confer high resistance against infectious diseases but, on the other hand, may increase susceptibility to inflammation-based diseases throughout life. An anti-inflammatory trend, on the other hand, may increase vulnerability to infections and may prevent achievement of old age. Elevated rates of inflammation seen in PLWH, even if their viral loads are suppressed and their CD4 counts are preserved, are associated with this accelerated ageing (Inflammaging). However, there is no data about inflammaging in the HIV population in Sub-Saharan Africa and Uganda, in particular a place with chronic endemic infections yet the inflammaging profiles are influenced by genes, polymorphisms and the environment. Therefore, we sought to determine the mean levels of inflammaging and anti-inflammaging cytokine profiles in HIV-seropositive geriatric population in Uganda, as well as the association between PLWH metadata variables and the inflammaging and anti-Inflammaging cytokines. Methods: This was a cross sectional study. The study utilized archived serum samples from 80 HIV-seropositive and 80 HIV-seronegative participants aged 60 years and above. Immunoassays were performed using a 14-plex Magnetic Luminex performance assay containing IL-1Ra, IL-4, IL-10, GM-CSF, TGF-β, CRP, IL-1R1, IL-6, IL-11, IL-12, IL-15, IL-17, TNF-α, and IFN-γ. Mann Whitney U test, correlations and regression analyses were performed using GraphPad Prism 9. Bray Curtis dissimilarity analysis and heat map cluster analysis were performed in R. Univariate analysis was done using metadeconfoundR (version 0.2.9).

Results: Serum levels of IL-6, CRP, GM-CSF were significantly higher in PLWH compared with HIV negative individuals ((P<0.0001). INF-γ, IL-12, IL-15, IL-1Ra, IL-17, IL-11, IL-4, IL-10 and TGF-β were significantly higher in HIV-un infected individuals compared with HIV-infected individuals (P<0.0001). There was no statistical difference in the serum levels IL-1R1, TNF-α and TGF-β in both groups (P>0.05). Stratification of the PLWH by CD4 cell count less or greater than 500 showed no significant differences between the two subgroups. Bray Curtis dissimilarity analysis and heat map cluster analysis showed significant differences between PLWH and HIV- negative population. No unconfounded associations were seen at FDR less than 0.1 following metadeconfoundR testing. Our linear regression model showed significant associations between GM-CSF and sarcopenia, IL-11 and chronic kidney disease, CRP and frailty, and IL-17 and CD4 counts (both current and CD4 at ART initiation) among PLWH.

Conclusion: We have shown that the inflamm- and anti-Inflammaging cytokines among aging PLWH in other settings have a similar profile to those among aging PLWH in Uganda.