Lockdowns Led to Altered Regulation of Inflammatory Responses in People Living With HIV

People living with HIV (PLHIV) may have had exacerbated immune responses associated with lockdowns imposed during the height of the COVID-19 pandemic, according to a study published in Frontiers in Immunology.¹ The mechanisms could include changes in regulation of inflammatory responses, which the authors write could be due to lack of normal exposure to environmental stimuli or changes in physical activity and diet during the lockdowns.

Lockdowns due to the COVID-19 pandemic began in March 2020,² as the population did not have the immune response necessary to combat the new strain of coronavirus. Masking and social distancing were also employed to protect those who were at increased risk of morbidity or mortality due to the virus. However, these measures could also affect immune responses in the population.¹ This study aimed to assess the changes in immune response of PLHIV who were exposed to COVID-19 infection, lockdowns, and vaccinations.

Data from 2 studies were used for this analysis. The 2 studies, 2000HIV and 200FG, are ongoing studies within the Human Functional Genomics Project and enrolled suppressed asymptomatic PLHIV and healthy adults aged 18 years or older, respectively. Dutch HIV treatment centers, university medical centers, and 1 general hospital were used to gather participants for the 2000HIV study. A validation cohort was recruited from a separate HIV expertise center.

People living with HIV could have affected immune responses after lockdowns caused by the COVID-19 pandemic | Image credit: artegorov3@gmail - stock.adobe.com

Blood was collected from all participants in the 2000HIV study. Unvaccinated COVID-19 negative PLHIV were compared before and after the first lockdown order in the Netherlands. Unvaccinated PLHIV both with and without a COVID-19 infection in the past and PLHIV with and without a COVID-19 vaccination were also compared. Participants who had a previous infection of COVID-19 were excluded. People on immunosuppressants, who had no COVID-19 serology data, who had positive COVID-19 serology before the pandemic, or who had both a vaccination and positive COVID-19 status were also excluded. The healthy volunteers had their cytokine production capacity evaluated between 2020 and 2022 whereas the participants in the 2000HIV study were recruited from October 2019 to October 2021.

Potential confounders considered in this study included seasonality, ethnicity, age, sex, body mass index, CD4 count, smoking status, latest viral load, and center of inclusion. Relevant covariates were identified using a backward stepwise regression.

There were 1478 participants in the discovery cohort and 320 participants in the validation cohort, respectively. Patients recruited prior to the pandemic were more often of European ancestry and more often men. The median (IQR) duration between either infection or vaccination against COVID-19 and the blood drawing was 117 (40-177) days and 49 (20-71) days in the discovery cohort and 74 (35-140) days and 21 (11-34) days in the validation cohort.

The prepandemic group had significant differences compared with the postlockdown group (P < .0001), the postlockdown group had significant differences to the COVID-19 group (P < .0001), and the postlockdown group had significant differences to the vaccinated group (P = .029) when conducting a principal component analysis. A differential abundance analysis found that there were 294 downregulated and 5 upregulated proteins in the COVID-19 group and 943 downregulated and 215 upregulated proteins in the COVID-19 vaccinated group when compared with the postlockdown proteome profile. Scatter plots with log-fold change found that 888 proteins were validated as downregulated and 107 as upregulated in both the discovery and validation cohorts of the 2000HIV study.

Past infection with COVID-19 did not have a significant effect on immune response in either cohort. COVID-19 vaccination led to a decrease in production in 2 cytokines and an increase in 1. These results were mirrored in the healthy cohort of patients. T-cell responsiveness was not affected by any of vaccination, COVID-19, or lockdowns. An epigenome-wide association study was conducted and suggested that vaccination and lockdown could produce DNA methylation changes for more than 3 months compared with COVID-19 infection, which had no effect on DNA methylation.

“In our daily lives, we are constantly exposed to various microorganisms. This helps train our immune system, teaching it to recognize which microorganisms are dangerous and which are harmless," Mihai G. Netea, co-author of the study, said in a statement to The American Journal of Managed Care^®. "During the lockdown, we missed that interaction because everyone stayed home and avoided each other. As a result, during and immediately after the lockdown periods, immune cells were no longer able to respond in a balanced way when encountering microbes, predisposing us to pathological processes associated with an inappropriately strong inflammation.”

There were some limitations to this study. The included number of healthy volunteers was small, and underlying mechanisms of functional immunological changes could not be evaluated. The study had a cross-sectional design. The data also are focused on PLHIV, who have different immune responses compared with healthy individuals.

The researchers concluded that “limitations of social interactions to prevent exposure to infectious agents, such as lockdowns, [have] broad consequences on the immune system and may as such have unforeseen medical consequences, apart from the obvious psychological concerns.” PLHIV having profound effects on their immune response could be an indicator for the population at large, the authors suggested.

References

1. Otten T, Jiang X, Gupta MK, et al. Impact of COVID-19, lockdowns and vaccination on immune responses in a HIV cohort in the Netherlands. Front Immunol. 2024;15:1459593. doi:10.3389/fimmu.2024.1459593
2. AJMC Staff. A timeline of COVID-19 developments in 2020. Updated January 1, 2021. Accessed January 2, 2025. https://www.ajmc.com/view/a-timeline-of-covid19-developments-in-2020