Impact of pre-existing chronic viral infection and reactivation on the development of long COVID.

BACKGROUND: The presence and reactivation of chronic viral infections such as Epstein-Barr virus (EBV), cytomegalovirus (CMV) and human immunodeficiency virus (HIV) have been proposed as potential contributors to Long COVID (LC), but studies in well-characterized post-acute cohorts of individuals with COVID-19 over a longer time course consistent with current case definitions of LC are limited. METHODS: In a cohort of 280 adults with prior SARS-CoV-2 infection, we assessed the presence and types of LC symptoms and prior medical history (including COVID-19 history and HIV status), and performed serological testing for EBV and CMV using a commercial laboratory. We used covariate-adjusted binary logistic regression models to identify independent associations between variables and LC symptoms. RESULTS: We observed that LC symptoms such as fatigue and neurocognitive dysfunction at a median of 4months following initial diagnosis were independently associated with serological evidence suggesting recent EBV reactivation (early antigen-D [EA-D] IgG positivity) or high nuclear antigen (EBNA) IgG levels, but not with ongoing EBV viremia. Serological evidence suggesting recent EBV reactivation (EA-D IgG) was most strongly associated with fatigue (OR 2.12). Underlying HIV infection was also independently associated with neurocognitive LC (OR 2.5). Interestingly, participants who had serologic evidence of prior CMV infection were less likely to develop neurocognitive LC (OR 0.52). CONCLUSION: Overall, these findings suggest differential effects of chronic viral co-infections on the likelihood of developing LC and predicted distinct syndromic patterns. Further assessment during the acute phase of COVID-19 is warranted. TRIAL REGISTRATION: Long-term Impact of Infection with Novel Coronavirus (LIINC); NCT04362150FUNDING. This work was supported by the National Institute of Allergy and Infectious Diseases NIH/NIAID 3R01AI141003-03S1 to TJ Henrich, R01AI158013 to M Gandhi and M Spinelli, K24AI145806 to P Hunt, and by the Zuckerberg San Francisco Hospital Department of Medicine and Division of HIV, Infectious Diseases, and Global Medicine. MJP is supported on K23 A137522 and received support from the UCSFBay Area Center for AIDS Research (P30-AI027763).

Postacute sequelae and adaptive immune responses in people with HIV recovering from SARS-COV-2 infection.

BACKGROUND: Limited data are available on the long-term clinical and immunologic consequences of SARS-CoV-2 infection in people with HIV (PWH). METHODS: We measured SARS-CoV-2-specific humoral and cellular responses in people with and without HIV recovering from COVID-19 ( n  = 39 and n  = 43, respectively) using binding antibody, surrogate virus neutralization, intracellular cytokine staining, and inflammatory marker assays. We identified individuals experiencing postacute sequelae of SARS-CoV-2 infection (PASC) and evaluated immunologic parameters. We used linear regression and generalized linear models to examine differences by HIV status in the magnitude of inflammatory and virus-specific antibody and T-cell responses, as well as differences in the prevalence of PASC. RESULTS: Among PWH, we found broadly similar SARS-CoV-2-specific antibody and T-cell responses as compared with a well matched group of HIV-negative individuals. PWH had 70% lower relative levels of SARS-CoV-2-specific memory CD8 + T cells ( P  = 0.007) and 53% higher relative levels of PD-1+ SARS-CoV-2-specific CD4 + T cells ( P  = 0.007). Higher CD4 + /CD8 + ratio was associated with lower PD-1 expression on SARS-CoV-2-specific CD8 + T cells (0.34-fold effect, P  = 0.02). HIV status was strongly associated with PASC (odds ratio 4.01, P  = 0.008), and levels of certain inflammatory markers (IL-6, TNF-alpha, and IP-10) were associated with persistent symptoms. CONCLUSION: We identified potentially important differences in SARS-CoV-2-specific CD4 + and CD8 + T cells in PWH and HIV-negative participants that might have implications for long-term immunity conferred by natural infection. HIV status strongly predicted the presence of PASC. Larger and more detailed studies of PASC in PWH are urgently needed.