Divergent adaptive immune responses define two types of long COVID.

Background: The role of adaptive immune responses in long COVID remains poorly understood, with contrasting hypotheses suggesting either an insufficient antiviral response or an excessive immune response associated with inflammatory damage. To address this issue, we set to characterize humoral and CD4+ T cell responses in long COVID patients prior to SARS-CoV-2 vaccination. Methods: Long COVID patients who were seropositive (LC+, n=28) or seronegative (LC-, n=23) by spike ELISA assay were recruited based on (i) an initial SARS-CoV-2 infection documented by PCR or the conjunction of three major signs of COVID-19 and (ii) the persistence or resurgence of at least 3 symptoms for over 3 months. They were compared to COVID patients with resolved symptoms (RE, n=29) and uninfected control individuals (HD, n=29). Results: The spectrum of persistent symptoms proved similar in both long COVID groups, with a trend for a higher number of symptoms in the seronegative group (median=6 vs 4.5; P=0.01). The use a highly sensitive S-flow assay enabled the detection of low levels of SARS-CoV-2 spike-specific IgG in 22.7% of ELISA-seronegative long COVID (LC-) patients. In contrast, spike-specific IgG levels were uniformly high in the LC+ and RE groups. Multiplexed antibody analyses to 30 different viral antigens showed that LC- patients had defective antibody responses to all SARS-CoV-2 proteins tested but had in most cases preserved responses to other viruses. A sensitive primary T cell line assay revealed low but detectable SARS-CoV-2-specific CD4 responses in 39.1% of LC- patients, while response frequencies were high in the LC+ and RE groups. Correlation analyses showed overall strong associations between humoral and cellular responses, with exceptions in the LC- group. Conclusions: These findings provide evidence for two major types of antiviral immune responses in long COVID. Seropositive patients showed coordinated cellular and humoral responses at least as high as those of recovered patients. In contrast, ELISA-seronegative long COVID patients showed overall low antiviral responses, with detectable specific CD4+ T cells and/or antibodies in close to half of patients (52.2%). These divergent findings in patients sharing a comparable spectrum of persistent symptoms raise the possibility of multiple etiologies in long COVID.

A cohort study of enfuvirtide immunological and virological efficacy in clinical practice.

The aim of the study was to evaluate, under routine circumstances, the immunological and virological efficacy of antiretroviral regimens containing enfuvirtide in multi-class experienced HIV-1 infected patients. This retrospective monocentric study analyzed the clinical, immunological, and virological data of 18 HIV-1 infected patients who started enfuvirtide and completed at least 3 months of therapy. Following 3 months of enfuvirtide therapy, 11 (61%) patients had HIV-1 RNA below 400 copies/ml, among whom 8 (44%) patients below 50 copies/ml. In the ten patients still receiving enfuvirtide after 12 months, the median increase in CD4 cell count was 159 cells/microl (range, -25 to +301) and the mean decrease in HIV-1 RNA was 2.5 +/- 1.4 log(10) copies/ml; in six of these patients, viral load remained below 50 copies/ml. Five patients discontinued enfuvirtide for virological failure but none as a consequence of adverse event. Mutations located within the 36-45 amino acid domain of HR1 region of gp41 and associated to enfuvirtide resistance were found in all seven patients with persistent viral replication. In addition, a new mutation, A50V, emerged in one patient with late viral rebound. Its disappearance after treatment discontinuation suggests that it could play a role in resistance to enfuvirtide. In conclusion, enfuvirtide may be a good therapeutic option as rescue therapy in treatment-experienced patients. However, the mutations conferring resistance to enfuvirtide develop rapidly when viral load is not controlled confirming that enfuvirtide should be prescribed in association with an active background regimen.