ABSTRACT
Efforts to cure HIV have focused on reactivating latent proviruses to enable elimination by CD8+ cytotoxic T-cells. Clinical studies of latency reversing agents (LRA) in antiretroviral therapy (ART)-treated individuals have shown increases in HIV transcription, but without reductions in virologic measures, or evidence that HIV-specific CD8+ T-cells were productively engaged. Here, we show that the SARS-CoV-2 mRNA vaccine BNT162b2 activates the RIG-I/TLR - TNF - NFκb axis, resulting in transcription of HIV proviruses with minimal perturbations of T-cell activation and host transcription. T-cells specific for the early gene-product HIV-Nef uniquely increased in frequency and acquired effector function (granzyme-B) in ART-treated individuals following SARS-CoV-2 mRNA vaccination. These parameters of CD8+ T-cell induction correlated with significant decreases in cell-associated HIV mRNA, suggesting killing or suppression of cells transcribing HIV. Thus, we report the observation of an intervention-induced reduction in a measure of HIV persistence, accompanied by precise immune correlates, in ART-suppressed individuals. However, we did not observe significant depletions of intact proviruses, underscoring challenges to achieving (or measuring) HIV reservoir reductions. Overall, our results support prioritizing the measurement of granzyme-B-producing Nef-specific responses in latency reversal studies and add impetus to developing HIV-targeted mRNA therapeutic vaccines that leverage built-in LRA activity.
Subject(s)
CD8-Positive T-Lymphocytes , COVID-19 Vaccines , COVID-19 , HIV Infections , HIV-1 , BNT162 Vaccine , CD4-Positive T-Lymphocytes , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/virology , COVID-19/prevention & control , COVID-19 Vaccines/immunology , Granzymes , HIV Infections/immunology , Humans , RNA, Messenger/genetics , RNA, Messenger/therapeutic use , SARS-CoV-2 , Vaccination , Vaccines, Synthetic , Virus Latency , mRNA Vaccines , nef Gene Products, Human Immunodeficiency Virus/geneticsABSTRACT
BACKGROUND AND PURPOSE: The aim of this study was to assess whether the severity of tinnitus, as measured using ratings of tinnitus loudness, annoyance, and effect on life, was influenced by the lockdown related to the coronavirus disease 2019 (COVID-19) pandemic. RESEARCH DESIGN: This was a retrospective study. STUDY SAMPLE: The data for 105 consecutive patients who were seen at a tinnitus clinic in an audiology department in the United Kingdom during the COVID-19 lockdown between April and June 2020 and 123 patients seen in the same period of the previous year, prior to the COVID-19 pandemic were included. DATA COLLECTION: Demographic data for the patients, results of their pure-tone audiometry, and their score on visual analog scale (VAS) of tinnitus loudness, annoyance, and effect on life were imported from their records held at the audiology department. This was a retrospective survey comparing ratings on the VAS of tinnitus loudness, annoyance, and effect on life for consecutive patients seen during the COVID-19 lockdown and consecutive patients seen in the same period of the previous year, prior to the COVID-19 pandemic. Patients seen prior to lockdown used a pen and paper version of the VAS, while the patients who were assessed during the COVID-19 lockdown used an adapted version of the VAS, via telephone. All patients were seeking help for their tinnitus for the first time. RESULTS: The mean scores for tinnitus loudness, annoyance, and effect on life did not differ significantly for the groups seen prior to and during lockdown. CONCLUSION: Any changes in psychological well-being or stress produced by the lockdown did not significantly affect ratings of the severity of tinnitus.