In late 2019, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) triggered the global coronavirus disease 2019 (COVID-19) pandemic. Although most infections cause a self-limited syndrome comparable to other upper respiratory viral pathogens, a portion of individuals develop severe illness leading to substantial morbidity and mortality. Furthermore, an estimated 10%–20% of SARS-CoV-2 infections are followed by post-acute sequelae of COVID-19 (PASC), or long COVID. Long COVID is associated with a wide variety of clinical manifestations including cardiopulmonary complications, persistent fatigue, and neurocognitive dysfunction. Severe acute COVID-19 is associated with hyperactivation and increased inflammation, which may be an underlying cause of long COVID in a subset of individuals. However, the immunologic mechanisms driving long COVID development are still under investigation. Early in the pandemic, our group and others observed immune dysregulation persisted into convalescence after acute COVID-19. We subsequently observed persistent immune dysregulation in a cohort of individuals experiencing long COVID. We demonstrated increased SARS-CoV-2-specific CD4+ and CD8+ T-cell responses and antibody affinity in patients experiencing long COVID symptoms. These data suggest a portion of long COVID symptoms may be due to chronic immune activation and the presence of persistent SARS-CoV-2 antigen. This review summarizes the COVID-19 literature to date detailing acute COVID-19 and convalescence and how these observations relate to the development of long COVID. In addition, we discuss recent findings in support of persistent antigen and the evidence that this phenomenon contributes to local and systemic inflammation and the heterogeneous nature of clinical manifestations seen in long COVID.

OBJECTIVES/GOALS: Despite highly effective antiretroviral therapy, people living with HIV (PLWH) experience chronic immune activation and inflammation which may influence the progression of infections such as SARS-CoV-2. Here, we explore the immune response and clinical outcomes in HIV(+) and HIV(-) individuals experiencing acute COVID-19 and long COVID (LC). METHODS/STUDY POPULATION: We performed flow cytometric analyses on peripheral blood mononuclear cells from the following: 1) HIV(-) individuals experiencing acute COVID-19, 2) PLWH experiencing acute COVID-19, and 3) pre-COVID-19 pandemic PLWH. Additionally, we will perform similar analyses for the following: 1) PLWH experiencing LC, 2) PLWH previously infected with SARS-CoV-2 who recovered, 3) pre-COVID-19 pandemic PLWH, and 4) HIV(-) individuals experiencing LC. Flow cytometry panels include surface markers for immune cell populations, activation and exhaustion surface markers (with and without SARS-CoV-2-specific antigen stimulation), and intracellular cytokine staining. We will also analyze how chronic HIV infection and other clinical and demographic factors (e.g., age, CD4 %) impact persistent symptomatic burden. RESULTS/ANTICIPATED RESULTS: Acute COVID-19 results–Overall, PLWH had higher baseline expression of activation markers OX40 and CD137 on CD4+ and CD8+ T cells, along with increased levels of TNFa producing CD8+ T cells. Interestingly, PLWH had increased expression of exhaustion markers PD1 and TIGIT but decreased expression of TIM3 on CD4+ and CD8+ T cells. Additionally, PLWH had decreased levels of IL-2 and IFNg producing CD4+ T cells which suggests functional exhaustion. Long COVID-19 expected results–we hypothesize that the activation and inflammation seen in chronic HIV infection will lead to more immune dysregulation and subsequently worsened symptomatic burden. Additionally, we hypothesize that PLWH may have different frequencies of certain LC manifestations, such as increased rates of neurocognitive impairment. DISCUSSION/SIGNIFICANCE: Our findings suggest that chronic HIV infection influences acute immune response during SARS-CoV-2 infection, and that PLWH have variable expression of exhaustion markers which warrants further study. Additionally, our findings in the LC cohort will aid in characterizing clinical manifestations and immunologic mechanisms of LC in PLWH.

Despite decades of research, an effective HIV-1 vaccine remains elusive. Vaccine strategies leading to the generation of broadly neutralizing antibodies are likely needed to provide the best opportunity of generating a protective immune response against HIV-1.