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1.
Topics in Antiviral Medicine ; 30(1 SUPPL):75, 2022.
Article in English | EMBASE | ID: covidwho-1880788

ABSTRACT

Background: SARS-CoV-2 infection results in a spectrum of disease severity attributable to the magnitude of the underlying inflammatory response. Aged individuals with co-morbidities are most vulnerable and severely affected, but the mechanisms driving aberrant immune responses fueling SARS-CoV-2 immunopathology in this high-risk population are not fully elucidated. We hypothesized that asymptomatic CMV infection might exacerbate SARS-CoV-2 pathogenesis since its replication is both a cause and consequence of inflammation and appears to worsen oxygenation in critically ill patients (Limaye, JAMA, 2017). CMV-seropositivity was associated with increased hospitalization among people with SARS-CoV-2 infection (Shrock, Science, 2020). To begin to address this hypothesis, we utilized the rhesus macaque model of natural rhesus (Rh)CMV infection to investigate the extent to which SARS-CoV-2 induces CMV reactivation in the anatomic sites of SARS-CoV-2 pathology. Methods: To assess CMV reactivation, eight aged, type 2 diabetic RhCMV-seropositive rhesus macaques (sera anti-CMV IgG: 300-1400 ng/ml) were infected with high-dose SARS-CoV-2 (2.5x10 6 PFU) and monitored for 7 days prior to euthanasia. Samples from the respiratory tract, intestinal tract, and blood were collected to assess viral and inflammatory dynamics in distinct tissue compartments. Results: Following infection, SARS-CoV-2 replication was observed throughout the respiratory tract, which was associated with local and systemic inflammation and immune activation. Lung histopathological assessments revealed development of interstitial pneumonia with colocalization of SARS nucleocapsid protein within pneumocytes. qPCR assays targeting RhCMV gB showed CMV DNA within the caudal lung lobe (up to 103 CMV DNA copies/mg of tissue) in all animals at day 7, and the animal with the highest CMV DNA presented with the most profound clinical symptoms. Strikingly, CMV DNA copies strongly correlated with CD4 and CD8 T cell activation indices in blood and spleen (r = 0.96, p< 0.001). Additionally, we found RhCMV reactivation in the ileum, where high levels of ACE2 are reported. Conclusion: SARS-CoV-2 infection of RhCMV-seropositive macaques results in CMV reactivation in the anatomic sites where SARS-CoV-2 causes pathology. Future experimental studies should address whether CMV reactivation exacerbates SARS-CoV-2 pathogenesis.

3.
PubMed; 2021.
Preprint in English | PubMed | ID: ppcovidwho-296541

ABSTRACT

Objectives: To define the incidence of clinically-detected COVID-19 in people with HIV (PWH) in the US and evaluate how racial and ethnic disparities, comorbidities, and HIV-related factors contribute to risk of COVID-19. Design: Observational study within the CFAR Network of Integrated Clinical Systems cohort in 7 cities during 2020. Methods: We calculated cumulative incidence rates of COVID-19 diagnosis among PWH in routine care by key characteristics including race/ethnicity, current and lowest CD4 count, and geographic area. We evaluated risk factors for COVID-19 among PWH using relative risk regression models adjusted with disease risk scores. Results: Among 16,056 PWH in care, of whom 44.5% were Black, 12.5% were Hispanic, with a median age of 52 years (IQR 40-59), 18% had a current CD4 count < 350, including 7% < 200;95.5% were on antiretroviral therapy, and 85.6% were virologically suppressed. Overall in 2020, 649 PWH were diagnosed with COVID-19 for a rate of 4.94 cases per 100 person-years. The cumulative incidence of COVID-19 was 2.4-fold and 1.7-fold higher in Hispanic and Black PWH respectively, than non-Hispanic White PWH. In adjusted analyses, factors associated with COVID-19 included female sex, Hispanic or Black identity, lowest historical CD4 count <350 (proxy for CD4 nadir), current low CD4/CD8 ratio, diabetes, and obesity. Conclusions: Our results suggest that the presence of structural racial inequities above and beyond medical comorbidities increased the risk of COVID-19 among PWHPWH with immune exhaustion as evidenced by lowest historical CD4 or current low CD4:CD8 ratio had greater risk of COVID-19.

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