HIV-seropositive patients are at higher risk for atherosclerosis than HIV-seronegative persons. This has been variably attributed to antiretroviral drug toxicity, immunodeficiency, and/or HIV-associated inflammation. To evaluate the contributions of these factors to HIV-associated atherosclerosis, we assessed carotid artery intima-media thickness in a diverse cohort of HIV-seronegative and seropositive adults, including a unique group of HIV-infected patients who were untreated, had undetectable viral loads, and had preserved CD4 T-cell counts (HIV controllers).Carotid intima-media thickness was measured in 494 participants, including 33 HIV controllers and 93 HIV-seronegative controls. HIV controllers had higher intima-media thickness than seronegative controls even after adjustment for traditional risk factors (P = 0.003). Intima-media thickness in controllers was similar to antiretroviral-untreated patients with detectable viremia. Across all participants, intima-media thickness was strongly associated with the presence of HIV disease rather than viral load or CD4 T-cell count. C-reactive protein was higher in HIV controllers than HIV-seronegative persons. Antiretroviral drug exposure was also associated with higher intima-media thickness.Increased atherosclerosis with HIV infection can occur in the absence of antiretroviral therapy, detectable viremia, or overt immunodeficiency. Chronic inflammation - which is higher in controllers than in HIV-uninfected persons - may account for early atherosclerosis in these patients.
Patients with systemic lupus erythematosus (SLE) can present with multiple cardiovascular pathologies, including pulmonary hypertension, valvular disease, pericarditis, myocarditis, and premature atherosclerosis. SLE medications can also cause cardiovascular side effects. We present a patient who developed a severe cardiomyopathy secondary to the hydroxychloroquine prescribed to treat her SLE. (Level of Difficulty: Beginner.)
HIV-infected patients have accelerated atherosclerosis. Abacavir has been associated with increased risk of cardiovascular events, for reasons that remain to be elucidated. As endothelial dysfunction is central to the pathogenesis of atherosclerosis, we tested the hypothesis that current treatment with abacavir is associated with impaired endothelial function.We studied a cohort of 61 antiretroviral-treated patients who had undetectable plasma HIV RNA levels. Endothelial function was assessed by measuring flow-mediated dilation (FMD) of the brachial artery. We compared FMD in patients treated with or without abacavir, while adjusting for traditional risk factors and HIV-specific characteristics.The median age was 50 years (interquartile range 45-57). The median duration of HIV infection was 18 years, and the median CD4 cell count was 369 cells/microl. Thirty patients (49%) were receiving abacavir. Overall, the median FMD in the HIV-infected patients was low (3.5%; interquartile range 2.3-5.6%). The FMD was lower in the abacavir-treated patients than those not on abacavir (2.8 vs. 4.9%, P = 0.01). After adjustment for traditional risk factors, HIV-specific factors, and baseline brachial artery diameter, current abacavir use was independently associated with lower FMD (P = 0.017). Duration of therapy and CD4 cell count were not associated with reduced FMD.Endothelial function, a central mechanism in atherosclerosis and a marker of cardiovascular risk, is impaired among antiretroviral-treated patients with undetectable viral loads. Current use of abacavir was independently associated with impaired endothelial function. This finding suggests that abnormal endothelial function may underlie the clinically observed increased risk in myocardial infarction among abacavir-treated patients.
Abstract Background We recently identified DOCK8 as a novel gene associated with cytokine storm syndrome (CSS). Heterozygous missense mutations in DOCK8 diminish NK cell lytic function and contribute to increased pro-inflammatory cytokine production (CSS). CSS is a potential complication of COVID-19 with severe consequences. Children are at risk of a SARS-CoV-2 post-infectious CSS, multisystem inflammatory syndrome in children (MIS-C). Host genetic factors associated with COVID-19 CSS and MIS-C CSS are unknown. Methods To date, 16 adult patients enrolled in a COVID-19 CSS clinical trial at UAB had whole genome sequencing. Four (25%) had rare heterozygous DOCK8 mutations (3 missense, 1 intronic). A COVID-19 CSS adult patient in Seattle also had a DOCK8 missense mutation. In addition, DOCK8 missense mutations were identified in 5 children (UAB & Northwell) hospitalized with MIS-C. DOCK8 mutations, or wild-type (WT) sequence controls, were introduced into human NK-92 cells by FOAMY virus transduction. WT and mutant DOCK8-expressing NK-92 cells were incubated with K562 target cells and compared for cytolysis and degranulation (CD107a). Results One COVID-19 patient DOCK8 mutation (Gly523Arg) reduced NK cell degranulation by 30% and cytolysis by 23% (n=3). Similar studies of 3 MIS-C patients with DOCK8 missense mutations revealed up to 31% reduced NK cell degranulation and 48% reduction in cytolysis by 3 mutations (n=3). Two-way ANOVA analysis revealed statistically significant (p<0.05) differences in NK cell degranulation and lysis for 4 unique DOCK8 mutations. Conclusion Heterozygous DOCK8 missense mutations may contribute to severe COVID-19 and MIS-C CSS by partial dominant-negative effects yielding decreased NK cell cytolysis.
HIV infection is associated with increased rates of cardiovascular disease. We sought to evaluate whether initiation of HIV therapy at higher nadir CD4(+) T-cell counts might reduce cardiovascular risk, as measured by arterial stiffness.We conducted a cross-sectional study of 80 HIV-infected men who were antiretroviral-treated with undetectable plasma HIV RNA levels.Participants underwent noninvasive assessment of arterial stiffness by pulse wave analysis (augmentation index normalized for heart rate of 75 bpm) and carotid-femoral pulse wave velocity, both sensitive measures of cardiovascular risk. A generalized linear model was used to determine the relationship between cardiovascular and HIV-related predictors, and arterial stiffness.In unadjusted analyses, predictors of arterial stiffness included age, blood pressure, antihypertensive medication use, and nadir CD4(+) T-cell count below 350 cells/microl (all P < 0.05). After adjusting for both cardiovascular risk factors (age, blood pressure, antihypertensive medication use, diabetes, hypercholesterolemia, and smoking) and HIV-related covariates, nadir CD4(+) T-cell count below 350 cells/microl was independently associated with a 0.41 m/s increase in pulse wave velocity (95% confidence interval 0.03-0.79, P = 0.03) and a 7.3% increase in augmentation index (augmentation index normalized for heart rate of 75 bpm; 95% confidence interval 2.6-11.9, P = 0.003). Neither duration of antiretroviral therapy nor exposure to protease inhibitors was associated with arterial stiffness.Among treated HIV-infected individuals, arterial stiffness is independently associated with both traditional cardiovascular risk factors as well as a low nadir CD4(+) T-cell count. Our data suggest that cardiovascular risk among HIV-infected individuals could be reduced through early initiation of antiretroviral therapy, before CD4 T-cell counts are depressed, a concept that should be tested prospectively in future studies.
