Cytomegalovirus Infection Facilitates the Costimulation of CD57+CD28- CD8 T Cells in HIV Infection and Atherosclerosis via the CD2-LFA-3 Axis.

CD8 T cells are emerging as important mediators in atherosclerosis and cardiovascular disease (CVD). Immune activation may play a particular role in people with HIV (PWH) who are at an increased risk of CVD, even after controlling for known CVD risk factors. Latent CMV infection is associated with increased CVD risk for both PWH and people without HIV, and human CMV-specific CD4 and CD8 T cells are enriched for an immunosenescent phenotype. We previously showed that CMV coinfection in PWH promotes vascular homing and activation of inflammatory CD4 T cells through the CD2-LFA-3 axis. However, the role of CD2/LFA3 costimulation of CD8 T cells in PWH with CMV has yet to be described. In the present study, we demonstrate that CD2 expression on CX3CR1+CD57+CD28- inflammescent CD8 T cells is increased on cells from CMV-seropositive PWH. In vitro CD2/LFA-3 costimulation enhances TCR-mediated activation of these inflammatory CD8 memory T cells. Finally, we show that LFA-3 is highly expressed in aortas of SIV-infected rhesus macaques and in atherosclerotic plaques of people without HIV. Our findings are consistent with a model in which CMV infection enhances CD2 expression on highly proinflammatory CD8 T cells that can then be stimulated by LFA-3 expressed in the vasculature, even in the absence of CD28 costimulation. This model, in which CMV infection exacerbates toxic cytokine and granzyme production by CD8 T cells within the vasculature, highlights a potential therapeutic target in atherosclerosis development and progression, especially for PWH.

Protection Conferred by Delta and BA.1/BA.2 Infection Against BA.4/BA.5 Infection and Hospitalization: A Retrospective Cohort Study.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 immunity has declined with subsequent waves and accrual of viral mutations. In vitro studies raise concern for immune escape by BA.4/BA.5, and a study in Qatar showed moderate protection, but these findings have yet to be reproduced. METHODS: This retrospective cohort study included individuals tested for coronavirus disease 2019 by polymerase chain reaction during Delta or BA.1/BA.2 and retested during BA.4/BA.5. The preventable fraction (PF) was calculated as ratio of the infection to the hospitalization rate for initially positive patients divided by the ratio for initially negative patients, stratified by age and adjusted for age, sex, comorbid conditions, and vaccination using logistic regression. RESULTS: A total of 20 987 patients met inclusion criteria. Prior Delta infection provided no protection against BA.4/BA.5 infection (adjusted PF, 11.9% [95% confidence interval, .8%-21.8%]); P = .04) and minimal protection against hospitalization (10.7% [4.9%-21.7%]; P = .003). In adjusted models, prior BA.1/BA.2 infection provided 45.9% (95% confidence interval, 36.2%-54.1%; P < .001) protection against BA.4/BA.5 reinfection and 18.8% (10.3%-28.3%; (P < .001) protection against hospitalization. Up-to-date vaccination provided modest protection against reinfection with BA.4/BA.5 and hospitalization. CONCLUSIONS: Prior infection with BA.1/BA.2 and up-to-date vaccination provided modest protection against infection with BA.4/BA.5 and hospitalization, while prior Delta infection provided minimal protection against hospitalization and none against infection.

Eight-day Inpatient Directly Observed Therapy for Antiretroviral Therapy (ART) Failure: A Tool For Preventing Unnecessary ART Changes and Optimizing Adherence Support.

Eight-day inpatient directly observed therapy confirmed nonadherence as the major cause of virologic failure for 9 (45%) of 20 highly treatment-experienced persons with human immunodeficiency virus, extensive antiretroviral drug resistance, and high self-reported adherence rates, preventing unnecessary regimen changes.