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. 2022 Nov 11;226(10):1823-1833.
doi: 10.1093/infdis/jiac301.

Increased Macrophage-Specific Arterial Infiltration Relates to Noncalcified Plaque and Systemic Immune Activation in People With Human Immunodeficiency Virus

Mabel Toribio  1 , Moses Q Wilks  2 , Sandeep Hedgire  3 , Michael T Lu  3 , Madeline Cetlin  1 , Melissa Wang  1 , Iad Alhallak  1 , Claudia G Durbin  1 , Kevin S White  4 , Zoey Wallis  4 , Samuel R Schnittman  5 , Takara L Stanley  1 , Georges El-Fakhri  2 , Hang Lee  6 , Patrick Autissier  4 , Markella V Zanni  1 , Kenneth C Williams  4 , Steven K Grinspoon  1
Affiliations

Increased Macrophage-Specific Arterial Infiltration Relates to Noncalcified Plaque and Systemic Immune Activation in People With Human Immunodeficiency Virus

Mabel Toribio et al. J Infect Dis. .

Abstract

Background: Persistent immune activation is thought to contribute to heightened atherosclerotic cardiovascular disease (ASCVD) risk among people with human immunodeficiency virus (PWH).

Methods: Participants (≥18 years) with or without human immunodeficiency virus (HIV) and without history of clinical ASCVD were enrolled. We hypothesized that increased macrophage-specific arterial infiltration would relate to plaque composition and systemic immune activation among PWH. We applied a novel targeted molecular imaging approach (technetium-99m [99mTc]-tilmanocept single photon emission computed tomography [SPECT]/CT) and comprehensive immune phenotyping.

Results: Aortic 99mTc-tilmanocept uptake was significantly higher among PWH (n = 20) than participants without HIV (n = 10) with similar 10-year ASCVD risk (P = .02). Among PWH, but not among participants without HIV, noncalcified aortic plaque volume related directly to aortic 99mTc-tilmanocept uptake at different uptake thresholds. An interaction (P = .001) was seen between HIV status and noncalcified plaque volume, but not calcified plaque (P = .83). Systemic levels of caspase-1 (P = .004), CD14-CD16+ (nonclassical/patrolling/homing) monocytes (P = .0004) and CD8+ T cells (P = .005) related positively and CD4+/CD8+ T-cell ratio (P = .02) inversely to aortic 99mTc-tilmanocept uptake volume.

Conclusions: Macrophage-specific arterial infiltration was higher among PWH and related to noncalcified aortic plaque volume only among PWH. Key systemic markers of immune activation relating to macrophage-specific arterial infiltration may contribute to heightened ASCVD risk among PWH.

Clinical trials registration: NCT02542371.

Keywords: CD206; HIV; NLRP3 inflammasome; SPECT; T-cell senescence; arterial inflammation; caspase-1; macrophages; noncalcified plaque; tilmanocept.

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Conflict of interest statement

Potential conflicts of interest. M. T. L. reports grant funding to his institution from AstraZeneca/MedImmune and Kowa Pharmaceuticals and consulting fees from PQBypass, unrelated to the present project. T. L. S. reports unrelated grant funding to her institution from Pfizer and Novo Nordisk. M. V. Z. is principal investigator of an industry-sponsored research grant from Gilead Sciences to her institution, unrelated to the present project. S. K. G. has grant funding to his institution from Gilead Sciences, KOWA Pharmaceuticals, and Theratechnologies, unrelated to the present project, and serves as a consultant for Theratechnologies, Regeneron, and ViiV Healthcare. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
Figure 1.
Aortic technetium-99m (99mTc)–tilmanocept single photon emission computed tomography (SPECT/CT) imaging among participants with or without human immunodeficiency virus (HIV). A, Aortic99mTc-tilmanocept SPECT/CT. Representative axial SPECT/CT cuts from a participant with HIV (left) and a participant without HIV (right). Higher signal-to-background ratio (ie, 99mTc-tilmanocept uptake signal-to-background ratio [SBR]) is depicted by red-orange on SPECT/CT images whereas a lower SBR is depicted by blue-purple on SPECT/CT images. The SPECT/CT image from the participant with HIV demonstrates a higher level of aortic 99mTc-tilmanocept uptake. B, Aortic99mTc-tilmanocept uptake on SPECT/CT. The percentage of aortic volume with 99mTc-tilmanocept on SPECT/CT is demonstrated across different thresholds (3–6 times) at or above muscle activity. Each line (red for participants with HIV and blue for participants without HIV) connects the data for a single participant. Participants with HIV had a significantly higher percentage aortic volume with 99mTc-tilmanocept uptake across different thresholds above muscle activity compared to participants without HIV (P = .02).
Figure 2.
Figure 2.
Aortic volume with technetium-99m (99mTc)–tilmanocept uptake across different thresholds in relation to aortic noncalcified plaque volume. The relationship between aortic volume with 99mTc-tilmanocept uptake and aortic noncalcified plaque volume is demonstrated here. Each vertical set of circles represents the aortic volume with 99mTc-tilmanocept uptake at a given threshold as a function of the aortic noncalcified plaque volume for each participant. Furthermore, linear regression lines for each uptake threshold are also shown. Using linear regression modeling, aortic volume with 99mTc-tilmanocept uptake across different thresholds related significantly to aortic noncalcified plaque volume among participants with human immunodeficiency virus (HIV) (and not among participants without HIV). *P < .05.
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