Selected 2017 Publications

Highly oxidized low density lipoprotein mediates activation of monocytes but does not confer IL-1β secretion nor IL-15 transpresentation function.

Sieg SF, Bazdar DA, Zidar D, Freeman M, Lederman MM, Funderburg NT.

Immunology 2019 Oct;():. doi: . Epub.

Abstract: Oxidized LDL contributes to cardiovascular disease in part by mediating activation and maturation of monocytes and macrophages. Furthermore, co-localization studies using histochemical approaches have implicated a potential role for oxidized LDL as a mediator of IL-15 expression in myeloid cells of atherosclerotic plaque. The latter activity could be an important pro-inflammatory mechanism that mediates myeloid cell/T cell crosstalk. Here, we examined responses of primary human monocytes to highly oxidized LDL molecules. Oxidized LDL readily induced secretion of chemokines MCP-1 (CCL2) and GRO-α (CXCL1) but unlike LPS, has limited capacity to induce a variety of other cytokines including TNF- α, IL-6, IL-1β and IP-10 and also displayed a poor capacity to induce p-Akt or P-S6 signaling. Failure of oxidized LDL to induce IL-1β secretion was associated with limited induction of caspase-1 activation. Furthermore, despite finding evidence that oxidized LDL could enhance the expression of IL-15 and IL-15R expression in monocytes, we found no evidence that it could confer IL-15 transpresentation capability to these cells. This observation contrasted with induction of IL-15 transpresentation in LPS stimulated monocytes. Overall, our data suggest that highly oxidized LDL is a selective inducer of monocyte activation. Sterile inflammatory mediators, particularly those implicated in TLR4 signaling, may play a role in vascular pathology but the activities of these agents are not uniform. © Immunology.

Fingolimod retains cytolytic T cells and limits T follicular helper cell infection in lymphoid sites of SIV persistence.

Pino M, Paganini S, Deleage C, Padhan K, Harper JL, King CT, Micci L, Cervasi B, Mudd JC, Gill KP, Jean SM, Easley K, Silvestri G, Estes JD, Petrovas C, Lederman MM, Paiardini M.

PLoS Pathog. 2019 Oct;15(10):e1008081. doi: PPATHOGENS-D-19-00870. Epub.

Abstract: Lymph nodes (LN) and their resident T follicular helper CD4+ T cells (Tfh) are a critical site for HIV replication and persistence. Therefore, optimizing antiviral activity in lymphoid tissues will be needed to reduce or eliminate the HIV reservoir. In this study, we retained effector immune cells in LN of cART-suppressed, SIV-infected rhesus macaques by treatment with the lysophospholipid sphingosine-1 phosphate receptor modulator FTY720 (fingolimod). FTY720 was remarkably effective in reducing circulating CD4+ and CD8+ T cells, including those with cytolytic potential, and in increasing the number of these T cells retained in LN, as determined directly in situ by histocytometry and immunohistochemistry. The FTY720-induced inhibition of T cell egress from LN resulted in a measurable decrease of SIV-DNA content in blood as well as in LN Tfh cells in most treated animals. In conclusion, FTY720 administration has the potential to limit viral persistence, including in the critical Tfh cellular reservoir. These findings provide rationale for strategies designed to retain antiviral T cells in lymphoid tissues to target HIV remission. © PLoS Pathogens.

Pneumoproteins are associated with pulmonary function in HIV-infected persons.

Jeon D, Chang EG, McGing M, Hartman-Filson M, Sommers M, Lewis E, Balmes JR, Moisi D, Lederman MM, Madsen KA, Woodruff PG, Hunt PW, Huang L, .

PLoS ONE 2019 ;14(10):e0223263. doi: PONE-D-19-17773. Epub.

Abstract: COPD is a common HIV comorbidity, and HIV-infected individuals have a higher incidence and earlier onset of COPD compared to HIV-uninfected individuals. While the pathogenesis of HIV-associated COPD is largely unknown, chronic inflammation may contribute. Four pneumoproteins known to be markers of lung injury and inflammation have been associated with COPD in HIV-uninfected individuals: PARC/CCL-18, SP-D, CC-16, and sRAGE. © PloS One.

HIV infection is associated with elevated biomarkers of immune activation in Ugandan adults with pneumonia.

Wang RJ, Moore J, Moisi D, Chang EG, Byanyima P, Kaswabuli S, Musisi E, Sanyu I, Sessolo A, Lalitha R, Worodria W, Davis JL, Crothers K, Lin J, Lederman MM, Hunt PW, Huang L.

PLoS ONE 2019 ;14(5):e0216680. doi: PONE-D-19-07580. Epub.

Abstract: Pneumonia is an important cause of morbidity and mortality in persons living with human immunodeficiency virus (HIV) infection. How immune activation differs among HIV-infected and HIV-uninfected adults with pneumonia is unknown. © PloS One.

Altered Lipidome Composition Is Related to Markers of Monocyte and Immune Activation in Antiretroviral Therapy Treated Human Immunodeficiency Virus (HIV) Infection and in Uninfected Persons.

Bowman ER, Kulkarni M, Gabriel J, Cichon MJ, Riedl K, Belury MA, Lake JE, Richardson B, Cameron C, Cameron M, Koletar SL, Lederman MM, Sieg SF, Funderburg NT.

Front Immunol 2019 ;10():785. doi: PMC6477036. Epub.

Abstract: HIV infection and antiretroviral therapy (ART) have both been linked to dyslipidemia and increased cardiovascular disease (CVD) risk. Alterations in the composition of saturated (SaFA), monounsaturated (MUFA), and polyunsaturated (PUFA) fatty acids are related to inflammation and CVD progression in HIV-uninfected (HIV-) populations. The relationships among the lipidome and markers of monocyte and immune activation in HIV-infected (HIV+) individuals are not well understood. Concentrations of serum lipids and their fatty acid composition were measured by direct infusion-tandem mass spectrometry in samples from 20 ART-treated HIV+ individuals and 20 HIV- individuals. HIV+ individuals had increased levels of free fatty acids (FFAs) with enrichment of SaFAs, including palmitic acid (16:0) and stearic acid (18:0), and these levels were directly associated with markers of monocyte (CD40, HLA-DR, TLR4, CD36) and serum inflammation (LBP, CRP). PUFA levels were reduced significantly in HIV+ individuals, and many individual PUFA species levels were inversely related to markers of monocyte activation, such as tissue factor, TLR4, CD69, and SR-A. Also in HIV+ individuals, the composition of lysophosphatidylcholine (LPC) was enriched for SaFAs; LPC species containing SaFAs were directly associated with IL-6 levels and monocyte activation. We similarly observed direct relationships between levels of SaFAs and inflammation in HIV uninfected individuals. Further, SaFA exposure altered monocyte subset phenotypes and inflammatory cytokine production . The lipidome is altered in ART-treated HIV infection, and may contribute to inflammation and CVD progression. Detailed lipidomic analyses may better assess CVD risk in both HIV+ and HIV- individuals than does traditional lipid profiling. © Frontiers In Immunology.

Stability of plasma indices of inflammation/coagulation and homeostasis after fatty and non-fatty meals in treated people with HIV.

Dorazio D, Kitch DW, Utay NS, Macatangay BJ, Landay A, Brown T, Bosch RJ, Pelger AL, Baum JE, Asaad R, Rodriguez B, Lederman MM.

J Virus Erad 2019 Jan;5(1):28-32. doi: . Epub.

Abstract: The relationship between lipid levels in plasma and inflammatory indices is complex and fatty meals alter plasma inflammatory markers in people with diabetes. There is interest in monitoring the effects of interventions on plasma inflammatory and coagulation elements in people with HIV, as they have been linked to risk for morbid outcomes and HIV persistence. Understanding the effects of feeding and time of specimen acquisition is important for the correct scheduling of clinical sampling. © Journal Of Virus Eradication.

CD8+ T-Cell-Derived Tumor Necrosis Factor Can Induce Tissue Factor Expression on Monocytes.

Freeman ML, Panigrahi S, Chen B, Juchnowski S, Sieg SF, Lederman MM, Funderburg NT, Zidar DA.

J. Infect. Dis. 2019 Jun;220(1):73-77. doi: 10.1093/infdis/jiz051. Epub.

Abstract: Circulating CD8+ T cells and monocytes are activated during human immunodeficiency virus (HIV) infection and colocalize in the aortas of simian immunodeficiency virus-infected nonhuman primates. We hypothesized that CD8+ T cells could exert a proatherosclerotic effect via paracrine actions on monocytes. We found that T-cell receptor-stimulated CD8+ T cells induce monocytes to express tissue factor, a potent activator of coagulation. Tumor necrosis factor was both necessary and sufficient for this effect. © The Journal Of Infectious Diseases.

Soluble Urokinase Plasminogen Activator Receptor (suPAR) is predictive of Non-AIDS Events during Antiretroviral Therapy-mediated Viral Suppression.

Hoenigl M, Moser C, Funderburg N, Bosch R, Kantor A, Zhang Y, Eugen-Olsen J, Finkelman M, Reiser J, Landay A, Moisi D, Lederman MM, Gianella S, .

Clin. Infect. Dis. 2018 Nov;():. doi: 10.1093/cid/ciy966. Epub.

Abstract: Despite effective antiretroviral therapy (ART), HIV infection remains associated with higher morbidity/mortality, driven- in part -by increased inflammation. The objective of this study is to identify associations between levels of plasma biomarkers of chronic inflammation, microbial translocation, and monocyte activation, measured prior to and during suppressive ART, with occurrence of non-AIDS events. © Clinical Infectious Diseases : An Official Publication Of The Infectious Diseases Society Of America.

Physical Activity Intensity is Associated with Symptom Distress in the CNICS Cohort.

Webel AR, Willig AL, Liu W, Sattar A, Boswell S, Crane HM, Hunt P, Kitahata M, Matthews WC, Saag MS, Lederman MM, Rodriguez B.

AIDS Behav 2019 Mar;23(3):627-635. doi: 10.1007/s10461-018-2319-7. Epub.

Abstract: Symptom distress remains a challenging aspect of living with HIV. Physical activity is a promising symptom management strategy, but its effect on symptom distress has not been examined in a large, longitudinal HIV-infected cohort. We hypothesized that higher physical activity intensity would be associated with reduced symptom distress. We included 5370 people living with HIV (PLHIV) who completed patient-reported assessments of symptom distress, physical activity, alcohol and substance use, and HIV medication adherence between 2005 and 2016. The most frequent and burdensome symptoms were fatigue (reported by 56%), insomnia (50%), pain (46%), sadness (45%), and anxiety (45%), with women experiencing more symptoms and more burdensome symptoms than men. After adjusting for age, sex, race, time, HIV medication adherence, alcohol and substance use, site, and HIV RNA, greater physical activity intensity was associated with lower symptom intensity. Although individual symptoms may be a barrier to physical activity (e.g. pain), the consistent association between symptoms with physical activity suggests that more intense physical activity could mitigate symptoms experienced by PLHIV. © AIDS And Behavior.

Cycling CD4+ T cells in HIV-infected immune nonresponders have mitochondrial dysfunction.

Younes SA, Talla A, Pereira Ribeiro S, Saidakova EV, Korolevskaya LB, Shmagel KV, Shive CL, Freeman ML, Panigrahi S, Zweig S, Balderas R, Margolis L, Douek DC, Anthony DD, Pandiyan P, Cameron M, Sieg SF, Calabrese LH, Rodriguez B, Lederman MM.

J. Clin. Invest. 2018 11;128(11):5083-5094. doi: 10.1172/JCI120245. Epub.

Abstract: Immune nonresponder (INR) HIV-1-infected subjects are characterized by their inability to reconstitute the CD4+ T cell pool after antiretroviral therapy. This is linked to poor clinical outcome. Mechanisms underlying immune reconstitution failure are poorly understood, although, counterintuitively, INRs often have increased frequencies of circulating CD4+ T cells in the cell cycle. While cycling CD4+ T cells from healthy controls and HIV+ patients with restored CD4+ T cell numbers complete cell division in vitro, cycling CD4+ T cells from INRs do not. Here, we show that cells with the phenotype and transcriptional profile of Tregs were enriched among cycling cells in health and in HIV infection. Yet there were diminished frequencies and numbers of Tregs among cycling CD4+ T cells in INRs, and cycling CD4+ T cells from INR subjects displayed transcriptional profiles associated with the impaired development and maintenance of functional Tregs. Flow cytometric assessment of TGF-β activity confirmed the dysfunction of Tregs in INR subjects. Transcriptional profiling and flow cytometry revealed diminished mitochondrial fitness in Tregs among INRs, and cycling Tregs from INRs had low expression of the mitochondrial biogenesis regulators peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1α) and transcription factor A for mitochondria (TFAM). In vitro exposure to IL-15 allowed cells to complete division, restored the expression of PGC1α and TFAM, and regenerated mitochondrial fitness in the cycling Tregs of INRs. Our data suggest that rescuing mitochondrial function could correct the immune dysfunction characteristic of Tregs in HIV-1-infected subjects who fail to restore CD4+ T cells during antiretroviral therapy. © The Journal Of Clinical Investigation.