Increased renin angiotensin aldosterone system(RAAS) activity may contribute to excess cardiovascular disease in people with HIV(PWH). We investigated how RAAS blockade may improve myocardial perfusion, injury and function among well-treated PWH. 40 PWH, on stable ART, without known heart disease were randomized to eplerenone 50 mg PO BID(n=20) or identical placebo(n=20) for 12 months. The primary endpoints were: 1) myocardial perfusion assessed by coronary flow reserve(CFR) on cardiac PET or stress myocardial blood flow(sMBF) on cardiac MRI or 2) myocardial inflammation by extracellular mass index(ECMi) on cardiac MRI. Beneficial effects on myocardial perfusion were seen for sMBF by cardiac MRI[mean(SD) 0.09(0.56) vs. -0.53(0.68)mL/min/g, P=.03], but not CFR by cardiac PET[0.01(0.64) vs. -0.07(0.48), P=.72, eplerenone vs. placebo]. Eplerenone improved parameters of myocardial function on cardiac MRI including left ventricular end diastolic volume[-13(28) vs. 10(26)mL, P=.03] and global circumferential strain[median (GCS, median(interquartile range 25^th-75^th), -1.3(-2.9-1.0) vs. 2.3(-0.4-4.1)%, P=.03], eplerenone vs. placebo respectively. On cardiac MRI, improvement in sMBF related to improvement in GCS(ρ=-0.65, P=.057) among those treated with eplerenone. Selecting for those with impaired myocardial perfusion(CFR<2.5 and/or sMBF<1.8), there was a treatment effect of eplerenone vs. placebo to improve CFR[0.28(0.27) vs. -0.05(0.36), P=.04]. Eplerenone prevented a small increase in troponin[0.00(-0.13-0.00) vs. 0.00(0.00-0.74)ng/L, P=.03] without effects on ECMi[0.9(-2.3-4.3) vs. -0.7(-2.2-^-0.1)g/m², P=.38). CD4+ T cell count[127(-38-286) vs. -6(-168-53)cells/μL, P=.02] increased in the eplerenone vs. placebo-treated groups. RAAS blockade with eplerenone benefitted key indices and prevented worsening of myocardial perfusion, injury and function among PWH with subclinical cardiac disease when compared to placebo.

HIV-associated distal sensory polyneuropathy (HIV-DSP) remains prevalent even in the antiretroviral therapy (ART) era. Previously, we identified the upregulation of nociceptive ion channels transient receptor potential vanilloid 1 (TRPV1) and ankyrin 1 (TRPA1) in the dorsal root ganglia (DRG) of simian immunodeficiency virus (SIV)-infected ART-treated macaques. To investigate upstream mechanisms, we performed bulk RNA-seq and pathway analysis on DRGs from uninfected, SIV-infected, and SIV-infected/ART macaques. SIV infection drove strong activation of upstream regulators of interferon γ (IFNγ) and lipopolysaccharide (LPS). Although ART reduced overall IFNγ and LPS pathway activity, the IFNγ-inducible chemokines C-X-C motif chemokine ligand (CXCL)9 and CXCL10 remained significantly upregulated. To determine whether these chemokines influence TRPV1/TRPA1 expression, we treated induced pluripotent stem cell-derived peripheral sensory neurons (iPSC-PSNs) with CXCL9 and CXCL10, which induced a significant increase in TRPV1 but not TRPA1 expression. In parallel experiments, IFNγ but not LPS stimulated monocyte-derived macrophages (MDMs) to release CXCL9 and CXCL10. Conditioned media from IFNγ-treated MDMs modestly increased TRPV1 expression in iPSC-PSNs, and pharmacological inhibition of CXCR3, the receptor of CXCL9/10, did not reduce this effect. Together, these data indicate that persistent IFNγ-driven CXCL9/10 signaling may be one contributor to nociceptor sensitization underlying HIV-DSP, even in the presence of ART.

Although neurological disease is common in people with human immunodeficiency virus (HIV) (PWH), the contributing factors and underlying inflammatory mechanisms remain challenging to identify. Extracellular vesicles (EVs) constitute a relatively uncharacterized modality of intercellular communication and bioactive cargo transport in the setting of viral infection and pathogenesis. EVs carry inflammatory mediators to areas of the periphery during antiretroviral therapy (ART) suppression but are understudied in the brain. Using a biologically relevant simian–human immunodeficiency chimeric virus with a clade D HIV envelope (SHIV.D)-infected rhesus macaque (RM) model of HIV persistence in the central nervous system (CNS), we investigate circulating EV populations and the protein cargo of myeloid-derived EVs during SHIV infection. Using EV flow cytometry to quantify specific EV subpopulations, we found a significant increase in TMEM119+ microglial EVs and CD171+ neuronal EVs in RM plasma during viremia and ART suppression. Using primary RM monocyte-derived macrophages (MDMs), we determined that MDMs increased EV production after SHIV infection. Whole proteomic analysis of these EVs demonstrated that myeloid EVs isolated from SHIV.D-infected MDMs carried significantly increased levels of neuropathogenic and inflammatory proteins. Altogether, these studies improve our understanding of the contribution of myeloid EVs to neurological disease during SHIV/HIV infection.