α4-Integrin Antibody Treatment Blocks Monocyte/Macrophage Traffic to, Vascular Cell Adhesion Molecule-1 Expression in, and Pathology of the Dorsal Root Ganglia in an SIV Macaque Model of HIV-Peripheral Neuropathy.

Traffic of activated monocytes into the dorsal root ganglia (DRG) is critical for pathology in HIV peripheral neuropathy. We have shown that accumulation of recently recruited (bromodeoxyuridine(+) MAC387(+)) monocytes is associated with severe DRG pathology and loss of intraepidermal nerve fibers in SIV-infected macaques. Herein, we blocked leukocyte traffic by treating animals with natalizumab, which binds to α4-integrins. SIV-infected CD8-depleted macaques treated with natalizumab either early (the day of infection) or late (28 days after infection) were compared with untreated SIV-infected animals sacrificed at similar times. Histopathology showed diminished DRG pathology with natalizumab treatment, including decreased inflammation, neuronophagia, and Nageotte nodules. Natalizumab treatment resulted in a decrease in the number of bromodeoxyuridine(+) (early), MAC387(+) (late), CD68(+) (early and late), and SIVp28(+) (late) macrophages in DRG tissues. The number of CD3(+) T lymphocytes in DRGs was not affected by natalizumab treatment. Vascular cell adhesion molecule 1, an adhesion molecule that mediates leukocyte traffic, was diminished in DRGs of all natalizumab-treated animals. These data show that blocking monocyte, but not T lymphocyte, traffic to the DRG results in decreased inflammation and pathology, supporting a role for monocyte traffic and activation in HIV peripheral neuropathy.

Anti-α4 antibody treatment blocks virus traffic to the brain and gut early, and stabilizes CNS injury late in infection.

Four SIV-infected monkeys with high plasma virus and CNS injury were treated with an anti-α4 blocking antibody (natalizumab) once a week for three weeks beginning on 28 days post-infection (late). Infection in the brain and gut were quantified, and neuronal injury in the CNS was assessed by MR spectroscopy, and compared to controls with AIDS and SIV encephalitis. Treatment resulted in stabilization of ongoing neuronal injury (NAA/Cr by 1H MRS), and decreased numbers of monocytes/macrophages and productive infection (SIV p28+, RNA+) in brain and gut. Antibody treatment of six SIV infected monkeys at the time of infection (early) for 3 weeks blocked monocyte/macrophage traffic and infection in the CNS, and significantly decreased leukocyte traffic and infection in the gut. SIV - RNA and p28 was absent in the CNS and the gut. SIV DNA was undetectable in brains of five of six early treated macaques, but proviral DNA in guts of treated and control animals was equivalent. Early treated animals had low-to-no plasma LPS and sCD163. These results support the notion that monocyte/macrophage traffic late in infection drives neuronal injury and maintains CNS viral reservoirs and lesions. Leukocyte traffic early in infection seeds the CNS with virus and contributes to productive infection in the gut. Leukocyte traffic early contributes to gut pathology, bacterial translocation, and activation of innate immunity.

Anti-α4 Integrin Antibody Blocks Monocyte/Macrophage Traffic to the Heart and Decreases Cardiac Pathology in a SIV Infection Model of AIDS.

BACKGROUND: Cardiovascular disease (CVD), myocarditis and fibrosis are comorbidities of HIV(+) individuals on durable antiretroviral therapy (ART). Although mechanisms for these vary, monocytes/macrophages are increasingly demonstrated to be key players. METHODS AND RESULTS: We directly blocked monocyte/macrophage traffic to the heart in an SIV model of AIDS using an anti-alpha-4 integrin antibody (natalizumab). Nineteen Rhesus macaques were SIVmac251 infected and CD8-lymphocyte depleted for the development of rapid AIDS. Ten animals received natalizumab once a week, for 3 weeks, and were sacrificed 1 week later. Six animals began treatment at the time of infection (early) and the remaining 4 began treatment 28 days post-infection (late), a time point we have previously established when significant cardiac inflammation occurs. Nine animals were untreated controls; of these, 3 were sacrificed early and 6 were sacrificed late. At necropsy, we found decreased SIV-associated cardiac pathology in late natalizumab-treated animals, compared to untreated controls. Early and late treatment resulted in significant reductions in numbers of CD163(+) and CD68(+) macrophages in cardiac tissues, compared to untreated controls, and a trend in decreasing numbers of newly recruited MAC387(+) and BrdU(+) (recruited) monocytes/macrophages. In late treated animals, decreased macrophage numbers in cardiac tissues correlated with decreased fibrosis. Early and late treatment resulted in decreased cardiomyocyte damage. CONCLUSIONS: These data demonstrate a role for macrophages in the development of cardiac inflammation and fibrosis, and suggest that blocking monocyte/macrophage traffic to the heart can alleviate HIV- and SIV-associated myocarditis and fibrosis. They underscore the importance of targeting macrophage activation and traffic as an adjunctive therapy in HIV infection.

The importance of monocytes and macrophages in HIV pathogenesis, treatment, and cure.

Monocytes and macrophages play critical roles in HIV transmission, viral spread early in infection, and as a reservoir of virus throughout infection. There has been a recent resurgence of interest in the biology of monocyte subsets and macrophages and their role in HIV pathogenesis, partly fuelled by efforts to understand difficulties in achieving HIV eradication. This article examines the importance of monocyte subsets and tissue macrophages in HIV pathogenesis. Additionally, we will review the role of monocytes and macrophages in the development of serious non-AIDS events including cardiovascular disease and neurocognitive impairment, their significance in viral persistence, and how these cells represent an important obstacle to achieving HIV eradication.

Increased coronary atherosclerosis and immune activation in HIV-1 elite controllers.

HIV-1 elite controllers spontaneously maintain suppressed levels of viremia, but exhibit significant immune activation. We investigated coronary atherosclerosis by coronary computed tomography angiography (CTA) in elite controllers, nonelite controller, chronically HIV-1 infected, antiretroviral therapy (ART)-treated patients with undetectable viral load ('chronic HIV'), and HIV-negative controls. Prevalence of atherosclerosis (78 vs. 42%, P < 0.05) and markers of immune activation were increased in elite controllers compared with HIV-negative controls. sCD163, a monocyte activation marker, was increased in elite controllers compared with chronic HIV-1 (P < 0.05) and compared with HIV-negative controls (P < 0.05). These data suggest a significant degree of coronary atherosclerosis and monocyte activation among elite controllers.

Minocycline inhibition of monocyte activation correlates with neuronal protection in SIV neuroAIDS.

BACKGROUND: Minocycline is a tetracycline antibiotic that has been proposed as a potential conjunctive therapy for HIV-1 associated cognitive disorders. Precise mechanism(s) of minocycline's functions are not well defined. METHODS: Fourteen rhesus macaques were SIV infected and neuronal metabolites measured by proton magnetic resonance spectroscopy ((1)H MRS). Seven received minocycline (4 mg/kg) daily starting at day 28 post-infection (pi). Monocyte expansion and activation were assessed by flow cytometry, cell traffic to lymph nodes, CD16 regulation, viral replication, and cytokine production were studied. RESULTS: Minocycline treatment decreased plasma virus and pro-inflammatory CD14+CD16+ and CD14(lo)CD16+ monocytes, and reduced their expression of CD11b, CD163, CD64, CCR2 and HLA-DR. There was reduced recruitment of monocyte/macrophages and productively infected cells in axillary lymph nodes. There was an inverse correlation between brain NAA/Cr (neuronal injury) and circulating CD14+CD16+ and CD14(lo)CD16+ monocytes. Minocycline treatment in vitro reduced SIV replication CD16 expression on activated CD14+CD16+ monocytes, and IL-6 production by monocytes following LPS stimulation. CONCLUSION: Neuroprotective effects of minocycline are due in part to reduction of activated monocytes, monocyte traffic. Mechanisms for these effects include CD16 regulation, reduced viral replication, and inhibited immune activation.