Prevention and treatment of HIV infection and cognitive disease in mice by innate immune responses

et al. 2023

Sci Rep

Self Cite

HIV enters the brain within days of infection causing neurocognitive impairment (NCI) in up to half of infected people despite suppressive antiretroviral therapy. The virus is believed to enter the brain in infected monocytes through chemotaxis to the major monocyte chemokine, CCL2, but the roles of CCL2 in established NCI are not fully defined. We addressed this question during infection of conventional and CCL2 knockout mice with EcoHIV in which NCI can be verified in behavioral tests. EcoHIV enters mouse brain within 5 days of infection, but NCI develops gradually with established cognitive disease starting 25 days after infection. CCL2 knockout mice infected by intraperitoneal injection of virus failed to develop brain infection and NCI. However, when EcoHIV was directly injected into the brain, CCL2 knockout mice developed NCI. Knockout of CCL2 or its principal receptor, CCR2, slightly reduced macrophage infection in culture. Treatment of mice prior to and during EcoHIV infection with the CCL2 transcriptional inhibitor, bindarit, prevented brain infection and NCI and reduced macrophage infection. In contrast, bindarit treatment of mice 4 weeks after infection affected neither brain virus burden nor NCI. Based on these findings we propose that HIV enters the brain mainly through infected monocytes but that resident brain cells are sufficient to maintain NCI. These findings suggest that NCI therapy must act within the brain.

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CCL2 is required for initiation but not persistence of HIV infection mediated neurocognitive disease in mice

Kim

Hadas

et al. 2023

Sci Rep

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“…Indeed, we previously showed that leukocytes that in ltrate the brains of infected mice carry integrated EcoHIV DNA 28 . The likely signal for this migration is CCL2; it is the major monocyte chemokine 42 and is highly induced by EcoHIV infection in mouse macrophages 43 and in astrocytes and monocytes/microglia in the HIV or EcoHIV-infected brain 8, 44 . We exploited a mouse strain with knockout of CCL2 and compared the course of its EcoHIV infection to that of wildtype C57BL/6 mice (Fig.…”

Section: Monocyte Chemotaxis To Ccl2 Contributes To Ecohiv Ncimentioning

confidence: 99%

CCL2 is required for initiation but not persistence of HIV infection mediated neurocognitive disease in mice

Kim

Hadas

et al. 2023

Preprint

Self Cite

HIV enters the brain within days of infection causing neurocognitive impairment (NCI) in up to half of infected people despite suppressive antiretroviral therapy. The virus is believed to enter the brain in infected monocytes through chemotaxis to the major monocyte chemokine, CCL2, but direct demonstration of the role of CCL2 in NCI pathogenesis in vivo is lacking. We addressed this question during infection of conventional or CCL2 knockout mice with EcoHIV in which NCI can be verified in behavioral tests. NCI develops gradually during EcoHIV infection of mice, with chronic cognitive disease starting 25 days after infection. CCL2 knockout mice infected by intraperitoneal injection of virus failed to develop brain infection and NCI. However, when EcoHIV was directly injected into the brain, CCL2 knockout mice developed NCI. Knockout of CCL2 or its principal receptor, CCR2, slightly reduced macrophage infection in culture. Treatment of mice prior to and during EcoHIV infection with the CCL2 transcriptional inhibitor, bindarit, prevented brain infection and NCI, and reduced macrophage infection. In contrast, bindarit treatment of mice four weeks after infection affected neither brain virus burden nor NCI, suggesting that once established, brain disease was independent of CCL2. Our results indicate that HIV enters the brain mainly through infected monocytes but that resident brain cells are sufficient to maintain NCI. A conclusion from these findings is that NCI therapy must act within the brain. .

“…HIV-NCI is a spectrum of cognitive deficits that negatively impact the quality of life for PWH and is an independent risk factor for morbidity and mortality (5,6,9,10). Despite several successful treatment attempts for HIV-NCI in preclinical animal models no approved therapy for NCI in PWH has emerged (11)(12)(13)(14)(15)(16)(17).…”

Section: Introductionmentioning

confidence: 99%

Buprenorphine reverses neurocognitive impairment in EcoHIV infected mice: A potential therapy for HIV-NCI

Murphy

et al. 2022

Front. Immunol.

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Thirty-eight million people worldwide are living with HIV, PWH, a major public health problem. Antiretroviral therapy (ART) revolutionized HIV treatment and significantly increased the lifespan of PWH. However, approximately 15-50% of PWH develop HIV associated neurocognitive disorders (HIV-NCI), a spectrum of cognitive deficits, that negatively impact quality of life. Many PWH also have opioid use disorder (OUD), and studies in animal models of HIV infection as well as in PWH suggest that OUD can contribute to HIV-NCI. The synthetic opioid agonist, buprenorphine, treats OUD but its effects on HIV-NCI are unclear. We reported that human mature inflammatory monocytes express the opioid receptors MOR and KOR, and that buprenorphine reduces important steps in monocyte transmigration. Monocytes also serve as HIV reservoirs despite effective ART, enter the brain, and contribute to HIV brain disease. Using EcoHIV infected mice, an established model of HIV infection and HIV-NCI, we previously showed that pretreatment of mice prior to EcoHIV infection reduces mouse monocyte entry into the brain and prevents NCI. Here we show that buprenorphine treatment of EcoHIV infected mice with already established chronic NCI completely reverses the disease. Disease reversal was associated with a significant reduction in brain inflammatory monocytes and reversal of dendritic injury in the cortex and hippocampus. These results suggest that HIV-NCI persistence may require a continuing influx of inflammatory monocytes into the brain. Thus, we recommend buprenorphine as a potential therapy for mitigation of HIV brain disease in PWH with or without OUD.