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Results: 7

1.
FIGURE 1

FIGURE 1. From: Macrophage delivery of nanoformulated antiretroviral drug to the brain in a murine model of neuroAIDS.

Cellular NP uptake and IDV release. Fluorescence microscopy imaging of rDHPE-IDV-NP (red) treated BMM (green, CD68+) demonstrating intracellular localization of IDV-NP (A). Ingested NP appears as red fluorescent dots and is located within the cytoplasm of green CD68+ BMM. BMM-released IDV was assayed by RP-HPLC from cell lysates was performed (B). With subsequent media changes (wash, arrowheads) extracellular (media) and intracellular (BMM) IDV levels diminished (C).

Huanyu Dou, et al. J Immunol. ;183(1):661-669.
2.
FIGURE 2

FIGURE 2. From: Macrophage delivery of nanoformulated antiretroviral drug to the brain in a murine model of neuroAIDS.

BMM migration to HIVE affected brain tissue. SPIO-BMM were injected intravenously into HIVE or sham-operated mice. Histology assay examined BMM migration to diseased brain sites. Sections of brain from HIVE (A, C) and sham (B and D) mice were immunostained for HIV-1 p24 (A and B, brown) and GFAP for astrocytes (C and D, brown). Prussian blue staining (blue) revealed SPIO-labeled BMM (A and C, blue) migration into the area of HIV-1 infected MDM 5 days after adoptive transfer of BMM to recipient mice. In sham-operated mice (B and D), no significant BMM migration was detected. Original magnifications, × 200.

Huanyu Dou, et al. J Immunol. ;183(1):661-669.
3.
FIGURE 6

FIGURE 6. From: Macrophage delivery of nanoformulated antiretroviral drug to the brain in a murine model of neuroAIDS.

Antiretroviral activities of IDV-NP-BMM in HIVE mice. Stereotactic injection of HIV-1 infected MDM into the caudate/putamen of SCID mice was utilized to induce HIVE with resulting neuroinflammation, viral infection and neuronal injury. Immunostaining was performed on paraffin brain sections from HIVE mice (those animals injected with virus-infected MDM) with or without IDV-NP-BMM treatment (designated as HIVE and HIVE and IDV, respectively). Staining for Vim, HIV-1p24, and GFAP (brown) reflect the presence of human MDM, virus-infected cells, and neuroinflammatory responses (A). Microscopic images of human Vim+ and HIV-1 p24+ MDM and GFAP+ astrocytes showing similar human MDM reconstitution and astrogliosis were observed in the brains of all groups. Original magnification, × 200. Numbers of virus-infected MDM were assayed by percentage of HIV-1 p24+/Vim+ stained cells (B). A significant decrease in numbers of virus-infected cells was observed in IDV-NP-BMM treated HIVE mice. MGC, a known pathological hallmark of HIVE, were found in injection sites where HIV-1 p24+ were seen (A and C). Reduced numbers of MGC, and with reduced size, were seen in antiretroviral-treated HIVE mice. MGC formation was determined by numbers of MGC/total number of Vim+ MDM (Mean ± SEM) (C). IDV* represents IDV-NP-BMM. *p < 0.01 and **p < 0.01 compared to untreated HIVE mice.

Huanyu Dou, et al. J Immunol. ;183(1):661-669.
4.
FIGURE 3

FIGURE 3. From: Macrophage delivery of nanoformulated antiretroviral drug to the brain in a murine model of neuroAIDS.

Neuroinflammatory responses affect BMM migration. Stereotactic injection of HIV-1 infected MDM into the caudate/putamen of SCID mice was used to induce HIVE resulting in neuroinflammation by astrocytes and microglia activation. Immunostaining was performed on frozen brain sections from sham-operated and HIVE mice with or without rDHPE-IDV-NP-BMM. Confocal imaging of Iba-1 (green, A) and GFAP (green, B) immunoreactivity reflects astrogliosis and microgliosis responses. The red fluorescence spots were around and within the site of injection in HIVE mice 3 days after rDHPE-IDV-NP-BMM treatment. rDHPE-IDV-NP-BMM are co-located with GFAP reactive astrocytes in HIVE mice when compared to sham-operated animals (A). Confocal imaging of Iba-1 (green) reflects microgliosis (B). The Vim (blue) staining was used to distinguish between the human MDM and murine microglia in B with composite of IDV, Vim and Iba-1 immunostaining in C. The red rDHPE-IDV-NP-BMM differentiated microglia from migrated BMM. However, Iba-1 also labeled native circulating monocytes in the mice. Moreover, sham mice showed minimal glial reactions as visualized by GFAP and Iba-1 (green) in response to needle trauma with few rDHPE-IDV-NP-BMM. The photomicrograph shows BMM migration and brain immune responses in the infected animals. IDV* denotes rDHPE-IDV-NP-BMM. Original magnification, × 200.

Huanyu Dou, et al. J Immunol. ;183(1):661-669.
5.
FIGURE 4

FIGURE 4. From: Macrophage delivery of nanoformulated antiretroviral drug to the brain in a murine model of neuroAIDS.

Brain tissue distributions of rDHPE-IDV-NP-BMM. Sham and HIVE mice were injected with rDHPE-IDV-NP-BMM for 3 days, and frozen brain sections were stained with antibody to CD68, HIV-1p24 and GFAP (A and B). Confocal microscopy was used to assess the distribution of CD68+ cells (green) in and around injection areas of the brain in both sham and HIVE animals 3 days after IDV-NP-BMM treatment. CD68+ cells were located in and surrounding the injection line in all animals seen in A. The intensity of CD68+ cells was associated with rDHPE-IDV-NP-BMM (red, A) in treated mice compared to untreated mice in all groups. A substantial increase of rDHPE-IDV-NP-BMM (red, B) was observed in viral infection areas in HIVE mice compared to sham and MDM animals. Confocal imaging of brain sections with double immunostaining to HIV-1p24 (green, B) and GFAP (blue, B) showed increased red fluorescence (rDHPE-IDV-NP-BMM) in brain areas where there was active viral infection (HIV-1p24+ MDM). Greater levels of rDHPE-IDV-NP-BMM were in HIVE compared to sham animals. GFAP (blue, B) and rDHPE-IDV-NP-BMM (red, B) were linked to HIV-1 infection and GFAP astrogliosis (green, B and C); however, there was no correlation between rDHPE-IDV-NP-BMM levels and GFAP expression in treated animals compared to untreated mice in sham and HIVE mouse groups. IDV* denotes rDHPE-IDV-NP-BMM. Original magnification, × 200.

Huanyu Dou, et al. J Immunol. ;183(1):661-669.
6.
FIGURE 7

FIGURE 7. From: Macrophage delivery of nanoformulated antiretroviral drug to the brain in a murine model of neuroAIDS.

IDV-NP-BMM does not affect neural morphology. Neuronal immunostaining for NF, which included both the NF and p-NF forms, was performed in brain tissue sections of SCID mice 3 days after a single intravenous injection of rDHPE-IDV-NP-BMM (A). SCID mice were intracranially injected with saline, MDM or HIV-1 infected MDM. Serial 25 µm frozen brain tissue sections were stained with antibodies to NF (green). Spatial relationships between NF+ axon loss and p-NF neuronal body accumulation in viral infection were determined by confocal image analysis. The local rDHPE-IDV-NP-BMM (red) distribution showed no changes in NF+ axon loss and p-NF accumulation compared to three groups of animals that did not receive treatment. Original magnification, 200 X. Quantitative image analyses was used to assess immunostaining of NF (B), p-NF (C), GFAP (D) and Iba-1 (E). Absolute number of p-NF+ neuronal bodies was counted in HIVE mice with or without IDV-NP-BMM treatment. These results showed that there was no relationship between IDV-NP-BMM levels to either neuronal injury or neuroinflammatory responses. IDV* represents rDHPE-IDV-NP-BMM.

Huanyu Dou, et al. J Immunol. ;183(1):661-669.
7.
FIGURE 5

FIGURE 5. From: Macrophage delivery of nanoformulated antiretroviral drug to the brain in a murine model of neuroAIDS.

Brain tissue IDV concentration. Quantitative image analysis assayed the distribution of rDHPE-IDV-NP-BMM and CD68+ cells (A). The levels of rDHPE-IDV-NP-BMM (open bar) were significantly increased in HIVE compared to both sham-operated and MDM mice. Untreated animals counted as 0 (black bar). *p < 0.05 compared to sham and #p < 0.05 compared to MDM. CD68+ cells were assayed in the same brain slides by quantitative image analysis of untreated (closed bar) or treated (open bar) with rDHPE-IDV-NP-BMM (B). Mean (± SEM) percent area distribution of rDHPE-IDV-NP-BMM was determined for 5 mice per group. * p < 0.05 compared to untreated. IDV levels were assayed by HPLC from blood in HIVE mice treated with IDV-NP-BMM at day 1, 3, 7 and 14 (C and D). With a single dosage of treatment, IDV levels were testable by HPLC until reaching day 14. Blood IDV levels were obtained in treated HIVE mice at experimental time points after i.v injection via the tail vein. Mean (± SEM) µg of IDV/ ml blood was determined for 5 mice per group. IDV were assayed by HPLC from lysates of brain tissues (D). The diseased (ipsilateral) brain tissue levels of IDV were analyzed and compared to the contralateral hemisphere at the experimental time points. Mean (± SEM) µg of IDV/100mg brain tissue was determined for 5 mice per group. *p < 0.01 compared to the contralateral hemisphere.

Huanyu Dou, et al. J Immunol. ;183(1):661-669.

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