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The human immunodeficiency virus (HIV) accesses the central nervous system (CNS) early during infection, leading to HIV-associated cognitive impairment and establishment of a viral reservoir. Here, we describe a dichotomy in inflammatory responses in different CNS regions in simian immunodeficiency virus (SIV)-infected macaques, a model for HIV infection. We found increased expression of inflammatory genes and perivascular leukocyte infiltration in the midbrain of SIV-infected macaques. Conversely, the frontal lobe showed downregulation of inflammatory genes associated with interferon-γ and interleukin-6 pathways, and absence of perivascular cuffing. These immunologic alterations were not accompanied by differences in SIV transcriptional activity within the tissue. Altered expression of genes associated with neurotoxicity was observed in both midbrain and frontal lobe. The segregation of inflammatory responses to specific regions of the CNS may both account for HIV-associated neurological symptoms and constitute a critical hurdle for HIV eradication by shielding the CNS viral reservoir from antiviral immunity.

HIV-1 causes a progressive impairment of immune function. HIV-2 is a naturally attenuated form of HIV, and HIV-2 patients display a slow-progressing disease. The leading hypothesis for the difference in disease phenotype between HIV-1 and HIV-2 is that more efficient T cell–mediated immunity allows for immune-mediated control of HIV-2 infection, similar to that observed in the minority of HIV-1–infected long-term nonprogressors. Understanding how HIV-1 and HIV-2 differentially influence the immune function may highlight critical mechanisms determining disease outcome. We investigated the effects of exposing primary human peripheral blood cells to HIV-1 or HIV-2 in vitro. HIV-2 induced a gene expression profile distinct from HIV-1, characterized by reduced type I IFN, despite similar upregulation of IFN-stimulated genes and viral restriction factors. HIV-2 favored plasmacytoid dendritic cell (pDC) differentiation into cells with an APC phenotype rather than IFN-α–producing cells. HIV-2, but not HIV-1, inhibited IFN-α production in response to CpG-A. The balance between pDC maturation into IFN-α–producing cells or development of an APC phenotype differentiates the early response against HIV-1 and HIV-2. We propose that divergent paths of pDC differentiation driven by HIV-1 and HIV-2 cause the observed differences in pathogenicity between the two viruses.

Chronic activation of plasmacytoid dendritic cells (pDCs) is an important contributor to the immunopathogenesis of HIV infection. The quinolone derivative chloroquine (CQ) prevents endosomal acidification, required for toll-like receptor sensing of HIV by pDCs, and is currently under clinical trial as an immunotherapeutic approach. We tested three different 6-desfluoroquinolones (6-DFQs), structurally related to CQ and endowed with antiretroviral activity, for their ability to inhibit HIV-induced pDC activation and interferon (IFN)-α production in peripheral blood mononuclear cells (PBMCs) in vitro. PBMCs from six healthy donors were cultured overnight with aldrithiol-2 (AT-2)-inactivated HIV-1MN in the presence or absence of 6-DFQs or CQ. IFN-α production was measured by ELISA; pDC and monocyte activation was analyzed by flow cytometry. Incubation with HIV labeled with the fluorescent dye DyLight-488 (DL488) was used to test virus uptake by flow cytometry. We found that the 6-DFQs effectively inhibited HIV-induced IFN-α similar to CQ, but only 6-DFQs also inhibited the upregulation of the pDC activation marker CD83. Interestingly, HIV-induced expression of the costimulatory molecule CD80 and, to a lesser extent CD86, was further enhanced on pDCs by 6-DFQs, but not CQ. Conversely, 6-DFQs and CQ had similar inhibitory effects on HIV-induced monocyte activation, consistent with the primary mechanism being associated with IFN-α signaling. Finally, 6-DFQs interfered with HIV interaction with pDCs and monocytes, but not myeloid DCs. Our data indicate that 6-DFQs may interfere with pDC-mediated and IFN-α-dependent immunopathogenesis while supporting pDC differentiation into mature antigen-presenting cells by favoring expression of costimulatory molecules.

Pregnancies complicated by new-onset hypertension are associated with increased sensitivity to angiotensin II, but it is unclear whether this sensitivity persists postpartum. We studied pressor response to infused angiotensin II in 25 normotensive postpartum women in both high- and low-sodium balance. Ten women had a history of hypertensive pregnancy (5 with preeclampsia; 5 with transient hypertension of pregnancy), and 15 women had a history of uncomplicated, normotensive pregnancy. Systolic and diastolic blood pressures, aldosterone, and soluble fms-like tyrosine kinase 1 levels were measured before and after angiotensin II infusion in both dietary phases. In high sodium balance, women with a history of hypertensive pregnancy were normotensive but had significantly higher systolic and diastolic blood pressures than controls (115 versus 104 mm Hg and 73 versus 65 mm Hg, respectively; P P =0.03), greater increase in aldosterone (56.8 versus 30.8 ng/dL; P =0.03), and increase in soluble fms-like tyrosine kinase 1 levels (11.0 versus −18.9 pg/mL; P =0.02) after infusion of angiotensin II in low-sodium balance compared with controls. Thus, women with a history of hypertensive pregnancy demonstrated salt sensitivity of blood pressure and had increased pressor, adrenal, and soluble fms-like tyrosine kinase 1 responses to infused angiotensin II in low-sodium balance. Increased sensitivity to angiotensin II observed during pregnancy in women with hypertensive pregnancy is present postpartum; this feature may contribute to future cardiovascular risk in these women.

NK cells that populate the decidua are important regulators of normal placentation. In contrast to peripheral blood NK cells, decidual NK (dNK) cells lack cytotoxicity, secrete proangiogenic factors, and regulate trophoblast invasion. In this study we show that exposure to a combination of hypoxia, TGF-β1, and a demethylating agent results in NK cells that express killer cell Ig-like receptors, the dNK cell markers CD9 and CD49a, and a dNK pattern of chemokine receptors. These cells secrete vascular endothelial growth factor (a potent proangiogenic molecule), display reduced cytotoxicity, and promote invasion of human trophoblast cell lines. These findings have potential therapeutic applications for placental disorders associated with altered NK cell biology.

A delicate balance between immunostimulatory and immunosuppressive signals mediated by dendritic cells (DCs) and other antigen-presenting cells (APCs) regulates the strength and efficacy of antiviral T-cell responses. HIV is a potent activator of plasmacytoid DCs (pDCs), and chronic pDC activation by HIV promotes the pathogenesis of AIDS. Cholesterol is pivotal in maintaining HIV envelope integrity and allowing HIV-cell interaction. By depleting envelope-associated cholesterol to different degrees, we generated virions with reduced ability to activate pDCs. We found that APC activation was dissociated from the induction of type I IFN-α/β and indoleamine-2,3-dioxygenase (IDO)–mediated immunosuppression in vitro. Extensive cholesterol withdrawal, resulting in partial protein and RNA loss from the virions, rendered HIV a more powerful recall immunogen for stimulating memory CD8 T-cell responses in HIV-exposed, uninfected individuals. These enhanced responses were dependent on the inability of cholesterol-depleted HIV to induce IFN-α/β.