HIV-1-associated neuroinflammation persists even with effective combined anti-retroviral therapy (cART), and is associated with the presence of activated monocytes/macrophages within the CNS. In order to infiltrate the CNS, monocytes transmigrate across the selectively permeable blood brain barrier (BBB), which is compromised during HIV infection. Interestingly, platelet-derived excess soluble CD40L (sCD40L) found in the plasma and cerebrospinal fluid (CSF) of HIV-1 infected individuals with cognitive impairment has previously been implicated in increased BBB permeability. Here we show that sCD40L also promotes the formation of complexes between inflammatory monocytes and activated platelets (PMCs), which are detected by flow cytometry as monocytes that express excess of CD61, a platelet marker and that these complexes are increased in individuals with HIV infection. PMCs exhibit an enhanced ability to adhere to human brain microvascular endothelial cells as compared to monocytes alone and migrate across transendothelial barrier. These complexes can be found marginalized in the lumen of post-capillary venules in post-mortem brain tissue derived from cases of HIV-1-associated encephalitis (HIV-E). The extravasation of monocytes across the brain endothelium may exacerbate neuroinflammation, indicating that enhancing this event via platelet interaction may be a contributing factor in the development of cognitive impairment. Thus, dampening platelet activation, and in turn PMC formation, with anti-platelet agents may prove beneficial in developing adjunctive therapies for use in combination with cART in an effort to reduce HIV-1-associated neurological deficit

The number of HIV-1 positive individuals developing some form of HIV-associated neurocognitive disorder (HAND) is increasing. In these individuals, the integrity of the blood-brain barrier (BBB) is compromised due to an increase in exposure to pro-inflammatory mediators, viral proteins, and virus released from infected cells. It has been shown that soluble CD40L (sCD40L) is released upon platelet activation and is an important mediator of the pathogenesis of HAND but the underlying mechanisms are unclear, emphasizing the need of an effective animal model. Here, we have utilized a novel animal model in which wild-type (WT) mice were infected with EcoHIV; a derivative of HIV-1 that contains a substitution of envelope protein gp120 with that of gp80 derived from murine leukemia virus-1 (MuLV-1). As early as two-weeks post-infection, EcoHIV led to increased permeability of the BBB associated with decreased expression of tight junction protein claudin-5, in CD40L and platelet activation-dependent manner. Treatment with an antiplatelet drug, eptifibatide, in EcoHIV-infected mice normalized BBB function, sCD40L release and platelet activity, thus implicating platelet activation and platelet-derived CD40L in virally induced BBB dysfunction. Our results also validate and underscore the importance of EcoHIV infection mouse model as a tool to explore therapeutic targets for HAND.

Highlights d Specific LDH inhibition in vivo reduces growth rate of glycolytic tumors d Depth and duration of tumor LDH inhibition can be monitored in real time by HP-MRSI d LDH inhibition in vivo redirects pyruvate to support oxidative phosphorylation d Inhibiting mitochondrial complex 1 and LDH enhances durability of anti-tumor response

To simplify the specification of a desired trajectory for some subset of the variables of a dynamic control system, it may be advantageous to designate a set of intercept points that the trajectory is required to pass through. The system controls can then be computed in terms of a spline function to meet these requirements for dynamic interpolation. Optimization of a cost function under continuity constraints can be embedded in the determination of spline coefficients to obtain certain desirable geometric properties of the resulting trajectory.

Human immunodeficiency virus type 1 (HIV) continues to be one of the most prevalent global health afflictions to date. The advent and introduction of combined antiretroviral therapy (cART) has made a significant impact on the course of infection. However, as patients are living longer, many HIV-associated illnesses are becoming prevalent among the infected population, especially those associated with chronic inflammation. Consistently, HIV-associated neuroinflammation is believed to be a major catalyst in the development of HIV-associated neurocognitive disorders (HAND), which are estimated to persist in approximately 50% of infected individuals regardless of cART. This dramatically underscores the need to develop effective adjunctive therapies capable of controlling this aspect of the disease, which are currently lacking.We previously demonstrated that the inflammatory mediator soluble CD40 ligand (sCD40L) is elevated in both the plasma and cerebrospinal fluid of cognitively impaired infected individuals compared to their non-impaired infected counterparts. Our group, and others have recently demonstrated that there is an increasing role for this inflammatory mediator in the pathogenesis of HIV-associated neuroinflammation, thereby identifying this molecule as a potential therapeutic target for the management of HAND. Platelets are the major source of circulating sCD40L, and these small cells are increasingly implicated in a multitude of inflammatory disorders, including those common during HIV infection. Thus, antiplatelet therapies that minimize the release of platelet-derived inflammatory mediators such as sCD40L are an innovative, non-traditional approach for the treatment of HIV-associated neuroinflammation, with the potential to benefit other HIV-associated illnesses.

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Background Microvesicles are cell membrane–derived vesicles that have been shown to augment inflammation. Specifically, monocyte‐derived microvesicles (MDMVs), which can express the coagulation protein tissue factor, contribute to thrombus formation and cardiovascular disease. People living with HIV experience higher prevalence of cardiovascular disease and also exhibit increased levels of plasma microvesicles. The process of microvesicle release has striking similarity to budding of enveloped viruses. The surface protein tetherin inhibits viral budding by physically tethering budding virus particles to cells. Hence, we investigated the role of tetherin in regulating the release of MDMVs during HIV infection. Methods and Results The plasma of aviremic HIV‐infected individuals had increased levels of tissue factor + MDMVs, as measured by flow cytometry, and correlated to reduced tetherin expression on monocytes. Superresolution confocal and electron microscopy showed that tetherin localized at the site of budding MDMVs. Mechanistic studies revealed that the exposure of monocytes to HIV‐encoded Tat triggered tetherin loss and subsequent rise in MDMV production. Overexpression of tetherin in monocytes led to morphologic changes in the pseudopodia directly underneath the MDMVs. Further, tetherin knockout mice demonstrated a higher number of circulating MDMVs and less time to bleeding cessation. Conclusions Our studies define a novel regulatory mechanism of MDMV release through tetherin and explore its contribution to the procoagulatory state that is frequently observed in people with HIV. Such insights could lead to improved therapies for individuals infected with HIV and also for those with cardiovascular disease.

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