The Role of Inflammation in CNS Mechanisms of Anhedonia and Psychomotor Slowing in Depressed PWH as Determined using a Next Generation TNF Antagonist

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PROJECT SUMMARY Risk of depression is substantially higher in people with HIV (PWH) than the general population, and depression in PWH confers worse outcomes regarding treatment adherence, morbidity and mortality. Risk for depression is further increased in PWH with elevated biomarkers of inflammation, e.g., the acute phase reactant C-reactive protein (CRP) and inflammatory cytokines like tumor necrosis factor (TNF), that contribute to resistance to antidepressant therapies. Moreover, increased inflammation in the context of chronic depression in PWH is characterized by worsened cognitive function including impaired processing speed and motor activity. Our recent neuroimaging studies in HIV-negative patients with major depression (MD) demonstrate that endogenous elevations in inflammation (as reflected by increased plasma CRP) are associated with decreased functional connectivity (FC) within corticostriatal reward and motor circuits involving the ventral and dorsal striatum and frontal cortical regions in relation to symptoms of anhedonia and psychomotor retardation. Anhedonia and psychomotor slowing represent fundamental aspects of research domain criteria (RDoC) of Positive and Negative Valence systems, and are closely aligned with a symptom cluster overrepresented in PWH referred to as apathy, which is thought to be driven by similar medial prefrontal and subcortical circuitry. Previous work from our group also suggests that reducing inflammation with a traditional TNF antagonist improves symptoms of anhedonia and psychomotor retardation in HIV-negative patients with MD, but only in patients with higher levels of CRP. These data suggest the hypothesis that inflammation driven by TNF plays a role in anhedonia and motor slowing through effects on corticostriatal reward and motor circuits in PWH. TNF and specifically its soluble species, sTNF, sits at the apex of the inflammatory cascade that drives chronic inflammation, whereas immunologic and neuro “protective” signaling is mediated by transmembrane (tm)TNF. Although existing TNF inhibitors have been safely used in PWH, the risk associated with blocking both the pathologic and protective aspects of TNF signaling, including liability for infection, limits viability of “first generation” anti-TNF therapies to examine the role of inflammation in depressive and neurocognitive symptoms in PWH. XPro1595 is a “next generation” TNF inhibitor designed to selectively neutralize inflammatory sTNF, while sparing protective tmTNF signaling. XPro1595 is safe and well-tolerated, and in preliminary data, reduces not only plasma CRP but also inflammatory cytokines and chemokines in cerebrospinal fluid (CSF), as well as free water diffusion imaging measures of neuroinflammation. The goals of this proposal are to use a biomarker-driven approach to determine whether specific inhibition of sTNF with XPro1595 increases FC in corticostriatal reward and motor circuits (Aim 1) and improves anhedonia and psychomotor slowing (Aim 2) in association with reduced plasma inflammatory markers, as well as additional CSF, neuroimaging, peripheral blood immune cell, and virologic markers of inflammation and/or safety (Aim 3), in PWH with MD and high inflammation (plasma CRP>3 mg/L).