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

> **NIH NIH R01** · EMORY UNIVERSITY · 2022 · $607,957

## Abstract

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 slo...

## Key facts

- **NIH application ID:** 10487560
- **Project number:** 5R01MH128872-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Albert Anderson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $607,957
- **Award type:** 5
- **Project period:** 2021-09-10 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10487560

## Citation

> US National Institutes of Health, RePORTER application 10487560, The Role of Inflammation in CNS Mechanisms of Anhedonia and Psychomotor Slowing in Depressed PWH as Determined using a Next Generation TNF Antagonist (5R01MH128872-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10487560. Licensed CC0.

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