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HIV-1 Tat genetic variation impacts NeuroHIV

Award Number: R56NS089435
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2015
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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HIV-1 Tat genetic variation impacts NeuroHIV - Project Abstract/Summary HIV-1 viral load can be suppressed in people living with HIV (PLWH) through consistent use of antiretroviral therapy (ART). Despite this, between 15 to 40% of LWH are predicted to suffer from HIV-associated neurocognitive impairment (NCI). Although the pathogenesis of NCI is incompletely understood, HIV-1 transactivator of transcription (Tat) is capable of being secreted from infected cells, and once extracellular in the central nervous system (CNS) it will induce neuronal dysregulation. Early in the infection, HIV-1 establishes a reservoir in the brain, either by entering as infected perivascular macrophages or infecting resident microglia, prior to the patient receiving ART. ART does not affect the production of Tat, which is continually made in these cells, leading to quantifiable levels of Tat in the absence of detectable viral load. Tat sequence composition varies within and between individuals due to HIV-1’s error-prone reverse transcriptase and host factors such as APOBEC3G. We have shown that this variation is associated with neurocognitive impairment (NCI), as shown by comparing the HIV-1 Tat protein sequence composition from impaired and non-impaired PLWH within the Drexel Medicine CNS AIDS Research and Eradication Study (CARES) Cohort. In the past 5 years, we have further demonstrated that Tat could be the product from intact or defective virions from cellular reservoirs in the brain namely microglia and astrocytes and other peripheral tissues that can cause blood-brain barrier disruption and NCI. Recombinant Tat101 injected directly into the prefrontal cortex (PFC) of adult rats produced impairment in learning and memory tasks and ex vivo analysis of the brain PFC tissue suggested upregulation of pathways that induce immune and cellular response to toxicity and down regulation of genes that are involved in promoting cognition, synaptic connectivity and dopamine and glutamate neurotransmission. Thus, we hypothesize that Tat produced by microglial and astrocyte reservoirs promote neurotoxicity and NCI by synergistic dysregulation of dopamine-glutamate homeostasis and heightened immune response promoting excitotoxicity in neurons. To investigate this, we propose the following three Aims. Aim 1 will use near full-length sequencing of proviral DNA from cellular reservoirs derived from PLWH from National NeuroHIV Tissue Consortium (NNTC) and CARES cohorts to determine the molecular architecture of the proviral reservoirs and the Tat variants expressed. Aim 2 will explore the function of the defective reservoir and Tat variants associated with intact and partially functional proviruses. Aim 3 will explore the impact of Tat variants on promoting excitotoxicity in PFC causing impaired executive function and impulse control disorders using an in vivo model of Tat neuropathogenesis. These studies will contribute to defining the differential and synergistic effects of Tat in promoting NCI. Overall, these studies will lead to a better understanding of the etiology of HAND, potential development of diagnostic assay for HAND, and identification of novel Tat-mediated targets to develop new therapeutics for treating NCI.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $628,940 )
2026	2026	DREXEL UNIVERSITY	3141 CHESTNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	11	8/31/2026	COMPETING CONTINUATION	$628,940
														Subtotal = $628,940

Grand Total All Awards = $628,940

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HIV-1 Tat genetic variation impacts NeuroHIV

Award Number: R56NS089435

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2015

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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