Roles of Misfolded Protein Aggregates on Latent Reservoirs in SIV-infected, ART-treated Aged Rhesus Macaques

The advancement of combination antiretroviral therapy (ART) has improved the lives of people living with HIV (PWH) to manageable diseases. However, due to the persistence of viral reservoirs, a cure for HIV remains elusive. Chronological aging is associated with cerebral and extracerebral progressive accumulation of amyloid fibrils, which plays a crucial role in the development of late-onset Alzheimer's and Alzheimer's disease-related dementias (AD-ADRD). More than ten precursor proteins, including transthyretin, amylin, lactadherin, Aβ1-42, α- synuclein, epidermal growth factor-containing fibulin-like extracellular matrix protein 1, semenogelin, and others, are implicated in age-associated amyloidosis. Age-associated amyloidosis results in activation of microglia in the brain, T cells and myeloid cells in the periphery, M1 polarization of macrophages, and creates a systemic chronic inflammatory milieu. In the United States, more than half of all the people living with HIV (PWH) are aged 50 years or older. Additionally, more than 15% of newly HIV diagnosed Americans are over 50 years of age. Therefore, it becomes paramount to understand the impact of amyloid fibril deposition on the reactivation and expansion of lymphoid and myeloid latent reservoirs in older people living with HIV. Conversely, HIV infection and chronological aging are two mutually exclusive comorbid conditions for the development of AD-ADRD. Therefore, it is indispensable to understand the role of HIV in enhancing the deposition of amyloid fibrils and in the development/acceleration of AD–ADRD among older people living with HIV. The commonly used small animal models of AD, not comprehensively recapitulate the heterogeneous manifestations of late onset of AD. On the contrary, rhesus macaques naturally develop age-associated cognitive decline and deposition of amyloid fibrils closely mirrored in humans. This proposal aims to address the knowledge gaps in the field described above. In Aim 1, we will study the impact of age-associated deposition of amyloid fibrils on HIV reservoirs, and in Aim 2, assess the impact of viral infection on the enhancement of chronological aging-associated amyloidosis, and subsequent development of AD-ADRD phenotypes. We anticipate that understanding the aging-associated reactivation and expansion of the viral reservoir will help to provide a more informed approach to designing HIV cure research interventions for older people living with HIV, as well as understanding the role of HIV on the development of late-onset AD-ADRD will aid in the development of customized care modalities, including treatment for comorbid conditions. Project Number: 1R21AG102223-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Siddappa Byrareddy (+1 co-PI) | Institution: UNIVERSITY OF NEBRASKA MEDICAL CENTER, OMAHA, NE | Award Amount: $422,125 | Activity Code: R21 | Study Section: HIV Comorbidities and Clinical Studies Study Section[HCCS] View on NIH RePORTER: https://reporter.nih.gov/project-details/11411766