Date of Award
1-1-2023
Document Type
Dissertation
Degree Name
Ph.D. in Pharmaceutical Sciences
First Advisor
Jason J. Paris
Second Advisor
Alberto J Del Arco Gonzalez
Third Advisor
James A. Stewart
School
University of Mississippi
Relational Format
dissertation/thesis
Abstract
The primary objectives of this dissertation are to assess the interaction between human immunodeficiency virus type-1 (HIV-1) trans-activator of transcription (Tat) protein and neuroendocrine status on the pathology of Tat/age-related comorbidities and to investigate the potential benefit of hormonal therapy in attenuating Tat/age insults. The advent of combined antiretroviral therapy (cART) has increased longevity among people living with HIV (PLWH). However, cART cannot fully eradicate viral reservoirs within the central nervous system (CNS). Therefore, ~50-60% of virally-suppressed PLWH experience neurological and psychological sequelae called “neuroHIV”. Moreover, PLWH are more vulnerable to developing premature age-related comorbidities. In PLWH, hypogonadism is common and occurs earlier than in age-matched seronegative people. Although the underlying mechanisms are unknown, Tat alters neuroendocrine capacity in Tat transgenic mice. The overall hypothesis of this dissertation is that Tat would accelerate age-related comorbidities associated with neuroendocrine deficits. Furthermore, restoring neuroendocrine capacity using allopregnanolone (AlloP) would ameliorate Tat/age insults. Chapter 2 assessed the interaction between Tat expression and neuroendocrine status in developing neuroHIV and age-related comorbidities in adult and middle-aged male mice. Tat expression in adult males is likely to accelerate neuroendocrine dysregulation, demonstrated by greater circulating progesterone (P4), an endocrine profile observed in middle age. Tat also disrupted neuroendocrine milieu correlated with Tat-induced behavioral deficits. Chapter 3 investigated the impact of Tat expression and ovarian capacity on the pathogenesis of Tat/age-related comorbidities among middle-aged females defined as pre-, peri-, or post-estropause. Tat expression and neuroendocrine deficits determined independent and interactive effects to accelerate Tat/age-related comorbidities. Moreover, maintaining the ovarian capacity in per-estropause attenuated Tat/age-related affective and cognitive comorbidities. Chapter 4 investigated AlloP-based therapy in ameliorating Tat/age-related comorbidities in peri-and post-estropause. Tat expression and estropause transition trigger neuroendocrine abnormalities and increase the susceptibility to Tat/age-related comorbidities. Moreover, the intervention of AlloP-based therapy during peri-estropause alleviated some aspects of Tat/age-related comorbidities. Thus, this study demonstrated novel preclinical findings, suggesting a promising approach to attenuate HIV/age-related deficits among older PLWH. Given the recent surge in the longevity and incidence of age-related comorbidities in PLWH, this study provided fundamental data for further investigation to improve geriatric care in the era of cART.
Recommended Citation
Qrareya, Alaa Nader, "HIV-1 Tat and Neuroendocrine Aging: Potential Benefits of Neurosteroid-Based Therapy to Attenuate Premature Age-Related Comorbidities in The Era of Antiretroviral Therapy" (2023). Electronic Theses and Dissertations. 2564.
https://egrove.olemiss.edu/etd/2564