In the United States, approximately 1.2 million people are living with human immunodeficiency virus type-1 (HIV-1), with men responsible for the majority of cases (~75%). About half of people infected with HIV are 50 years of age and older. People with HIV suffer from an accelerated occurrence of age-related diseases and disorders; however, the pathophysiology underlying accelerated aging is poorly understood.
Although the mechanisms are unknown, the HIV-1 trans-activator of transcription (Tat) protein disrupts neuroendocrine function in mice, in part through mitochondrial dysregulation and neurosteroidogenesis.
Researchers Alaa N. Qrareya, Fakhri Mahdi, Marc J. Kaufman, Nicole M. Ashpole, and Jason J. Paris, of the University of Mississippi and Harvard Medical School’s McLean Hospital, examined the combined effects of aging and HIV-1 Tat expression on the development of neuroHIV-like sequelae in young adult (6-8 months) and middle-aged (11-13 months) male mice to determine whether Tat causes age-related dysfunction.
“We hypothesized that conditional Tat expression in middle-aged male transgenic mice [Tat(+)] would promote age-related comorbidities compared to age-matched controls [Tat(−)]. We expected Tat to alter the steroid hormone milieu in line with behavioral deficits.”
Middle-aged Tat(+) mice had lower circulating testosterone and progesterone than age-matched controls and more circulating corticosterone and central allopregnanolone than other groups. Young Tat(+) mice had greater circulating progesterone and estradiol-to-testosterone ratios. Older age or exposure to Tat increased anxiety-like behavior (open field; increased plus maze), increased cognitive errors (water maze of the radial arm), and decreased grip strength. Young Tat(+), or middle-aged Tat(−), males had higher mechanical nociceptive thresholds than peers. Steroid levels correlated with behavior. For example, Tat may contribute to HIV-accelerated aging.
“In conclusion, our data suggest that older age and Tat expression exert independent and interactive effects to exacerbate neuroendocrine, affective, cognitive and neuromuscular comorbidities. Novel steroid replacement therapies may be useful adjunct therapies to cART in the aging HIV+ population.”
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Alaa N. Qrareya et al, Age-related neuroendocrine, cognitive and behavioral comorbidities are promoted by HIV-1 Tat expression in male mice, Aging (2022). DOI: 10.18632/aging.204166
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