Contributions of HIV infection in the hypothalamus and substance abuse/use to HPT dysregulation

Abstract

Over the last two decades, consequences of HIV infection of the CNS on disease severity and clinical neuropsychiatric manifestations have changed. These changes are due, in part, to improved control of peripheral infection by new anti-retroviral medications and more efficient CNS penetration of combination anti-retroviral therapies (cART). While the life spans of HIVinfected patients have been prolonged with successful cART, the spectrum of cognitive alterations observed in these patients has broadened. Recent studies report that there does not appear to be a single prototypical pattern of neuropsychological impairment associated with HIV, but rather it includes diverse manifestations. Some co-morbidities such as substance abuse or depression, likely play significant roles in the neuropsychiatric profiles of some HIV-infected patients. Newly recognized factors contributing to neurocognitive impairments include ageing and unanticipated side effects from cART. Likewise, disturbances in neuroendocrine functioning are emerging as potentially important contributors to HIV-associated neurocognitive alterations. A retrospective review of clinical data from a small cohort of HIV-infected patients admitted to the psychiatric unit of an inner city hospital indicates that thyroid stimulating hormone levels were abnormal in 27% of the patients. Our data from analyses of post-mortem tissues from HIV patients show for the first time HIV infection of the hypothalamus and altered levels of thyroid hormone processing enzymes. Decreased vasopressin and oxytocin immunoreactivity in hypothalamic neurons was also observed. Thus, HIV infection of the CNS may contribute to changes in hypothalamic hormone signaling, thereby resulting in abnormal hypothalamic-pituitary-thyroid axis feedback and neuropsychiatric dysfunction.

Conditional Tat protein expression in the GT-tg bigenic mouse brain induces gray matter density reductions

“…Given the greater incidence of mood disorder among HIV-afflicted individuals (Bing et al, 2001), our finding of a hypothalamic gray matter density abnormality could be relevant to previous observations that hypothalamic dysfunction in HIV infection may promote the prevalence of mood disorders (Langford et al, 2011). Tat-induced disruptions of hypothalamic activity were shown to disrupt circadian signaling in mice (Clark et al, 2005), an event associated with depressive symptomology in people and rodents (Lall et al, 2012).…”

“…The brain areas we found to exhibit Tat-induced abnormalities are thought to subserve the cognitive domains that demonstrate impairment in Dox-induced GT-tg mice (Carey et al, 2012), suggesting that the findings are consistent with behavioral effects of Tat expression. We also found reduced gray matter density in the hypothalamus, a target for HIV (Langford et al, 2011) and Tat protein (Banks et al, 2005; Clark et al, 2005). …”

Impact of genetic polymorphisms associated with nonalcoholic fatty liver disease on HIV-infected individuals

“…However, it is known that the HIV can infect the central nervous system including the hypothalamus. This fact could explain the disturbances in neuroendocrine functioning observed in some HIV-infected patients [24]. Because of the role that the hypothalamus plays in the control of lipid metabolism [25], the association between the LPPR4 variant and FLD in the HIV-infected population reported herein could be pointing out a specific link between the HIV-associated damage of the central nervous system and the metabolic alterations in the HIV infection setting.…”

Approaches Mediating Oxytocin Regulation of the Immune System

“…Conversely, the OSS is also the target of immune diseases. For example, OT neurophysin shares an antigen with human lung carcinoma LX-1 cells (53); OT neurons are a major target of many autoimmune diseases such as multiple sclerosis (45, 54); OT in hypothalamic neurons decreased in HIV-infected patients (55). In response to immune challenges, IL-6 (50) and IL-1β (56) can activate rodent OT neurons in the PVN and/or SON, while microglia in the PVN can increase OT secretion and sympathetic activity (57).…”