The mechanisms by which viral infection causes this hormonal deregulation are still not clear and have been analyzed mostly in HIV infection. Although the mechanisms leading to adverse effects on HPA axis activity in HIV infection are not fully understood, several lines of evidence suggest that a number of mechanisms may be involved, including homologies in molecular structures of various mediators of neuroendocrine activity and HIV-related structures, HIV as a chronic stress model, and virus-induced toxic factors.
A possibility could be that the immune response, activated to fight the virus, triggers several signaling pathways, mainly mediated by cytokines, which could interfere with the regulatory mechanisms of the neuroendocrine system. On the other hand, the infection could be interfering with the endocrine routes in a direct way, through the interaction of the virus or its products with elements of the neuroendocrine system (for example, infection in the hypothalamus) (direct regulation). The virus could also interact with the end components of the HPA axis, the adrenal glands, without affecting the other elements of the endocrine control. Data supporting either route are discussed below.
In the case of indirect regulation, mediated by the activation of the immune response, it has been shown that both FeLV and FIV infections lead to an increase in the expression of proinflammatory cytokines such as IL-1, IL-6, TNFα and can activate the HPA axis. This activation would lead to an increase in levels of circulating GCs as has been shown for HIV-1. Alterations in the production of adrenal steroids and a complex pattern of deregulation in cytokine profiles accompany the progression of HIV infection. It has been observed that in some viral infections (cytomegalovirus, or Newcastle disease paramyxovirus 1) the presence of certain cytokines, such as IL-1 or IL-6, can be decisive for the activation of this circuit.
Although these interactions are known in acute phase responses, it has not been determined what happens really in cases of continuous stimulation or in conditions of chronic pathologies, as could be the case of retroviral infections. Numerous observations endorse also the hypothesis of a direct regulation of the HPA axis by the virus or its proteins. These viruses and other related viruses, such as HIV, are known to cross the brain-blood barrier and invade the central nervous system (CNS) and cause neurological damages in the host. The presence of the virus within the control centers could alter the activation routes of the hypothalamus-pituitary axis and modify the endocrine regulation of the HPA axis, leading to the production of anomalous hormone levels. In this sense, the presence of FeLV or its proteins in the hypothalamus has been linked to an endocrine deregulation, affecting the concentrations of growth hormone. Cytoplasmic viral antigens have been detected by indirect immunofluorescence assays in the fibers of hypothalamic preoptic region of FeLV-infected cats A similar dysfunction could be due to the presence of FIV in these regulating elements. The neurological damages associated to the lentiviral infection are partly mediated by the neurotoxicity of the envelope protein of the virus.