The hallmark of herpetic disease is the ability of the virus to become latent in ganglia and cause recurrent disease. While recovery from a primary infection with Herpes simplex virus (HSV) is associated with the development of virus-specific immunologic memory, reactivation of latent virus causes symptomatic disease in many patients. The observation that in immunocompetent hosts, HSV lesions are limited and of relatively short duration, whereas individuals with impaired T cell response suffer severe herpetic recurrences, has led to the hypothesis that recurrent disease is associated with regulatory defects in virus-specific T cell responses. Recently, data have been collected that indicate that the immune system and the nervous system communicate through the release of soluble factors (cytokines). It has been argued that this communication is bi-directional with products of the nervous system affecting the biological behavior cells of the immune system and vice-versa. Experimental studies have also demonstrated that neuropeptides (NP) such as vasoactive intestinal peptide (VIP), somatostatin (SOM), substance P (SP), gastrin-releasing peptide (GRP) can affect lymphocyte proliferation and lymphokine production. Furthermore, it has been established that lymphatic tissues are extensively innervated and contain various neurotransmitters. Taken together with the fact that lymphocytes and monocytes express specific receptors for various neuropeptides, these data provide the evidence for a regulatory network that involves NP and immunocyte interactions. HSV causes a latent infection in which the latent viral genome resides in the sciatic (genital infections) or trigeminal (labial infections) ganglia. Upon reactivation of the latent virus, axonal transport mechanisms within the neuron carry the viral entity towards the permissive cells (epithelial). It is postulated that reactivation is associated with the localized release of neurotransmitters and cotransmitters (such as VIP) by the neurons and that these substances can regulate the biologic behavior of lymphocytes that arrive at the site of virus replication. If this is the case, then HSV specific lymphocytes should express functional receptors for neurotransmitters. And further, the binding of neurotransmitter to an HSV-stimulated lymphocyte should alter the biologic response of the cell. Therefore, the specific aim of this proposal is to determine if neuropeptides modulate the proliferation and lymphokine secretion of human lymphocytes stimulated with HSV antigen. To accomplish this goal mononuclear cells (containing monocytes and lymphocytes) will bc obtained from the peripheral blood of normal individuals and patients during recurrent HSV disease. Cell cultures will be established containing cells, viral antigen and neuropeptides. Initially four neuropeptides will be studied (VIP, SOM, SP and GRP). Antigen-specific proliferation will be measured and culture supernatant will be assayed for lymphokine (IL-2, IL-4, INF-gamma, and LIF). Both dose response and kinetics studies will be performed with each of the neuropeptides. The results from patients with recurrent disease will be compared to results obtained from normal volunteers without recurrent disease.
