Progression to AIDS, a clinical AIDS condition and mortality: psychosocial and physiological predictors.

BACKGROUND: The primary aim of this study is to examine prospectively the association of stressful life events, social support, depressive symptoms, anger, serum cortisol and lymphocyte subsets with changes in multiple measures of human immunodeficiency virus (HIV) disease progression. METHODS: Ninety-six HIV-infected gay men without symptoms or anti-retroviral medication use at baseline were studied every 6 months for up to 9 years. Disease progression was defined in three ways using the Centers for Disease Control (CDC) classifications (e.g. AIDS, clinical AIDS condition and mortality). Cox regression models with time-dependent covariates were used, adjusting for control variables (e.g. race, age, baseline, CD4 T cells and viral load, number of anti-retroviral medications). RESULTS: Higher cumulative average stressful life events and lower cumulative average social support predicted faster progression to both the CDC AIDS classification and a clinical AIDS condition. Higher anger scores and CD8 T cells were associated with faster progression to AIDS, and depressive symptoms were associated with faster development of an AIDS clinical condition. Higher levels of serum cortisol predicted all three measures of disease progression. CONCLUSIONS: These results suggest that stressful life events, dysphoric mood and limited social support are associated with more rapid clinical progression in HIV infection, with serum cortisol also exerting an independent effect on disease progression.

Elevated substance P levels in HIV-infected men.

The neuropeptide, substance P, is a potent modulator of neuroimmunoregulation. Substance P and its receptor modulate HIV infection. HIV-seropositive men had significantly higher plasma substance P levels compared with uninfected controls, which were associated with decreased CD16 and CD56 natural killer (NK) cell populations. The changes in plasma substance P levels and decreases in NK subsets did not correlate with CD4 cell levels, but a diurnal pattern was suggested for substance P. The balance between substance P expression and functions of immune cells may be important in the immunopathogenesis of HIV infection.

Psychosocial-immune relationships in HIV disease.

Human immunodeficiency virus (HIV) is now commonly viewed as a chronic disease, which often consists of a wide array of recurrent and sometimes severe psychosocial stressors. An individual's response to these multiple challenges over time may impact their health. In this article, we review research examining the relationship of psychologic factors (eg, depression, stressful life events, coping, social support) with immune system function and disease course. We also explore some of the potential physiologic pathways that may underlie these types of psychosocial-immune relationships, as well as the effects of psychologic interventions, particularly cognitive-behavioral stress management (CBSM), on the psychosocial, neuroendocrine, and immune functioning of people living with HIV. We conclude by suggesting some areas for future research, particularly the study of HIV-positive women.

Obsessive compulsive disorder: is there an association with childhood streptococcal infections and altered immune function?

During the last few years, an increased interest in the possibility of immune mediated pathophysiology of obsessive compulsive disorder (OCD) and related disorders has been seen. In the late 1980s, the National Institute of Mental Health reported an increase of obsessive compulsive symptoms in patients with Sydenham chorea (SC). Subsequently, a precipitating streptococcal infection in children with sudden onset of OCD symptoms but no chorea led to the coining of PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcus). This association has furthered interest in studying immune parameters in non-PANDAS OCD as well. This article will review the neuropsychiatric findings in OCD and Tourette syndrome (TS) with emphasis placed on PANDAS, and its association with SC, and a review of the existing studies that have assessed immunologic measures in patients with OCD and TS.

Cloning the full-length IL-2/15 receptor-beta cDNA sequence from mouse brain: evidence of enrichment in hippocampal formation neurons.

Numerous studies have implicated interleukin-2 (IL-2) in various brain processes, and more recently, several studies have also attributed neurobiological actions to interleukin-15 (IL-15). On lymphocytes, receptors for IL-2 and IL-15 share a common subunit, the IL-2/15 receptor-beta (IL-2/15Rbeta) that is essential for intracellular signaling. Although a short segment of IL-2/15Rbeta has been cloned (0.35 kb) from normal brain cells, attempts to isolate the full-length cDNA have been unsuccessful, suggesting the possibility that the genes expressed by brain cells and lymphocytes may differ. Using conventional and anchored PCR cloning strategies, we isolated the full-length cDNA of IL-2/15Rbeta (2038 bp) from well-perfused, normal mouse forebrain. The coding sequence and the adjacent 5' and 3' UTR sequences from brain and lymphocyte were found to be fully homologous. Although evidence of expression of IL-2/15Rbeta can be found in many brain regions using PCR, clear evidence of gene expression by in situ hybridization was detectable only in the hippocampal formation, habenula and piriform cortex. This same pattern of mRNA expression in situ was also observed for the common gamma subunit shared by IL-2 and IL-15. In the hippocampus, IL-2/15Rbeta expression was localized to neurons by high resolution in situ hybridization and evidence of IL-2 receptor protein expression was also detected by radioligand receptor binding using hippocampal homogenates. Comparison of undifferentiated and differentiated, immortalized H19-7 hippocampal neurons showed that IL-2/15Rbeta was constitutively expressed across disparate stages of hippocampal neuronal differentiation. These data indicate that IL-2/15Rbeta may serve to modulate neuronal processes in the hippocampus and associated limbic brain regions.

Brain-immune interactions in neuropsychiatry: highlights of the basic science and relevance to pathogenic factors and epiphenomena.

Unraveling the significant complexity of brain-immune interactions could provide essential new insights and potential treatment considerations for the clinical neurosciences. Despite considerable research relating immunological changes to major neuropsychiatric disorders, it has been difficult to establish that immunological processes are involved in the development of central nervous system pathology associated with these disorders. This brief article highlights some of the landmark basic studies and seeks to convey essential principles guiding research in brain-immune interactions. Research in this area often incorporates several disciplines, ranging from psychology and neuroscience to immunology and molecular genetics. The clinical implications of this area of research are discussed, with emphasis on the challenge of disentangling pathogenic factors and valid markers of disease from epiphenomena.

D(3) and D(2) dopamine receptor agonists differentially modulate isolation-induced social-emotional reactivity in mice.

Following isolation housing, mice typically exhibit heightened emotional reactivity to mild social stimulation. Aggression, social avoidance and a variety of defensive behaviors that differ in terms of motor activation (e.g. freezing, escape) can be observed depending on strain. Previous studies suggested that D(2)-like dopamine (DA) receptors play an important, albeit strain specific, role in the mediation of particular forms of defensive behavior. D(3) receptors are subtypes of D(2)-like receptors that are highly expressed in limbic areas of the brain and, therefore, they have been hypothesized to mediate emotional behavior. This study examined the effects of the putative D(3) receptor agonists 7-OH-DPAT and PD128907 on social-emotional behavior in isolated C57BL/6J and A/J mice. These effects were compared with those of the selective D(2) receptor agonist PNU91356A. All three DA agonists increased non-locomotor forms of defensive behavior (e.g. freezing, upright defensive posture). These effects were observed at low doses in C57BL/6J and at higher doses in A/J mice. Only the D(3) receptor agonists were effective in increasing locomotor forms of defensive behavior (i.e. escape, jump) at higher doses. These effects were more pronounced in C57BL/6J mice than A/J mice. The increases in stationary and locomotor defensive behavior were accompanied by marked reduction in social investigation in both the strains. Aggressive behavior was also abolished in the aggressive C57BL/6J strain. These results support previous findings and suggest that DA agonists potentiate defensive behavior and/or social fearfulness. They also suggest that D(3) and D(2) DA receptors differentially modulate the expression of social-emotional reactivity and indicate the importance of strain in examining the effects of DA ligands on emotional behavior.

Impact of stressful life events, depression, social support, coping, and cortisol on progression to AIDS.

OBJECTIVE: This study examined prospectively the effects of stressful events, depressive symptoms, social support, coping methods, and cortisol levels on progression of HIV-1 infection. METHOD: Eighty-two homosexual men with HIV type-1 infection without AIDS or symptoms at baseline were studied every 6 months for up to 7. 5 years. Men were recruited from rural and urban areas in North Carolina, and none was using antiretroviral medications at entry. Disease progression was defined as CD4(+) lymphocyte count <200/microl or the presence of an AIDS indicator condition. RESULTS: Cox regression models with time-dependent covariates were used adjusting for race, baseline CD4(+) count and viral load, and cumulative average antiretroviral medications. Faster progression to AIDS was associated with higher cumulative average stressful life events, coping by means of denial, and higher serum cortisol as well as with lower cumulative average satisfaction with social support. Other background (e.g., age, education) and health habit variables (e.g., tobacco use, risky sexual behavior) did not significantly predict disease progression. The risk of AIDS was approximately doubled for every 1.5-unit decrease in cumulative average support satisfaction and for every cumulative average increase of one severe stressor, one unit of denial, and 5 mg/dl of cortisol. CONCLUSIONS: Further research is needed to determine if treatments based on these findings might alter the clinical course of HIV-1 infection.

High versus low basal cortisol secretion in asymptomatic, medication-free HIV-infected men: differential effects of severe life stress on parameters of immune status.

The authors hypothesized that HIV-infected men with high basal cortisol secretion would exhibit greater stress-related reductions in the ratio of Th1/Th2 cell-derived cytokines and numbers of CD8+ T and NK lymphocytes than low basal cortisol secretors. A semistructured interview was used to assess life stress during the preceding 6 months of 94 HIV-infected men classified as high and low cortisol secretors (n = 47/group). Increased levels of severe life stress were highly correlated with lower numbers of CD8+ T cells, CD16+ and CD56+ NK cells, CD57+ cells, and higher DHEA-S concentrations in the high cortisol group. Conversely, no significant correlations were found in the low cortisol group. No correlations were found between stress and CD4+ T helper/inducer cell counts, cytokine production, or testosterone levels in either participating group. These data suggest that severe stress in combination with high glucocorticoid activity may modify select parameters of immune status in HIV-infected men.

Interleukin-2 gene deletion produces a robust reduction in susceptibility to experimental autoimmune encephalomyelitis in C57BL/6 mice.

Dysregulation of interleukin-2 (IL-2), the prototypical T cell growth factor and immunoregulatory cytokine, may modify self-tolerance and predisposition to autoimmunity. The available literature suggested that IL-2 could be hypothesized to either propagate or inhibit the development autoimmune demyelinating disorders of the central nervous system such as multiple sclerosis. Thus, the present study sought to test these competing hypotheses by examining whether disrupting one or both IL-2 gene alleles would render mice more or less vulnerable to experimental autoimmune encephalomyelitis (EAE). Myelin oligodendrocyte glycoprotein was used to induce EAE in C57BL/6-IL-2(-/-) knockout, C57BL/6-IL-2(+/-) heterozygote and C57BL/6-IL-2(+/+) wild-type mice. All of the wild-type and heterozygote mice developed signs of EAE compared with only 23% of the IL-2 knockout mice. Histopathological examination of lumbar spinal cord sections confirmed that subpial perivascular inflammatory infiltrates found in wild-type and heterozygote mice were absent in the unaffected IL-2 knockout mice. These data demonstrate that vulnerability to EAE is markedly reduced in C57BL/6 mice lacking IL-2, and suggest that this cytokine may play a critical role in autoimmune processes of the central nervous system.

Early social deprivation in nonhuman primates: long-term effects on survival and cell-mediated immunity.

BACKGROUND: Early differential social experience of non-human primates has resulted in long-term alterations in behavior and neurobiology. Although brief maternal separation has been associated with changes in immune status, the long-term effects on survival and immune function of prolonged early social deprivation are unknown. METHODS: Survival rates were examined in rhesus monkeys, half of which had been socially deprived during their first year of life. Repeated measures of immune status were tested in surviving monkeys (18-24 years old). Peripheral blood T, B, and natural killer lymphocytes, macrophages, and monocytes were measured by flow cytometry. Functional cellular immune activity measures included T-cell proliferative responses to mitogens (concanavalin and phytohemagglutinin), T-cell memory response to tetanus toxoid antigen, T-cell-dependent B-cell proliferative responses to mitogen (PWM) and natural killer cell cytotoxic activity. RESULTS: Despite identical environments following isolation, early social deprivation resulted in a significantly decreased survival rate, males being particularly vulnerable to early death. Early social deprivation was associated with a decrease in the ratio of helper to suppressor T cells, and a significant increase in natural killer cell number and in natural killer cell activity in the surviving monkeys. No differences in T- or B-lymphocyte proliferation following mitogen or tetanus toxoid antigen stimulation were observed. CONCLUSIONS: Prolonged early social deprivation of non-human primates profoundly affected mortality and resulted in lifelong effects on cell-mediated immune status.

Differences in NK cell function in mice bred for high and low aggression: genetic linkage between complex behavioral and immunological traits?

In previous studies, we found differences in cellular immune responsiveness in Institute for Cancer Research (ICR) mice selectively bred for high and low levels of aggression. Compared to the high aggressive line, the low aggressive line had low levels of natural killer (NK) and T cell activity and increased susceptibility to tumor development. To dissect further this novel association, experiments were designed to test two competing hypotheses. The first hypothesis was that the phenotypic expression of the line differences in NK cell activity are dependent on and regulated by the expression of high and low levels aggressive behavior in the lines. The alternative hypothesis was that the differences in immune status are independent of the expression of aggression by the lines, suggesting linkage between a subset of genes involved in determining these complex behavioral and immunological traits or pleiotropic gene effects on both traits. In Experiment 1, three conditions of postweaning social experience (mice singly housed, group housed within line, or group housed between lines) were tested in males to determine whether experiential conditions which modify the expression of aggression would in turn modify the line differences in NK cell activity. This experiment revealed that the difference in NK cell activity between high aggressive and low aggressive male mice was attributable to line only. The different postweaning social conditions examined had no effect on modifying the differences in NK activity, and social dominance hierarchy did not correlate with levels of NK cell activity. Whereas males of the high and low lines exhibit differences in aggressive behaviors across most contexts, females do not exhibit such differences except in response to an intruder during the postpartum period. Therefore, in Experiment 2 we compared the NK cell activity of nulliparous females of the high and low aggressive lines. Under these conditions, females of the low aggressive line had low levels of NK activity compared to high aggressive females (differences comparable to those seen between males of the high and low lines). Taken together, these experiments lend support to the hypothesis that this association may be due to a genetic linkage between subsets of genes involved in determining these complex behavioral and immunological traits, or may possibly represent a fortuitous association which occurred during the selective breeding.

Progression to AIDS: the effects of stress, depressive symptoms, and social support.

OBJECTIVE: We examined the effects of stress, depressive symptoms, and social support on the progression of HIV infection. METHODS: Eighty-two HIV-infected gay men without symptoms or AIDS at baseline were followed up every 6 months for up to 5.5 years. Men were recruited from rural and urban areas in North Carolina as part of the Coping in Health and Illness Project. Disease progression was defined using criteria for AIDS (CD4+ lymphocyte count of <200/microl and/or an AIDS-indicator condition). RESULTS: We used Cox regression models with time-dependent covariates, adjusting for age, education, race, baseline CD4+ count, tobacco use, and number of antiretroviral medications. Faster progression to AIDS was associated with more cumulative stressful life events (p = .002), more cumulative depressive symptoms (p = .008), and less cumulative social support (p = .0002). When all three variables were analyzed together, stress and social support remained significant in the model. At 5.5 years, the probability of getting AIDS was about two to three times as high among those above the median on stress or below the median on social support compared with those below the median on stress or above the median on support, respectively. CONCLUSIONS: These data are among the first to demonstrate that more stress and less social support may accelerate the course of HIV disease progression. Additional study will be necessary to elucidate the mechanisms that underlie these relationships and to determine whether interventions that address stress and social support can alter the course of HIV infection.

Impaired learning and memory and altered hippocampal neurodevelopment resulting from interleukin-2 gene deletion.

Interleukin-2 (IL-2), the protypical T cell growth factor and immunoregulatory cytokine produced by lymphocytes, has been implicated as a brain neurotrophic factor and neuromodulator. The consequences of the absence of endogenous IL-2 on brain development and function were unknown. Brain IL-2 receptors are enriched in the hippocampal formation, an area critical for the acquisition and consolidation of spatial learning and memory. Thus, we tested the hypothesis that mice lacking IL-2 would exhibit alterations in hippocampal-dependent learning and neurodevelopment. Compared with C57BL/6-IL-2+/+ wild-type mice, we observed that C57BL/6-IL-2-/- gene knockout mice had markedly impaired spatial learning and memory in the Morris water maze. No significant deficits in parameters of learning and memory performance were found in severe combined immunodeficient (SCID) mice (C57BL/6scid), however, suggesting that the impaired spatial learning and memory exhibited by IL-2 knockout mice is not attributable to generalized immunodeficiency resulting from the absence of endogenous IL-2. Examination of other domains of behavioral performance showed that the IL-2 knockout and wildtype mice did not differ in measures of fearfulness or locomotor activity in an elevated plus maze, or in reflexive startle responses to auditory stimuli--although prepulse inhibition of acoustic startle (PPI) was increased significantly in IL-2 knockout mice. The spatial learning and memory impairment in IL-2 knockout mice was accompanied by reductions in hippocampal infrapyramidal mossy neuronal fiber length, a factor shown previously to correlate positively with spatial learning ability. These findings indicate that, in addition to being a pivotal cytokine in immune regulation, IL-2 may play a role in the development and regulation of brain neurons involved in spatial learning and memory.

Depression in the medical setting: biopsychological interactions and treatment considerations.

This article examines depression in 6 medical conditions: coronary artery disease (CAD), cancer, human immunodeficiency virus (HIV) infection, Parkinson's disease, pain, and the sex hormone changes of aging. Research is beginning to define specific biological and psychological mechanisms underlying the adverse interactions between depression and these medical conditions. Antidepressant medications, psychosocial therapies, and hormonal manipulations are effective in reducing depressive symptoms. Specific psychosocial interventions may increase longevity in CAD and cancer and may enhance quality of life in HIV infection. Newer antidepressants appear to be safer and better tolerated than older agents for medically ill patients, but do not appear to be as effective for neuropathic pain. Dopamine agonists may benefit depression associated with Parkinson's disease. Hormone replacement therapy may improve subsyndromal depressive symptoms in postmenopausal women and may enhance antidepressant response for older women with major depression.

Molecular cloning of the cDNA coding sequence of IL-2 receptor-gamma (gammac) from human and murine forebrain: expression in the hippocampus in situ and by brain cells in vitro.

IL-2 has been implicated in various neurobiological processes of the mammalian CNS. To understand how IL-2 acts in the brain, our lab has sought to determine the molecular pharmacological characteristics of brain IL-2 receptors (IL-2R). The lymphocyte IL-2Rgamma, an essential subunit for IL-2 signaling, is also a common subunit (gammac) for multiple immune cytokine receptors (e.g., IL-4R, IL-7R, IL-9R, IL-15R). Having previously cloned the alpha and beta subunits of the IL-2R heterotrimer complex from normal murine forebrain, we examined the hypothesis that the brain IL-2Rgamma is derived from the same or a closely related gene coding sequence as that expressed by lymphocytes. In this study, we cloned and sequenced the full-length IL-2Rgamma coding region from saline-perfused mouse forebrain and from a human hippocampal library. The cDNA sequences of IL-2Rgamma from human and murine brain were 100% homologous to their lymphocyte sequences. Northern blot analysis showed that the mRNA transcripts in murine brain were the expected size, but the predominant transcript expressed in the brain was different than in the spleen. Compared to the spleen, very low levels of IL-2Rgamma were expressed in the forebrain. In the murine hippocampus, a region where a number of neurobiological actions of IL-2 have been reported, IL-2Rgamma mRNA was detected over the dentate gyrus and CA1-CA4 by in situ hybridization histochemistry. IL-2Rgamma was found to be constitutively expressed by murine HN33.dw hippocampal neuronal cells, murine NB41A3 neuroblastoma cells, astrocyte-enriched mixed glial cell cultures, and in SCID mouse forebrain. The human cortical neuronal cell lines, HCN-1A and HCN-2, did not express the IL-2Rgamma gene. These data suggest the possibility that, in addition to being essential in IL-2 signaling in brain, IL-2Rgamma could be a common subunit (gammac) for multiple cytokine receptors which may be operative in the mammalian CNS.

D2-like dopamine receptor mediation of social-emotional reactivity in a mouse model of anxiety: strain and experience effects.

We examined the effects of the D2-like dopamine receptor agonist quinpirole on social-emotional reactivity in two inbred mouse strains. An important objective of this study was to determine whether these effects could be modulated by differential housing conditions (i.e., isolation versus group housing). Moreover, as motor activity is an important control for the assessment of drug effects on emotional behavior, the effects of quinpirole were tested in two inbred mouse strains (A/J and C57BL/6J) low and high in motor activity, respectively. Levels of emotional reactivity were assessed in response to mild social stimulation provided by a nonaggressive conspecific. Quinpirole increased stationary forms of reactivity (i.e., startle, kicking, defensive posture, vocalization) in both isolated and group-housed A/J mice. This effect was more pronounced and observed at lower doses in isolated than in group-housed A/J mice. Quinpirole also induced jump behavior in isolated but not group-housed A/J mice. The shift to the left in the dose-response curve of quinpirole in isolated A/J mice indicated that D2-like dopamine receptor functions can be altered by social experience. Quinpirole only marginally increased stationary and locomotor reactivity (i.e., jump) in isolated C57BL/6J mice, whereas it markedly reduced motor activity in group-housed mice of this strain. The investigation of emotional reactivity within a social context and using strains that differ in motor activity permitted the effects of drugs on emotional reactivity to be dissociated from the effects on motor activity. Given that social-emotional reactivity was elicited by what typically should have been mild and nonthreatening stimuli, this model may be highly relevant to understanding the neurobiology of anxiety. Finally, these data support an important role for dopamine in the mediation of social-emotional reactivity.

Isolation of IL-2 receptor-beta cDNA clones from AtT-20 pituitary cells: constitutive expression and role in signal transduction.

Interleukin-2 (IL-2) has been shown to stimulate ACTH secretion by anterior pituitary cells and has been implicated in pathophysiological processes of the pituitary and brain in several major neuropsychiatric disorders. The present study tested the hypothesis that IL-2 receptor-beta (IL-2R beta), a constitutively expressed and essential subunit for IL-2 signaling in lymphocytes, is expressed by AtT-20 pituitary cells and involved in transducing intracellular signals induced by IL-2. We isolated and sequenced three overlapping IL-2R beta cDNA clones from AtT-20 pituitary cells representing key regions of the gene protein coding sequence. These cDNA clones including conserved sequences shared by growth hormone and prolactin as well as intracytoplasmic Src and JAK family homology domains of nonreceptor protein tyrosine kinases essential for IL-2 signaling in lymphocytes. Their nucleotide sequences were 100% homologous with those expressed by lymphocytes (together they comprised 70% of the full length coding sequence). The IL-2R beta gene is constitutively expressed by AtT-20 pituitary cells, and its transcription was upregulated after CRF stimulation. Species-specific Il-2 induced intracellular signals in AtT-20 cells known to be mediated by Il-2R beta, including a transient increase in c-myc nuclear proto-oncogene transcription and the dose-dependent induction of DNA replication as measured by [3H]thymidine incorporation. The IL-2-induced DNA replication signal was not delivered by heat inactivated IL-2 and was partially blocked by a murine anti-IL-2R beta monoclonal antibody. These studies suggest that IL-2R beta may be a critical target involved in mediating the neuroimmunological actions of this prototypical cytokine in endocrine cells.

Severe life stress as a predictor of early disease progression in HIV infection.

OBJECTIVE: Although there is evidence that stress is associated with alterations in immunity, the role of emotional factors in the onset and course of immune-based diseases such as cancer and AIDS has not been established. This prospective study was designed to test the hypothesis that stressful life events accelerate the course of HIV disease. METHOD: Ninety-three HIV-positive homosexual men who were without clinical symptoms at the time of entry into the study were studied for up to 42 months. Subjects received comprehensive medical, neurological, neuropsychological, and psychiatric assessments every 6 months, including assessment of stressful life events during the preceding 6-month interval. Several statistical approaches were used to assess the relation between stress and disease progression. RESULTS: The time of the first disease progression was analyzed with a proportional hazard survival method, which demonstrated that the more severe the life stress experienced, the greater the risk of early HIV disease progression. Specifically, for every one severe stress per 6-month study interval, the risk of early disease progression was doubled. Among a subset of 66 subjects who had been in the study for at least 24 months, logistic regression analyses showed that higher severe life stress increased the odds of developing HIV disease progression nearly fourfold. the degree of disease progression was also predicted by severe life stress when a proportional odds logistic regression model was used for analysis. CONCLUSIONS: This report presents the first evidence from a prospective research study that severe life event stress is associated with an increased rate of early HIV disease progression.