Inverse relationship between neopterin and immunoglobulin E

Polarized human T helper (Th) cells play a key role in the network of the specific immune system compartments. Cell-mediated immune response depends on activation of Th1-type cells, typically producing and releasing interferon-gamma and interleukin-2, whereas activation of Th2-type cells and production of cytokines such as interleukin-4, -5, and -10 are involved in humoral immune response and the production of immunoglobulins. Increased amounts of neopterin are produced during the Th1-type immune response by human monocytes/macrophages upon stimulation with the Th1-derived cytokine interferon-gamma, and thus the determination of neopterin concentrations allows us to monitor Th1-type immune response. We compared serum concentrations of neopterin with immunoglobulin E (IgE), a typical product of the Th2-type immune response, in order to examine the relationship between Th1-type and Th2-type immune system stimulation in 709 healthy outpatients, who visited the physician's office for a medical health checkup. Eleven percent presented with serum neopterin concentrations >8.7 nmol/L; 26% had increased serum concentrations of IgE (>100 kIU/L). There existed an inverse correlation between serum neopterin and IgE concentrations (Spearman's rank correlation coefficient: r(s) = -0.100; P < 0.01) which was stronger when excluding data < or = 8.7 nmol/L neopterin and < or = 100 kIU/L IgE (n = 246; r(s) = -0.519; P < 0.0001). Data indicate that increased serum neopterin concentrations are associated with low serum IgE and increased serum IgE with low serum neopterin concentrations. This finding fully agrees with the current understanding that in humans the activation of Th1 and Th2 cell-mediated immune responses are down-regulating each other.     

Immune activation markers to predict AIDS and survival in HIV-1 seropositives

Neopterin concentrations in body fluids of HIV-1 seropositives provide predictive information. In 1986, we examined serum and urine neopterin concentrations in 29 HIV-1 seropositives. Serum levels of soluble IL-2 receptor (sIL2R), soluble CD8 (sCD8), tumour necrosis factor alpha (TNF-alpha) and circulating immune complexes (CIC) were retrospectively analysed in 1989. All individuals had increased serum and urine neopterin, sIL2R and CIC concentrations, 27/29 had increased sCD8 concentrations, whereas all had normal TNF-alpha levels. During a 3-year follow-up, high urine and serum neopterin concentrations were significantly associated with progression to AIDS and with the occurrence of AIDS-associated death. Both neopterin variables were of similar predictive value (p less than 0.001, generalized Wilcoxon test). sIL2R concentrations were of borderline significance in predicting the onset of AIDS (p = 0.05). All other parameters lacked predictive information in our study. We conclude, that chronic immune activation is detectable in almost all HIV-1 seropositives. Chronic immune activation may be associated with HIV-1 replication and may contribute to the immunopathology of HIV-1 infection.     

Neopterin-induced expression of intercellular adhesion molecule-1 (ICAM-1) in type II-like alveolar epithelial cells

In order to examine the regulatory effects of major Th1-derived cytokines, such as IL-12, and Th2 cytokines, IL-4 and IL-10, on the formation of neopterin and degradation of tryptophan, two metabolic pathways induced by interferon-gamma (IFN-gamma) in human monocytes/macrophages, we investigated the human monocytic cell line THP-1, primary human macrophages, and peripheral blood mononuclear cells (PBMC). Neopterin formation and tryptophan degradation were induced similarly by IFN-gamma in all three cell types investigated, but the effects of interleukins were different between THP-1, primary macrophages and PBMC. In PBMC, but not in THP-1 cells and primary macrophages, IL-12 was found to be additive to the effects of IFN-gamma to superinduce neopterin formation and tryptophan degradation. IL-4 and IL-10 reduced the effects of IFN-gamma on monocytic cells, and both cytokines were additively antagonistic to IFN-gamma in PBMC and THP-1 cells. Finally, on preincubation, but not on addition of IL-12, the effects of IL-4 and IL-10 on PBMC could be abrogated, whereas no such effect was seen in THP-1 cells. The results show that IL-12 up-regulates neopterin formation and tryptophan degradation by inducing additional IFN-gamma production by Th1 cells, while a direct effect of IL-12 on monocytes/macrophages appears to be absent. Similarly, IL-4 and IL-10 inhibit neopterin production and tryptophan degradation in PBMC by down-regulating Th1-type cytokine production and possibly also via direct deactivation of IFN-gamma effects towards monocytes/macrophages. The results clearly show how Th1 cell-mediated immunity may be up- or down-regulated by endogenous cytokine production.     

Value of urinary neopterin in the differential diagnosis of bacterial and viral infections

Summary Neopterin is released by stimulated macrophages. In this study we analyzed the diagnostic potential of urinary neopterin concentrations in patients with bacterial and viral infection. All but one of 17 patients with viral infection had increased urinary neopterin concentrations. Patients with bacterial urinary tract infection also showed increased neopterin concentrations, whereas patients with bacterial pneumonia had significantly lower neopterin levels. In addition, patients with acute bacterial pneumonia had lower neopterin levels than patients with protracted infection. A significant inverse correlation between urinary neopterin and hemoglobin concentrations was found. Neopterin concentrations could serve as a helpful additional marker of infectious diseases. Combined with other clinical and laboratory parameters it is a useful parameter for distinguishing between viral and bacterial origins of infection, as was shown by multivariate stepwise linear discriminant analysis.Abbreviations ESR erythrocyte sedimentation rate     

High serum neopterin and low cytokine values may indicate a non-bacterial etiology for fever of unknown origin in neutropenic patients

Objective: To prospectively evaluate serum neopterin, a marker of cellular immune activation, in relation to blood culture findings and cytokine levels (tumor necrosis factor-α (TNF-α), interleukin (IL)-1 receptor antagonist, interferon-γ (IFN-γ), IL-6, and IL-10) at start of fever in neutropenic patients with hematologic malignancies.
Methods: Serum samples were obtained during the first 24 h after start of fever in 27 episodes of febrile neutropenia seen in 22 patients.
Results: Neopterin levels increased significantly at start of fever (time 0) compared to baseline values (samples obtained within 72 h before start of fever). Neopterin levels peaked at 2–4 h after start of fever and returned to baseline levels after 12 h. At start of fever no differences in neopterin values were seen with regard to blood culture findings (i.e. blood-culture-negative (BCN) fever episodes versus Gram-positive bacteria versus Gram-negative bacteremia). In five of seven BCN fever episodes, in patients without other clinical evidence of infection, a high neopterin/low TNF-α value was observed and the correlation ( r -value) between neopterin/TNF-α was negative in BCN fever episodes (-0.9; p <0.04), as opposed to the bacteremic episodes, where the correlation was positive (0.7; p <0.04).
Conclusion: The results of this study show that febrile neutropenic patients are able to react with increased neopterin values, and that some BCN fever episodes are characterized by high neopterin/low cytokine values which may be due to an occult non-bacterial infection.     

Increased serum neopterin in patients with HIV-1 infection is correlated with reduced in vitro interleukin-2 production.

Recently we have observed that the CD4+ T cell response of peripheral blood mononuclear cells (PBMC) to soluble antigens is the first to be lost in the course of HIV-1 infection followed by the loss of response to HLA alloantigens. In this study we compared serum neopterin concentrations of individuals with early stages of HIV-1 infection (stages WR1 and WR2, Walter Reed staging system) with in vitro interleukin-2 (IL-2) production of PBMC in response to stimulation with soluble antigens (influenza A virus and tetanus toxoid) and alloantigens. Neopterin concentrations were significantly higher in HIV-1-seropositive individuals who showed deficient IL-2 production in response to recall antigens only or to all of the stimuli tested in vitro, compared with HIV-1-seropositive individuals who exhibited no CD4+ T cell defects. No difference in serum neopterin concentrations was observed between the group that was functionally deficient to soluble antigens only versus those who were unresponsive to both types of stimuli. It appears that the selective loss of the MHC self-restricted CD4+ T cell function is associated with an increase in serum neopterin levels. Neopterin concentrations are an estimate of the activation status of macrophages. We conclude that defective in vitro production of lymphokines by T lymphocytes is associated with activated macrophages in vivo.     

Aspirin down-regulates tryptophan degradation in stimulated human peripheral blood mononuclear cells in vitro

Acetylsalicylic acid (aspirin) is one of the most widely used drugs worldwide, due mainly to its broad therapeutic spectrum with anti-inflammatory, antipyretic, antithrombotic and analgesic effects. However, the exact mechanisms by which aspirin influences inflammation, pain and immune system activation are only partly understood. Within activation of the cellular immune system, Th1-type cytokine interferon (IFN)-gamma induces enzyme indoleamine-2,3-dioxygenase (IDO) which converts tryptophan to kynurenine. In parallel, IFN-gamma induces enzyme GTP-cyclohydrolase I, which gives rise to neopterin production by activated human macrophages. Similarly, tryptophan degradation and neopterin formation increase during several disease states involving Th1-type immune activation. Using stimulated human peripheral blood mononuclear cells (PBMC), the effect of aspirin on tryptophan degradation and neopterin production was investigated. Stimulation of PBMC with mitogens concanavalin A, phytohaemagglutinin and pokeweed mitogen induced significant tryptophan catabolism as was reflected by a decline in tryptophan levels and a parallel increase in kynurenine concentrations compared with unstimulated cells. In parallel, neopterin production was enhanced. Treatment of stimulated PBMC with increasing doses of 1-5 mM aspirin significantly decreased stimulation-induced tryptophan degradation and neopterin production as well. All the effects of aspirin were dose-dependent. The parallel influence of aspirin on both biochemical pathways implies that there was no direct inhibitory effect of aspirin on IDO; rather, it inhibits production of IFN-gamma in mitogen-treated PBMC. The influence of aspirin on biochemical pathways induced by IFN-gamma may represent an important part of its broad pharmacological effect.     

Neopterin measurement provides evidence of altered cell-mediated immunity in patients with depression, but not with schizophrenia.

Neopterin is a validated marker of the activation of cell-mediated immunity in a variety of disease states. We measured neopterin and creatinine concentrations in the plasma and urine of 22 schizophrenic and 26 depressed patients admitted acutely to hospital, and compared results with those in a large group of normal controls. Neopterin/creatinine ratios were normal in the schizophrenic patients, but significantly elevated in the plasma of depressed patients. In each diagnostic group, the use of psychotropic drugs before admission had no effect on the neopterin ratios observed. Our findings indicate altered cell-mediated immunity in depression.     

Influence of neopterin and 7,8-dihydroneopterin on the replication of Coxsackie type B5 and influenza A viruses

Pteridine derivatives neopterin and 7,8-dihydroneopterin are produced by human macrophages and dendritic cells upon stimulation with interferon-γ (IFN-γ) and therefore become detectable in increased amounts in humans during cell-mediated (Th1-type) immune response. Compounds produced upon influence of cytokine IFN-γ often exert antiproliferative and antiviral activity. The aim of this study was to investigate the effect of neopterin and 7,8-dihydroneopterin on the replication of Coxsackie type B5 and influenza A viruses. The changes in the replication of these viruses were evaluated by the degree of cytopathic effect and their ability to form plaques in Coxsackie B5-infected human larynx carcinoma epithelial (Hep-2) cells and in influenza A-infected canine kidney epithelial cells (MDCK). Potential toxicity of neopterin and 7,8-dihydroneopterin was estimated by the incorporation of ³H-thymidine and ³H-uridine into Hep-2 and MDCK cells. Whereas 30 nmol/l neopterin delayed the development of the cytopathic effect of Coxsackie B5 virus in Hep-2 cells (P < 0.01), 7,8-dihydroneopterin did not have any essential influence at any of the concentrations tested between 10 nmol/l and 1,000 μmol/l. However, 100–1,500 μmol/l 7,8-dihydroneopterin significantly suppressed the propagation of influenza A virus. Neopterin and 7,8-dihydroneopterin were practically nontoxic for Hep-2 and MDCK cells even at high μM concentration. Results suggest that the increased production of neopterin derivatives by activated macrophages and dendritic cells may represent part of the antiviral armature induced by IFN-γ. The mechanisms of the inhibitory effects of neopterin and 7,8-dihydroneopterin on virus replication apparently are different.     

Cellular immune activation, neopterin production, tryptophan degradation and the development of immunodeficiency

Cellular (Th1-type) immune response is centrally involved in the pathogenesis of various diseases. Within the immunological cascades of Th1-type immunity, interferon gamma (IFN-gamma), among other cytokines, is critically involved. It triggers a series of immune-relevant reactions mostly directed towards forward regulation of the antigen specific immune response. However, in chronic states of immune activation, systemically increased IFN-gamma is no longer antigen specific and is associated with the development of immunodeficiency. IFN-gamma also stimulates the production of neopterin, a low-mass compound, in human monocytes/macrophages. Accordingly, neopterin concentrations in humans reflect the degree of Th1-type immune activation. Since IFN-gamma also stimulates the release of reactive oxygen species (ROS) from immunocompetents cells, the amount of neopterin produced also serves as an indirect estimate of oxidative stress. In parallel, IFN-gamma activates the degradation of tryptophan, which appears to limit the growth of intracellular pathogens and the proliferation of cells, including T lymphocytes. Thus, during persisting states of immune activation, the production of IFN-gamma is not only associated with forward regulation of the immune response, but also with immunosuppressive mechanisms. The increased formation of neopterin and degradation of tryptophan may result in a decreased T cell responsiveness and development of immunodeficiency.     

Potential role of immune system activation-associated production of neopterin derivatives in humans

Neopterin derivatives are produced by human monocyte-derived macrophages and dendritic cells upon stimulation with interferons. Neopterin concentrations measured in urine or blood reflect activation of cellular immunity and endogenous release of interferon-. This review focuses on the clinical utility of measuring neopterin levels in inflammatory disease and the potential functions of neopterin as a mediator and/or modulator in the course of inflammatory and infectious processes. In vitro-studies revealed that neopterin derivatives exhibit distinct biochemical effects, most likely via interactions with reactive oxygen or nitrogen intermediates, thereby affecting the cellular redox state. Data support the hypothesis that the release of neopterin enhances the cytotoxic potential of activated macrophages and dendritic cells. In vivo, a strong correlation between neopterin levels and the severity, progression, and outcome of infectious and inflammatory diseases was found. The influence of neopterin derivatives on the cellular metabolism may provide an explanation for these clinical observations.Received 21 January 2003; returned for revision 10 March 2003; accepted by C. J. Whelan 26 March 2003     

Antioxidants may increase the probability of developing allergic diseases and asthma

In addition to genetic predisposition, a lack of triggers for Th1 immune response like exposure to infections, endotoxins and dirt in childhood are supposed to be responsible for the higher incidence of allergic rhinitis and asthma (hygiene hypothesis). In vitro, beverages rich in antioxidants like green tea and wine were found to suppress formation of Th1-type cytokine interferon-gamma. Due to the existing cross-regulatory interplay between Th1- and Th2-type immune response, these beverages may thus slow-down Th1-type immune response and thereby favour an over-production of Th2-type cytokines. Also food rich in antioxidants may increase the risk of atopic disease. Thus, not only a lack of triggers for Th1 type immune response, but also a nutrition rich in antioxidants suppressing interferon-gamma would result in a persistence of Th2-type immune response and increase the susceptibility for allergic reactions and asthma. In addition to improved hygienic standards in the past decades, also social changes including the availability of functional food and food enriched in antioxidants may have increased the prevalence of atopic diseases in Western countries.     

Macrophage activation in falciparum malaria as measured by neopterin and interferon-gamma.

Macrophage activation during acute falciparum malaria in 71 Thai adults was investigated by measuring urinary neopterin and serum interferon-gamma (IFN-gamma). Neopterin, a product of IFN-gamma-activated macrophages, was elevated in 94% of patients upon admission (day 0, prior to treatment) and in all at some time during the period of study. Neopterin levels tended to rise further (days 1-5) before falling back towards the normal range as patients recovered following effective chemotherapy (days 6-8). IFN-gamma was measured in 32 patients and found to be directly related to neopterin concentration. Both neopterin and IFN-gamma values were highest in patients experiencing a first malaria infection. Among those with histories of prior malaria, neopterin and IFN-gamma levels were inversely related to the number of previous infections. Morbidity, as assessed by degree and duration of fever, was directly related to neopterin concentration. This longitudinal study quantitatively describes the extent and duration of macrophage activation in falciparum malaria. The data also suggest that with repeated malaria infection and antigen exposure, there is a progressive decrease or possibly suppression of the T cell-macrophage interaction mediated by IFN-gamma.     

Neopterin production in SCID mice injected with human peripheral blood mononuclear cells

Intraperitoneal transfer of peripheral blood mononuclear cells (PBMC) from human EBV+ donors into severe combined immunodeficiency (SCID) mice is a suitable model for studying some aspects of lymphomagenesis and immune activation. Neopterin is a soluble immune marker which was found to be a useful indicator for immune activation processes in humans, e.g. to monitor immunological complications in allograft recipients or to predict prognosis in HIV-infected individuals. In contrast, this pteridine compound is normally synthesized in murine organism in only very low amounts. The measurement of neopterin concentrations in serum and urine should be feasible in SCID mice reconstituted with human PBMC. In this study, we examined the usability of this experimental model for monitoring human T cell activation by neopterin measurements. The production of neopterin by SCID mice after injection of freshly isolated human PBMC, purified B or T cells and cultured Epstein-Barr virus (EBV)+ lymphoblastoid cells (LCL) was determined. It was found that neopterin can be detected early after injecting SCID mice with PBMC, whereas injection of purified human T or B cells did not result in neopterin production. Highest neopterin levels were detected in mice treated with LCL cells when developing lymphoma. We discuss the possible sources of neopterin along this process and its usefulness in this model.     

Down-regulatory effect of N-chlorotaurine on tryptophan degradation and neopterin production in human PBMC

N-Chlorotaurine (NCT) plays an important role in the human defense system as a main component of long-lived oxidants, and shows bactericidal, fungicidal, and virucidal activity. Besides this role, NCT seems to act regulatory on immunocompetent cells by altering cytokine production. NCT inhibited nitric oxide, TNF-alpha, and prostaglandin E(2) (PGE(2)) production in activated rodent macrophages, and suppressed superoxide anion, IL-6, and IL-8 formation in human polymorphonuclear leukocytes. In this study, the influence of NCT on the production of neopterin and the activation of the enzyme indoleamine-2,3 dioxygenase (IDO) was investigated in human peripheral blood mononuclear cells (PBMC). Both events are well established to be triggered by IFN-gamma and therefore related to Th1-type immune activation. Mitogen-induced neopterin production as well as tryptophan degradation were drastically reduced upon addition of NCT. Results fit in the concept of a reduction of pro-inflammatory cytokines by this compound. In contrast to earlier results, where NCT was suggested to act primarily down-regulatory on Th2 cells, we propose also a strong suppressive effect of NCT on Th1-type immunity.     

Neopterin im Serum und Urin zur Differentialdiagnose von Nierenfunktionsstörungen nach Nierentransplantation

Summary In a period of 10 months neopterin in serum and urine was determined by radioimmunoassay in 33 renal allograft recipients treated with cyclosporin A. While in allograft rejections the highest neopterin concentrations were found in the serum, patients with viral infections after renal transplantation showed the most elevated concentrations in the urine. For early diagnosis of allograft rejection the ratio of neopterin clearance and serum-neopterin was the most significant criterion of the parameters measured in this study. Patients without complications during the follow-up showed slightly elevated and stable neopterin levels in serum and urine. The presented results indicate that neopterin is a useful parameter for the follow-up after renal allograft transplantation and for the diagnosis of immunological complications.

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Abkürzungen CyA Cyclosporin A - Kr-Cl Kreatinin-Clearance - NPT-Cl Neopterin-Clearance - sKr Kreatinin im Serum - sNPT Neopterin im Serum - uNPT Neopterin im Urin     

Enhanced tryptophan degradation in systemic lupus erythematosus

In vitro and in vivo, tryptophan degradation was found to be associated with T cell functional loss and tolerance induction. In systemic lupus erythematosus (SLE) besides the Th2-type cytokine interleukin-10, Th1-type cytokines including interferon-gamma (IFN-gamma) are expressed especially during exacerbation of the disease. IFN-gamma stimulates the enzyme indoleamine (2,3)-dioxygenase (IDO) converting tryptophan to the metabolite kynurenine which in macrophages is subsequently degraded to other, partly neurotoxic compounds like quinolinic acid, and finally to nicrotinamides. We measured kynurenine and tryptophan concentrations in the sera of 55 SLE patients. In these patients, the concentrations of tryptophan (median, interquartile range: 53.9, 45.7-64.1 microM) were lower (p < 0.0001), and the kynurenine concentrations (2.45, 1.75-3.40 microM) were increased (p < 0.0005) compared to healthy blood donors (70.0, 63.8-80.6; 1.80, 1.45-2.27 microM, respectively). Also the kynurenine per tryptophan quotients (K/T), which allow to estimate IDO activity, were significantly higher in patients than in normals (0.043, 0.033-0.062 vs. 0.027, 0.021-0.030; p < 0.0001), indicating enhanced IDO-induced tryptophan degradation in SLE. There was no significant relationship between tryptophan, kynurenine and the SLEDAI, and also the correlation of K/T with SLEDAI was rather weak (rs = 0.243, p < 0.05). Higher K/T was found in patients presenting with serositis (p = 0.01), decrease of complement (c3, c4; p < 0.01) and blood count change (anemia, leucopenia, lymphopenia; p = 0.032) than in patients without such disease manifestations. The significant correlation found between K/T and neopterin (rs = 0.808, p < 0.001), a marker of immune activation, points to a role of immune activation to be responsible for tryptophan degradation in SLE patients.     

Circulating cytokines and CD30 in normal human pregnancy and recurrent spontaneous abortions

Concentrations of the T-helper (Th) 1 cytokines interleukin (IL)-2, tumour necrosis factor (TNF) -alpha, TNF-beta and interferon-gamma, Th2 cytokines IL-4, IL-5, IL-6, IL-10 as well as those of soluble CD30 in sera have been examined during the three trimesters of gestation, at delivery in normal pregnancy, and at the time of spontaneous abortion in women with a history of unexplained recurrent spontaneous abortion (RSA). Significantly higher concentrations of the Th2 cytokines IL-6 and IL-10 were found at normal delivery than in women with RSA, and conversely significantly increased concentrations of the Th1-type cytokine TNF-alpha were found in RSA as compared with successful pregnancy. In abortion-prone women who had a successful pregnancy, significantly higher concentrations of IL-6 and significantly lower concentrations of TNF-alpha were found as compared with abortion-prone women who had another abortion, supporting the notion that Th2- and Th1-bias are associated with successful and unsuccessful pregnancy respectively. Serum CD30 concentrations did not correlate with the outcome of pregnancy. These findings support observations drawn from experiments on the cytokine secretion profiles of peripheral blood mononuclear cells and decidual lymphocytes which suggest that normal pregnancy is Th2-biased and that unexplained RSA is associated with Th1-type reactivity.     

The Changes in the T helper 1 (Th1) and T helper 2 (Th2) Cytokine Balance During HIV-1 Infection are Indicative of an Allergic Response to Viral Proteins that may be Reversed by Th2 Cytokine Inhibitors and Immune Response Modifiers – a Review and Hypothesis

The HIV-1 infection in humans induces an early cellular immune response to react to the viral proteins with a cytotoxic T cell (CTL) response that fails to inhibit virus replication and the spread of the virus. It became evident that the progression of the disease causes chronic changes to the immune system of which a gradual increase in IgE antibodies is one of its features. When the HIV-1 epidemic began, the relation between the gradual increase in IgE content and AIDS was not understood, but later it became a marker for disease prognosis. The advances in the knowledge on T helper 1 (Th1) and T helper 2 (Th2) cells revealed that Th1 cells produce cytokines that stimulate the proliferation of CTLs. Th2 cells produce cytokines that are responsible for the activation of the humoral immune response in healthy people. Studies on both Th1 and Th2 cytokine synthesis revealed an aberration in HIV-1 infected people. Clerici and Shearer presented a hypothesis (1993) whereby Th1 cell activity declines and Th2 activity increases (the Th1 --> Th2 switch hypothesis) in HIV-1 infected people. In fact, experiments concerning this hypothesis ultimately supported the premise that the switch involves a critical change in the cytokine balance, which leads to the contraction of AIDS. However, the research community must still discern why such a Th1 --> Th2 switch takes place in infected people and how it can be reversed. The present review points to the fact that a similar Th1 --> Th2 switch constitutes the response of allergic people to environmental allergens. HIV-1 patients and allergic people that are exposed to allergens respond with an increased synthesis of Th2 cytokines and IgE, together with a decrease in Th1 cytokines. The studies on allergen-induced Th2 cells revealed that the Th2 cytokine IL-4 induces B cells to synthesize IgE, and cytokine IL-5 is the inducer of eosinophilia, just as in HIV-1 infection. The difference between the HIV-1 infection and allergies is the ability of IL-4 to induce the synthesis in T cells of the HIV-1 coreceptor CXCR4 that selects from the replicating virus a syncytium-inducing (SI) virus, a variant virus that replicates rapidly. The present hypothesis implicates the viral proteins in the induction of Th2 cytokine synthesis. This suggests that in viral proteins, allergen-like domains may be responsible for the activation of Th2 cytokine synthesis. Based on the analogy of the responses of humans to allergens and HIV-1, the following hypotheses is suggested: (a) Removal of allergen-like domains from viral genes by genetic engineering may provide viral proteins for vaccine development. (b) Attempts to treat allergic patients with IL-4 receptor inhibitors suggests that the "Th2 --> Th1 Reversion" constitutes a possible approach to inhibiting the Th2 cytokines and inducing a revival of the anti-viral Th1 response.