Evolution of viruses and their impact on human life: HIV-1 subgroup M.

The history of mankind over many millennia has been marred by many epidemics caused by viruses which infect the human respiratory system and alimentary tract. The current HIV-1/AIDS pandemic, however, is caused by one virus mutant, HIV-1M, which has evolved to infect humans through the genitals. The virus is able to use the innate system cells of the infected individual to inactivate the adaptive immune system, causing AIDS. The mechanisms used by HIV-1M to inhibit the immune system are presented. Understanding the viral mechanisms is leading to novel antiviral treatments and an approach to an HIV-1 vaccine.

HIV-1 gp41 heptad repeat 2 (HR2) possesses an amino acid domain that resembles the allergen domain in Aspergillus fumigatus Asp f1 protein: review, hypothesis and implications.

Enfuvirtide (ENF, T-20, Fuzeon) is the first synthetic peptide to be modeled according to the amino acid sequence of HIV-1 heptad repeat 2, which was used to treat cohorts of HIV-1-infected individuals who had failed to respond to treatment with the anti-HIV-1 cocktail HAART. It was reported that when injected subcutaneously, Enfuvirtide reduced viral RNA in patients' blood by 1.96 log(10), leading to a subsequent increase in the number of CD4(+) T cells in the blood. The drug treatment caused adverse effects at the injection site in a small number of treated individuals, and a gradual increase in IgE in the blood during prolonged treatment. Enfuvirtide was approved for treatment of HIV-1 patients who developed resistance to HAART. The present review attempts to explain the adverse effects of Enfuvirtide at the skin site of injection, and the gradual increase in IgE in patients' blood during treatment. These phenomena were reported to resemble the effect of allergens that cause asthma in humans. It is hypothesized that since the amino acid domain of the Asp f1 allergen from Aspergillus fumigatus was identified in the N-terminus of an 18 kDa protein, it may be useful to compare Asp f1 peptide aa 7-22 from the beta-hairpin sequence to the beta-hairpin sequence of the heptad repeat 2 of HIV-1 gp41. The comparison revealed that the amino acid sequence resembles part of the Asp f1 aa 7-22 allergenic domain. The heptad repeat 1 of gp41 also resembles the fungal allergen. It is suggested that the Enfuvirtide peptide be tested experimentally to determine if ENF peptide is capable of binding to IgE antibodies from Enfuvirtide-treated, HIV-1-infected patients, and whether the HR2-derived peptide is capable of inducing basophils that were isolated from healthy individuals and from ENF-treated and untreated HIV-1 patients to release histamine and IL-4.

The spreading of HIV-1 infection in the human organism is caused by fractalkine trafficking of the infected lymphocytes--a review, hypothesis and implications for treatment.

The reviews on HIV-1/AIDS [1-8] highlighted the mechanism by which HIV-1 virions utilize dendritic cells (DCs) for transport from the genitals, the portal of virus infection, to the draining lymph nodes where DCs carry HIV-1 virions and present viral antigens by HLA class I and II to CD4(+) T cells. Interaction of the T cells with viral antigens presented by HLA class II molecules polarizes them to become Th2 cells, the targets of HIV-1 infection and producers of HIV-1 progeny virions. The T cells which interact with viral antigen presented by HLA class I polarize to become Th1 cells, which stimulate the CD8(+) T cell precursors to develop into antiviral cytotoxic T cells. In addition, HIV-1 virions shed gp120 glycoprotein molecules which bind to IgE immunoglobulin molecules bound to FCepsilonRI+ innate system cells (basophils, mast cells and monocytes) and induce them to release large amounts of Th2 cytokines (IL-4, IL-5, IL-10, IL-13), thereby creating an allergy-like condition. The present review attempts to define the role of chemokine receptors like CCR5 and CXCR4, and especially fractalkine receptor CX3CR1 in the trafficking of lymphocytes in healthy individuals and HIV-1/AIDS patients. The role of chemokine receptors as co-receptors for HIV-1 virion gp120 glycoprotein has been defined, but the role of fractalkine and fractalkine receptor has been clarified only recently [9-19]. In healthy individuals fractalkine is expressed by blood vessel endothelial cells and the CX3CR1 receptors are expressed on leukocytes that migrate in the peripheral blood in the direction of increased fractalkine concentration. In HIV-1/AIDS patients the virus-infected CD4(+) Th2 cells migrate to organs that harbor the adaptive immune system cells in the thymus, genitals, gastrointestinal tract, and to the brain. A most significant finding which revealed the importance of the human CX3CR1 gene expression to the progression of the infection to the stage of AIDS was recently reported by Faure and collaborators [20, 21] who showed that the delayed or rapid progression to AIDS was affected in HIV-1-infected individuals who had inherited a fractalkine receptor gene with the polymorphisms V249I or T280M, respectively, located in the sixth and seventh transmembrane domains of CX3CR1 protein. The T280M mutation in the CX3CR1 gene caused a rapid progression to AIDS, while in patients with the V249I mutation progression to AIDS was much slower. These studies led to the idea that it might be possible to slow or prevent HIV-1/AIDS progression in HIV-1 patients by treating them with fractalkine antagonists that will bind to and inhibit the activity of the fractalkine receptor. It is hypothesized that treatment of HIV-1/AIDS patients with a combination of fractalkine antagonists, IL-4 antagonist IL-4delta2 and the adjuvant CpG ODN induced release of type I IFN from PDF, and may inhibit HIV-1 infection, especially in HAART-treated patients infected with drug-resistant HIV-1 mutants due to prevention of the availability of immune cells needed for the viral evasion of the immune response. The hypothesis implies that the advantage of the suggested mode of treatment of HIV-1-infected people is prevention of cellular processes that are used by the viral protein to cause immunodeficiency, and prevention of HIV-1 replication without induction of resistant mutants.

Respiratory syncytial virus (RSV) evades the human adaptive immune system by skewing the Th1/Th2 cytokine balance toward increased levels of Th2 cytokines and IgE, markers of allergy--a review.

Infection of infants in their first year of life, children and elderly people with the respiratory syncytial virus (RSV) endangers the life of the patient. An attempt to develop a formalin-inactivated RSV (FI-RSV) vaccine during the 1960s resulted in an aggravated infection in immunized children, leading to hospitalization, while infection of non-immunized children produced much milder symptoms. The reason for this remained an enigma, one which was gradually solved over the last decade by many researchers who studied the molecular biology of RSV infection of respiratory ciliary cells. Clinical studies of RSV-infected patients indicated increased levels of Th2 cytokines and IgE in the patients' sera, suggesting that an allergy-like condition developed during infection. The biomarkers of allergy caused by endogenous or environmental allergens include a marked increase of the Th2 cytokine IL-4 and IgE non-neutralizing antibodies to the allergen. The way allergens trigger allergy was deciphered recently, and will be discussed later. Studies of RSV infection led to the suggestion that RSV patients suffer from allergy prior to RSV infection, a concept that was later abandoned. Studies on HIV-1 [Y. Becker, Virus Genes 28, 319-331 (2005)] research led me to the hypothesis that since HIV-1 infection induces a marked increase of IL-4 and IgE in serum, an allergy-like condition, the AIDS stage is the result of an allergen motif that is embedded in the shed viral gp120 molecules. It is hypothesized that the viral-soluble G glycoprotein (sG) contains a T cell superantigen (Tsag) that is capable of binding to the V(H)3 domain of IgE/FcepsilonRI(+) hematopoietic cells, basophils, mast cells and monocytes, similar to the case of allergens, and that this aggregation causes these innate system cells to degranulate and release large amounts of Th2 cytokines (IL-4, IL-5, IL-10, IL-13) into the blood. The way these Th2 cytokines skew the Th1/Th2 balance toward Th2 > Th1 will be discussed. The aim of the present review is to base RSV pathogenicity on the numerous very good analyses of the virus genes and to suggest a therapeutic approach to treatment that is directed at preventing the inhibitory effects of Th2 cytokines on the adaptive immune system of the patients, instead of inhibiting RSV replication by antivirals. The review of the molecular research on the role of the viral fusion (F) and attachment (G) glycoproteins of RSV provided information on their role in the virus infection: early in infection the F glycoprotein induces Th1 cells to release the Th1 cytokines IL-2, IL-12 and IFN-gamma to activate precursors CTLs (pCTLs) to become anti-RSV CTLs. The G and sG glycoproteins attach to FKNR1(+) ciliary respiratory epithelial cells as well as directly to eosinophils to the lungs. The sG T cell antigen can also induce the release of large amounts of Th2 cytokines from CD4(+) T cells and from FCepsilonRI(+) mast cells, basophils and monocytes. By comparison to HIV-1 gp120 it is possible to show that in the G and sG proteins the T cell antigen resembles the CD4(+) T cell superantigen (=allergen) domain of HIV-1 gp120 which aggregates with IgE/FCepsilonRI(+) hematopoietic cells. The increased IL-4 level in the serum inhibits the adaptive immune response: IL-4Ralpha(+) Th1 cells stop Th1 cytokine synthesis and IL-4Ralpha(+) B cells stop the synthesis of antiviral IgG and IgA and switch to IgE synthesis. In addition, the hematopoietic cells release histamine and prostaglandin which induce wheezing. The gradual increase of sG molecules creates a gradient of fractalkine (FKN) which directs IL-5-activated eosinophils to the lungs of the patient.

Respiratory syncytial virus(RSV)-induced allergy may be controlled by IL-4 and CX3C fractalkine antagonists and CpG ODN as adjuvant: hypothesis and implications for treatment.

Based on the hypothesis that respiratory syncytial virus (RSV) sG protein causes allergy in patients, it is suggested that treatment of RSV patients with antagonists of IL-4 and FKN early in infection will prevent the increased level of IL-4 in the serum. Together with CpG ODNs that induce Toll-like receptor 9(+) (TLR9(+)) plasmacytoid dendritic cells to release type I IFN-alpha and -beta will reactivate the inhibited Th1 cells and the antiviral cytotoxic T leukocytes. In addition, binding of CpG ODNs to TLR9(+) B cells will stop IgE synthesis and antiviral IgG and IgA will continue. Together, the IL-4 and FKN antagonists and CpG ODNs reactivate the adaptive immune response to clear the virus and protect the patient from a second RSV infection. It is also suggested that the less-pathogenic RSV strain Long may be a candidate for vaccine development after deletion of the FKN and superantigen domains from the G gene.

Molecular immunological approaches to biotherapy of human cancers--a review, hypothesis and implications.

The immune system of the human organism comprises the innate system cells and the adaptive immune cells. The former include the hematopoietic cells, mast cells, basophils, monocytes, dendritic cells (DCs) and macrophages, and the latter include CD4+ T cells, CD8+ T cells, T regulatory cells (Tr) and B cells. The innate system DCs are the major antigen-presenting cells to Th(o) CD4+ T cells in lymph nodes that polarize into T helper 1 (Th1) and T helper 2 (Th2) cells, which subsequently produce different cytokines. Polarized Th1 cells produce interleukin (IL)-2, IL-12 and interferon (IFN)-gamma, and polarized Th2 cells and the hematopoietic cells produce IL-4, IL-5, IL-6, IL-10 and IL-13. In healthy individuals there is a Th1/Th2 cytokine balance, but during microbial-induced inflammation the pathogens induce an overproduction of the Th2 cytokines that inhibit the adaptive immune response against the pathogen. A review of studies on the Th1/Th2 cytokine balance in humans harboring different tumor types revealed that tumor cells induce increased Th2 cytokine levels in patients' sera that can serve as indicators for the existence of tumors. In this review, studies which correlated the presence of increased Th2 cytokines with the presence of early tumors and tumor progression are discussed. It was suggested that early monitoring of human populations for elevated Th2 cytokines may be used to identify individuals at an early stage of tumor development. A hypothesis is presented which suggests that increased Th2 cytokine synthesis in cancer patients, with early and late tumors, may be treated with Th2 cytokine antagonists. This new approach to cancer treatment will be supplemented by co-treatment with CpG oligodeoxynucleotides(ODNs) which reactivate the adaptive antitumor immune response. Studies that provide information on the efficiency of CpG ODN treatment of tumors in mice revealed that tumor regression was achieved by inducing Toll-like receptor 9+ plasmacytoid dendritic cells (PDCs) to release large amounts of type I interferons (IFN alpha and beta), which inhibit Th2 cytokine synthesis by hematopoietic cells and CD4+ T cells and enhance Th1 cytokine synthesis and activation of the adaptive immunity. It is hypothesized that Th2 cytokine (IL-4 and IL-6) antagonists may be an effective treatment for cancer patients since cytokine antagonists inhibit the increased Th2 cytokines in patients. Such an approach may replace Th2 cytokine monoclonal antibodies, the current treatment for cancer patients. It is hypothesized that the effective treatment of cancer patients with Th2 cytokine antagonists, combined with CpG ODNs, will lead to the inhibition of Th2 cytokines and reacTivation of the Th1-induced antitumor adaptive immunity that will destroy tumor cells and cure cancer patients.

The molecular mechanism of human resistance to HIV-1 infection in persistently infected individuals--a review, hypothesis and implications.

Resistance to HIV-1 infection in Europeans is associated with a mutation in the gene that codes for the CCR5 protein that is present in Th2 cells and serves as a coreceptor for HIV-1 R5 strain. A deletion of 32 amino acids from the cytokine receptor prevents infection. This mutation prevails in Europeans and is absent in Africans. However, duplication of a gene that codes for a chemokine that binds to the CCR5 was discovered in Africans (mean gene copy 6 while in non-Africans the mean gene copy is 3). Higher expression of these genes protects T cells against HIV-1 infection in vitro. It should be noted that resistance to HIV-1 R5 variant does not protect against HIV-1 R4 variant. It was reported that a minority of highly HIV-1 exposed African professional sex workers (APSW) were resistant to the virus infection during a 10 years period. Recently, the analysis of the cytokines in the serum of the persistently infected seronegative women revealed that the latter hypo-expresses the cytokine IL-4. Since the molecular events during HIV-1 infection are associated with a marked increase in the levels of IL-4 and IgE in the sera of the infected individuals, it suggests that AIDS is an allergy. Thus, a very low level of IL-4 production may abrogate the virus infection. Studies on the human IL-4 gene revealed that together with the IL-4 mRNA a spliced variant with a deletion of exon 2 is synthesized. The latter is a natural antagonist of IL-4 and when expressed in an individual at a level higher than IL-4, the person will resist a microbial infection (e.g. Mycobacterium tuberculosis) or asthma. The present hypothesis suggests that the HIV-1 resistant APSWs produce more IL-4 delta 2 molecules than IL-4 molecules. The binding of IL-4 delta 2 to IL-4 receptors on T and B cells prevents their functions and the infection by HIV-1. The implications of these studies are that treatment of HIV-1 infected people with drugs that will block the IL-4 receptors will stop HIV-1 infections and the determination of the levels of IL-4 and IL-4 delta 2 in the sera of HIV-1+ patients will enable to identify the individuals that have a natural resistance to HIV-l/AIDS and those who need treatments.

A point of view: HIV-1/AIDS is an allergy but CpG ODN treatments may inhibit virus replication and reactivate the adaptive immunity--hypothesis and implications.

Reevaluation of the increase in the levels of IgE and IL-4 in sera of HIV-1 infected and AIDS patients led to the suggestion that AIDS resembles allergy. Studies on the properties of the viral shed gp120 revealed that it resemble environmental allergens in their ability to induce hematopoietic cells to release large amounts of Th2 cytokines, inhibitors of the patients adaptive immune response. Yet, induction of TLR9+ plasmacytoid DCs by CpG ODNs cause the release of type I interferons, inhibitors of HIV-1 replication and IL-4 release from hematopoietic cells. CpG ODN binding to TLR+ B cells inhibits IgE synthesis and reactivates the failing adaptive immunity. The possible use of CpG ODNs as treatment to patients is discussed.

CpG ODNs treatments of HIV-1 infected patients may cause the decline of transmission in high risk populations - a review, hypothesis and implications.

The Joint United Nations Program on HIV-1/AIDS (UNAIDS) announced its goal to stop HIV-1 transmission by antiviral (HAART) treatment of patients since at the end of 2003 the number of people living with HIV-1 was 38 million, 25 million in the sub-Saharan region of Africa. The present review deals with a new approach to simultaneously treat HIV-1/AIDS patients in HIV-1 endemic regions with CpG oligodeoxynucleotides (ODNs) and people at high risk of infection with a vaccine containing CpG ODNs combined with synthetic HIV-1 peptides by intranasal and intradermal applications. During HIV-1 infection a gradual increase in the levels of IL-4 and IgE in the patients' serum, was reported. It was suggested that such an increase of the cytokine IL-4 and the IgE immunoglobulin are interconnected and may serve as indicators for the coming stage of AIDS. It was also suggested that the IL-4 and IgE increase in the serum of HIV-1 infected people resemble the increase of IL-4 and IgE levels in allergic patients that were exposed to endogenous or environmental allergens [Becker, Virus Genes 28, 5--18, 2004]. Indeed, it was reported that the HIV-1 virions' shed gp120 molecules, which contain a superantigen (superallergen) domain that enables the viral glycoprotein to bind the V(H)3 domain of IgE molecules that are bound to FcepsilonRI+ hematopoietic cells [basophils, mast cells, dendritic cells (DCs) and plasmacytoid DCs (pDCs)]. Such interaction was reported to induce the hematopoietic cells to release large amounts of Th2 cytokines IL-4, IL-5, IL-10 and IL-13. These findings led to the hypothesis [Op. cit.] that the cure of HIV-1/AIDS patients requires the induction of endogenous synthesis of type I interferons (INF alpha and beta) with a bacterial CpG rich DNA that will induce the patients' pDCs to release large amounts of type I IFNs. Under these conditions HIV-1 replication in polarized to Th2 cells is inhibited. Type I IFNs reactivate the patients' inhibited Th1 cells to synthesize IL-2 and IL-12 cytokines that activate the maturation of CTL precursors. The unmethylated bacterial DNA activates B synthesis to switch to IgG and IgA synthesis. The novel drug CpG ODNs is being tested for the prevention and the treatment of allergic humans and in the experimental system of allergic mice. It was also reported that treatment of mice with CpG ODN prior to or after retrovirus infections protected and cured, respectively, the retrovirus infection. It was also reported that CpG ODNs treatments of mice exposed to allergen protected them against the development of the allergic response. Phase I treatment of healthy people with CpG ODNs provided information on the safety of these compounds. The CpG ODNs A and B bind to Toll like receptors that are present in pDCs and B cells, respectively, CpG ODN - A is the ligand for TLR9+ pDCs and induce the release of large amounts of IFN-alpha, beta. CpG ODN-B is the ligand for TLR9+ in B cells and induce the synthesis of IgG and IgA. CpG ODN-C contains motifs from CpG ODNs A and B and is more active. The present review is based on findings from studies that reported that CpG ODNs treatment of retrovirus infected mice, monkeys and allergic mice prevented the virus and allergens caused diseases, respectively. Based on these studies, a hypothesis is presented that treatment of HIV-1 infected and AIDS patients with CpG ODN-A and B or CpG ODN-C have the potential to inhibit IL-4 synthesis and release from FcrepsilonRI+ hematopoietic cells by inducing TLR9+ pDCs to release large amounts of type I IFNs. TLR9+ B cells are induced by CpG ODN-B to switch from IgE to IgG, IgA synthesis. In addition, type I IFNs (alpha, beta) have the capacity to inhibit HIV-1 replication in polarized Th2 cells. Type I IFNs reactivate the patients' Th1 cells to synthesize IL-2 and IL-12 cytokines, activators of the precursor cytotoxic T cells (CTLs), leading to the reactivation of the inhibited adaptive immune response. Antiviral CTLs have the ability to clear the virus infection. The present novel approach to the treatment and of HIV-1/AIDS patients with CpG ODNs may prevent HIV-1 transmission and the AIDS pandemic if controlled studies on the treatments with CpG ODNs of HIV-1 infected people will be done by international and private agencies and companies to define the effective treatment regime and the efficacy of the treatments to HIV-1 infected people at different times post-infection. It is also hypothesized that in order to stop HIV-1 transmission in HIV-1 endemic regions the people at high risk of HIV-1 infection should be treated at the same time as HIV-1 infected people with a vaccine containing synthetic CpG-ODNs combined with synthetic HIV-1 peptides, compatible with the major HLA haplotypes of the regional population. The vaccine may be self-applied by people at high risk of infection by the intra-nasal route and by intra-dermal application as a "peplotion vaccine". The stimulation of the antiviral CTL response by HIV-1 infected people and the active antiviral immune response in the vaccinated population may lead to a decline in HIV-1 transmission and may be a model for control of the HIV-1/AIDS pandemic.

Low level laser irradiation stimulates mitochondrial membrane potential and disperses subnuclear promyelocytic leukemia protein.

BACKGROUND AND OBJECTIVES: Low level laser irradiation (LLLI) is used to promote wound healing. Molecularly it is known to stimulate mitochondrial membrane potential (MMP), cytokine secretion, and cell proliferation. This study was designed to determine the influence of LLLI on the kinetics of MMP stimulation and decay, specific cytokine gene expression, and subcellular localization of promyelocytic leukemia (PML) protein on HaCaT human keratinocytes. STUDY DESIGN/MATERIAL AND METHODS: The cells were irradiated by a 780 nm titanium-sapphire (Ti-Sa) laser with 2 J/cm(2) energy density. MMP was monitored with Mitotracker, a mitochondrial voltage-sensitive fluorescent dye. Cytokine gene expression was carried out using semi-quantitative-reverse transcription polymerase chain reaction. Subcellular localization of PML protein, a cell-cycle checkpoint protein, was determined using immunofluorescent staining. RESULTS: The fluorescence intensity of MMP was increased immediately after the end of LLLI by 148 +/- 6% over control (P<0.001). Subsequently it decayed, reaching 51 +/- 14% of the control level (P < 0.01) within 200 minutes. This decay was characterized by an exponential curve (R = 0.96) with a lifetime of 79 +/- 36 minutes (P < 0.05). Following irradiation, the expression of interleukin-1alpha, interleukin-6, and keratinocyte growth factor (KGF) genes were transiently upregulated; but the expression of the proinflammatory gene interleukin-1beta, was suppressed. The subnuclear distribution of PML was altered from discrete domains to its dispersed form within less than 1 hour after LLLI. CONCLUSIONS: These changes reflect a biostimulative boost that causes a shift of the cell from a quiescent to an activated stage in the cell cycle heralding proliferation and suppression of inflammation. Further characterization of MMP kinetics may provide a quantitative basis for assessment of the effect of LLLI in the clinical setting.

HIV-1 induced AIDS is an allergy and the allergen is the Shed gp120--a review, hypothesis, and implications.

The possibility that the induction of T helper 2 (Th2) cytokine synthesis and the gradual increase in interleukin 4 (IL-4) and IgE levels during HIV-1 infection are an allergic response to HIV-1 proteins was raised in the author's previous article [Becker, Virus Genes 28, 1-4, 2004]. The present review extends this hypothesis by citing experimental reports which indicate that HIV-1 shed gp120 virions share a striking resemblance with the allergens that bind to IgE molecules bound to Fc epsilon receptor I-positive (Fc epsilon RI) cells (mast cells, basophils, monocytes, and dendritic cells, DC) and then induce them to release and synthesize the IL-4 cytokine. In the earlier review, it was established that the IL-4 cytokine is responsible for the following processes: IgE synthesis by B cells and the inhibition of antiviral IgG synthesis; the inactivation of T helper 1 (Th1) cells; and the inhibition of the antiviral cytotoxic T cell (CTL) response. The binding of the shed gp120 to B cell-bound immunoglobulin (Ig) depletes these cells. Moreover, it was reported that the viral regulatory proteins Tat and Vpr also stimulate IL-4 release from basophils. The mode of action used by HIV-1 gp120 in the induction of IL-4 [Becker, Virus Genes 28, 1-14, 2004] revealed that the viral protein contains a superantigen (SAg) domain that is capable of binding to the V(H)3 domain of IgE and Ig; namely, the shed gp120 protein act as endogenous and environmental allergens that bind to IgE molecules, which are bound to the Fc epsilon RI receptors on hematopoietic cells. Based on these findings, it is hypothesized that gp120 is an allergen. Consequently, it can be inferred that the active replication of HIV-1 in infected individuals constantly exposes the immune system to an increase in the allergen content until the host immunity is eventually compromised. These finding suggest that HIV-1 engage in a two-pronged attack of the human immune system: it infects Th2 cells, macrophages, and DCs and then replicates at these venues; and the shed gp120 cells cause an allergy. This allergic condition consequently prevents the induction of Th1 cells, cytokine synthesis, and antiviral CTLs that are needed to clear the infecting virus and thus devitalizes the antivirals that are used to treat the virus infection. It was hypothesized [Becker, Virus Genus 28, 1-14, 2004] that the HIV-1 induced allergy can be treated with IL-4 inhibitors or immune response modifiers. A treatment that employs both antivirals and anti-allergen drugs may very well defeat the AIDS syndrome. Another implication of the present hypothesis is the need to improve the viral antigen used for vaccinating healthy individuals against HIV-1 infection. It is thus suggested harmful domains be eliminated from the gp120.

Immunization with a nonpathogenic HSV-1 strain prevents clinical and neuroendocrine changes of experimental HSV-1 encephalitis.

We examined whether immunization with the nonpathogenic strain R-15 of herpes simplex virus-1 (HSV-1) may prevent the clinical and neuroendocrine changes induced by the pathogenic HSV-1 strain Syn17+. Inoculation of strain Syn17+ to control rats induced fever, marked motor hyperactivity and aggressive behavior, and increased serum ACTH, corticosterone (CS) and brain prostaglandin-E2 production. Mortality was 100%. Immunization with strain R-15 prior to challenge with Syn17+ induced the production of neutralizing antibodies to HSV-1 Syn17+, and abolished the above clinical and neuroendocrine changes. Mortality was completely prevented. These results indicate that immunization with HSV-1 strain R-15 protects rats from lethal HSV-1 encephalitis and prevents its clinical and neurochemical manifestations.

HIV-1 gp120 binding to dendritic cell receptors mobilize the virus to the lymph nodes, but the induced IL-4 synthesis by FcepsilonRI+ hematopoietic cells damages the adaptive immunity--a review, hypothesis, and implications.

HIV-1 is equipped with the envelope gp160 glycoprotein for interaction with Langerhans cells (LCs) and dendritic cells (DCs), the members of the innate immune system, which confront the virus at the portal of virus entry in the human body. These cells are equipped with receptors by which they bind and endocytose the virus. The gp120 glycoprotein is used for binding to CD4 receptor and CCR5 co-receptor of T helper 2 (Th2) cells and the virions shed gp120 is able to induce FcepsilonRI+ hematopoietic cells to produce IL-4, which inactivate the host adaptive immune response. The properties of gp120s various functional domains are analyzed together with the regulatory viral proteins, which are involved in the damage to T and B cells during HIV-1 replication. The interaction of HIV-1 virions through their gp120 with LCs and DCs at the portal of virus entry will be discussed. A hypothesis will be presented that the understanding of the role of the different functional domains of gp120 in the life cycle of the virus and during AIDS will help in the design of approaches to prevent and abrogate HIV-1 infection and AIDS.

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.

Vaccinia virus pathogenicity in atopic dermatitis is caused by allergen-induced immune response that prevents the antiviral cellular and humoral immunity.

Atopic dermatitis (AD) serves as a contraindication for the immunization of AD patients with a live vaccinia virus (VV) vaccine. The antiallergen IgE interacts with the Fc receptors (FcepsilonRI) on dendritic cell (DC) membranes and with allergen molecules. The immunological events that lead to AD disease, the activation of the T-helper 2 (Th2) immune response, the synthesis of the cytokines IL-4, IL-5, IL-13, and the inhibition of the T-helper 1 (Th1) damage the capacity of the host to develop anti-VV cytotoxic cells (CTLs). In the presence of Th2-derived cytokine IL-4 in the AD skin and the synthesis of VV proteins that interfere recruitment of DCs by host cytokines, the VV can cause a generalized infection. Conceptually, new VV recombinants may be needed for human immunization. Such VV recombinants should lack the genes that interfere with the host immune system and express a mutated human IL-4 cytokine gene that will prevent negative regulatory mechanisms. Such improved VV recombinants may be used to express genes from pathogenic viruses.

Immunological and regulatory functions of uninfected and virus infected immature and mature subtypes of dendritic cells--a review.

In 1868, dendritic cells (DCs) were discovered in human skin by Paul Langerhans using gold staining. These cells were named Langerhans cells (LCs) after their discoverer who, due to their dendrites, regarded them as neurons. One hundred and eleven years were to pass until it was discovered that in vertebrates these cells originate in the bone marrow as monocytes. In the 1980s, DC research was mostly carried out on DCs that are present in different tissues of mice and humans. These studies revealed that after interaction with foreign antigens, skin LCs/DCs migrate through the lymph vessels to the draining lymph nodes and induce the two arms of the immune response. The isolation of DCs from tissue cell suspensions opened the way to studies on the cells' surface proteins and their ability to stimulate immune responses. During the 1990s, studies revealed the role of DCs in the activation of naive T cells in the lymph nodes and the regulatory properties of DCs in lymph nodes, thymus, gut, and spleen. Part A of the review deals with the DC system of human and mice and immunological and regulatory functions of subsets of DCs in the skin with reference to migrating and stationary DCs, as well as the connection between DCs and the nervous system. Furthermore, the origin of both follicular DCs that are present in lymphoid tissues and thymic DCs are discussed. Part B is devoted to virus infections of DCs with an emphasis on infections caused by human herpes viruses. Part C presents the modulation of DC gene expression in response to the influenza virus. Contemporary research focuses on the role of DCs in the immune systems of vertebrates. Moreover, studies are being conducted on the regulatory functions of DCs by tissue cells in different organs of vertebrates.

Milestones in the research on skin epidermal Langerhans/dendritic cells (LCs/DCs) from the discovery of Paul Langerhans 1868-1989.

Almost 100 years elapsed after the discovery of dendritic cells in the human skin epithelium by Paul Langerhans in 1868 until the initiation of research on those cells was reinitiated. The present paper provides the milestones in the research on Langerhans/dendritic cells (LCs/DCs) between 1960 and 1989. This historical review will explain how researchers gradually discovered the role of the bone marrow-derived dendritic cells in the immune response. The paper is an appendix to the manuscript entitled: "Immunological and regulatory functions of uninfected and infected immature and mature subtypes of dendritic cells" (Virus Genes 26: 119-130, 2003).

Herpes simplex virus evolved to use the human defense mechanisms to establish a lifelong infection in neurons--a review and hypothesis.

The review of recent studies using DNA microarrays shed new light on herpes simplex virus (HSV) replicative cycle, the response of immature dendritic cells (DCs) to pathogens and the response of neurons in trigeminal ganglia to virus reactivation. These studies provided a better understanding of the molecular biology of HSV during infection, latency and reactivation. The research on the sensory trigeminal neurons and the neuronal axons (type C fibers) that transverse the skin basal membrane, enter the skin epidermis and interact with the cell membrane of the skin resident immature DCs provided an insight on the connection between the nervous system and the host immune system. Based on these studies a hypothesis is presented suggesting that HSV evolved to use the human host defense systems (pain signals, the immune system cells and sensory neurons) to ensure its entry from the skin epithelium into the sensory neurons. Reactivated HSV in the neurons utilizes the same host defense systems to return to the skin epithelium.

Evolution of viruses by acquisition of genes that control nuclear functions in infected cells--an introduction.

The sequencing and deciphering of the human genome provided an insight into the gene complement of the human chromosomes as well as information on the nongenic sequences that constitute the chromosomal DNA molecules. The analyses of the genes and nongenic sequences in the human genome also provided important information on the presence of endogenous retroviruses, retroposons, retrotransposition of genes in the human genome as well as retroduplication of genes and distribution of the duplicated genes in different chromosomes. These issues were discussed in the first Special Issue of Virus Genes on Molecular Evolution of Viruses-Past and Present. In that issue, the discovery of the reverse transcriptase gene in archeabacteria, the retrovirus in drosophilae and endogenous retroviruses in the human genome were discussed. The aim of the present special issue on Molecular Evolution of Viruses is to consider the strategies developed by RNA and DNA viruses to control the nucleus and the nuclear functions in the infected cells.

The World of Microbes 2002: scientific advances and challenges--impressions and highlights from the 12th Congress of Virology.

Thousands of scientists participated in the World of Microbes Congress, which was organized by the International Union of the Microbiological Societies (IUMS) and took place in the Palais de Congres in Paris, France from 27 July to 1 August 2002. The attendees were members of the IUMS divisions of Bacteriology and Applied Microbiology, Mycology, and Virology. In addition to the symposia that were organized by each division, joined plenary symposia were held, which encompassed subjects of common interest to all microbiologists. The activities at the 12th Congress of Virology's plenary lectures, symposia, and poster sessions were organized to accommodate the presentation of over 1500 presentations. These brief comments are aimed to provide a sample of only a few presentations that dealt with subjects of emerging and re-emerging virus diseases, which are of general interest.