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R S Root-Bernstein

Publications and source records attributed to R S Root-Bernstein.

At least 19 recordsLinked to original sources
PubMed1995

Five myths about AIDS that have misdirected research and treatment.

A number of widely repeated and factually incorrect myths have pervaded the AIDS research literature, misdirecting research and treatment. Five of the most outstanding are: 1) that all risk groups develop AIDS at the same rate following HIV infection; 2) that there are no true seroreversions following HIV infection; 3) that antibody is protective against HIV infection; 4) that the only way to treat AIDS effectively is through retroviral therapies; and 5) that since HIV is so highly correlated with AIDS incidence, it must be the sole necessary and sufficient cause of AIDS. A huge body of research, reviewed in this paper, demonstrates the falsity of these myths. 1) The average number of years between HIV infection and AIDS is greater than 20 years for mild hemophiliacs, 14 years for young severe hemophiliacs, 10 years for old severe hemophiliacs, 10 years for homosexual men, 6 years for transfusion patients of all ages, 2 years for transplant patients, and 6 months for perinatally infected infants. These differences can only be explained in terms of risk-group associated cofactors. 2) Seroreversions are common. Between 10 and 20 percent of HIV-seronegative people in high risk groups have T-cell immunity to HIV, and may have had one or more verified positive HIV antibody tests in the past. 3) Antibody, far from being protective against HIV, appears to be highly diagnostic of loss of immune regulation of HIV, and some evidence of antibody-enhancement of infection exists. 4) Non-retroviral treatments of HIV infection, including safer sex practices, elimination of drug use, high nutrient diets, and limited reexposure to HIV and its cofactors have proven to be effective means of preventing or delaying onset of AIDS. 5) Many immunosuppressive factors, including drug use, multiple concurrent infections, and exposure to alloantigens, are as highly correlated with AIDS risk groups as HIV. These data are more consistent with AIDS being a multifactorial or synergistic disease than a monofactorial one.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Semen alloantigens and lymphocytotoxic antibodies in AIDS and ICL.

More than 90% of people with AIDS develop circulating immune complexes (CICs) and lymphocytotoxic antibodies (LCTAs). Animals infected with HIV, however, never display CICs or LCTAs, and remain healthy. Similarly, HIV-infected people who do not develop CICs or LCTAs also do not progress to AIDS. The appearance of CICs and LCTAs is, however, highly prognostic for AIDS and death. Since HIV infection does not, per se, lead to the development of CICs and LCTAs, other causes are likely. One such cause, for which both epidemiologic and experimental evidence exists, is semen. Semen components include sperm, seminal fluid, lymphocytes, and sometimes infectious agents, including HIV, mycoplasmas, and herpes and hepatitis viruses, all of which independently cause immune suppression. Extensive evidence demonstrates sperm (and various viruses) contains many proteins mimicking the CD4 protein of T-helper cells, while HIV, mycoplasmas, and seminal fluid mimic class II MHC proteins of other lymphocytes. We identify a large number of protein sequences that display such mimicry using computer homology searching, and demonstrate experimentally that sperm antibodies specifically precipitate antibodies against class II MHC mimics such as mycoplasmas, which in turn precipitate antibodies to lymphocyte antigens. These data prove that immunologic exposure to sperm and lymphocytes (as may occur in receptive anal intercourse, needle sharing, or blood transfusions) is theoretically capable of initiating lymphocytotoxic autoimmunity. Such autoimmunity may play a significant role in the pathogenesis of AIDS, and will need to be addressed clinically in high risk individuals regardless of HIV status and regardless of the success of anti-HIV prophylaxis and treatment.

Acquired Immunodeficiency Syndrome↗
PubMed1995

Preliminary evidence for idiotype-antiidiotype immune complexes cross-reactive with lymphocyte antigens in AIDS and lupus.

Several investigators have proposed that autoimmunity may be induced by idiotype-antiidiotype antibody networks. It is generally assumed that the antiidiotype is produced in response to the idiotype, and therefore that autoimmune diseases have single antigenic initiators. The theory of multiple-antigen-mediated autoimmunity (MAMA) proposes, on the other hand, that idiotype and antiidiotype result from two primary immune responses to two chemically complementary antigens. Because of the complementarity of the antigens, and the complementarity of the antibodies for the antigens, the antibodies will themselves be complementary. They will thus form circulating immune complexes, the self-nonself distinction diffusion (DAD) experiments (a modification of Ouchterlony immunodiffusion), in which 1800 pairs of antibodies were screened for their ability to form precipitating complexes. Four sets of antibodies associated with AIDS (HIV + Staphylococcus; HIV + Mycoplasma; CMV + Mycoplasma; and HBV + Mycoplasma) specifically precipitated each other, and one of the antibodies in each set also precipitated monoclonal antibodies against one or more lymphocyte protein markers. These results therefore demonstrate that idiotype-antiidiotype antibodies can be elicited by independent antigens and may induce AIDS-related forms of autoimmunity directed at lymphocytes.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Use of electrospray ionization mass spectrometry to probe antisense peptide interactions.

Electrospray ionization mass spectrometry with a magnetic sector instrument has been used to test for non-covalent interactions between human angiotensin II (M(r) 1046) and eight synthetic octapeptides that are considered complementary peptides (encoded by DNA sequences complementary to the DNA sequence that codes for human angiotensin II) or analogues of these antisense peptides. The relative abundance of the doubly charged heterodimer complex broadly correlates to the trend observed with solution-phase studies such as 1H nuclear magnetic resonance. Dissociation constants for the reaction in solution are in the high micromolar range. Electrospray ionization can potentially be a sensitive method for rapidly screening weak molecular interactions. Further work is necessary to study the possible gas-phase contributions to the observed binding interactions indicated in the mass spectrometry data.

Amino Acid Sequence↗
PubMed1994

CD4 similarity to proteins of infectious agents in AIDS and their role in autoimmunity.

Lymphocytotoxic autoimmunity (LA) is ubiquitous in AIDS. Its causes are unknown. We report that significant amino acid sequence similarities exist between the proteins of infectious organisms associated with AIDS and the CD4 protein of T-helper lymphocytes. These included: HIV, cytomegalovirus (CMV), Epstein-Barr virus (EBV), herpes simplex viruses (HSV), Varicella Zoster virus (VZV), Escherichia coli, Mycobacteria, Mycoplasmas, Plasmodium, and Staphylococcus. It has been reported previously that HIV proteins have significant similarities with human class II MHC (HLA class II) proteins. Since CD4 and HLA class II proteins are chemically complementary, pairs of homologous antigens will also be complementary. It follows that concurrent infections with CD4 and HLA class II-homologous antigens will result in idiotype-antiidiotype antibody pairs that cannot distinguish 'self' from 'nonself', that acts as lymphocytotoxins, and form circulating immune complexes. Thus, combined HIV-CMV, HIV-EBV, HIV-HBV, HIV-mycoplasma, or other appropriate infectious pairs may suffice to trigger LA in AIDS.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Does HIV "piggyback" on CD4-like surface proteins of sperm, viruses, and bacteria? Implications for co-transmission, cellular tropism and the induction of autoimmunity in AIDS.

Coinfections of human immunodeficiency virus (HIV), EBV, and HTLV or sperm proteins act synergistically to enhance infectivity and replication and expand cellular tropism. While some aspects of these synergisms are understood, others are not. We have found that membrane or surface proteins of CMV, HTLV, EBV and sperm proteins share large regions of similarity with the CD4 protein of T-helper lymphocytes. Since HIV uses CD4 as a receptor, it may bind to CD4 homologues on CMV, HTLV, EBV or sperm proteins. HIV could then "piggyback" with these viruses into cells with which it normally has no tropism. Similarly, HIV may expand the cellular tropism of CMV, or EBV. Such a piggyback mechanism may provide insight into the formation or presentation of CD4-like antigens from CMV, HTLV, EBV and sperm proteins with class II MHC-like antigens on HIV (gp160 and Nef proteins) and may break immunological tolerance, inducing the autoimmunity observed against both CD4+ and class II MHC+ T cells in AIDS patients.

Amino Acid Sequence↗
PubMed1990

Peptide displacement of [3H]5-hydroxytryptamine binding to bovine cortical membranes.

Chemical studies have demonstrated that peptides such as the encephalitogenic (EAE) peptide of myelin basic protein (MBP) and luteinizing hormone-releasing hormone (LHRH) can bind serotonin (5-hydroxytryptamine, 5-HT) in vitro. The present research was undertaken to determine whether such binding interferes with 5-HT binding to its 5-HT1 receptors on bovine cerebral cortical membranes. EAE peptide and LHRH displaced [3H]5-HT with IC50s of 4.0 x 10(-4) and 1.8 x 10(-3) M respectively. MBP itself also showed apparent displacing ability with an IC50 of 6.0 x 10(-5) M, though it also caused aggregation of cortical membranes that might have interfered with normal receptor binding. These results support previous suggestions that the tryptophan peptide region of MBP may act as a 5-HT receptor in the neural system. We also tested the effects of muramyl dipeptide (N-acetyl-muramyl-L-Ala-D-isoGln, MD), a bacterial cell-wall breakdown product that acts as a slow-wave sleep promoter, binds to LHRH and EAE peptide, and competes for 5-HT binding sites on macrophages. It showed no significant displacement of 5-HT binding to cortical membranes (IC50 greater than 10(-1) M), but its D-Ala analogue did (IC50 = 1.7 x 10(-3) M). Thus, it seems likely that the 5-HT-related effects of naturally occurring muramyl peptides are physiologically limited by receptor types.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1990

Serotonin binding sites. II. Muramyl dipeptide binds to serotonin binding sites on myelin basic protein, LHRH, and MSH-ACTH 4-10.

Previously, we reported the existence of structurally similar serotonin binding sites on myelin basic protein, LHRH, and MSH-ACTH 4-10. We now report that the adjuvant peptide, muramyl dipeptide (N-acetyl-muramyl-L-Ala-D-isoGln) also binds to these sites. This observation may help to explain previous observations of serotonin-like activity by muramyl peptides, including the promotion of slow-wave sleep and fever induction. The observation may also provide an important link between the immune system and the nervous system that may explain the role of muramyl dipeptide adjuvants in causing autoimmune diseases to serotonin-regulated proteins and their receptors, as well as the alterations in serotonin levels that are often observed in autoimmune diseases. The observation provides concrete evidence for a dual-antigen hypothesis for the induction of autoimmune diseases by an adjuvant-peptide complex. Application of such a mechanism for induction of autoimmunity may be of importance in understanding a number of postinfectious and postvaccinal neuropathies, and suggests a possible etiology for autism, in which many patients have high blood serotonin levels, autoimmune reactions to myelin basic protein, and antibodies to serotonin binding sites. Finally, the observation suggests that glycopeptides may act as neurotransmitters.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1987

Catecholamines bind to enkephalins, morphiceptin, and morphine.

Nuclear magnetic resonance spectroscopy, pH titration, and color reactions demonstrate that the catecholamines dopamine, epinephrine, and norepinephrine bind to the enkephalins. Binding constants are c. 6 X 10(3) per mole. Catecholamines also bound to the mu opiate receptor agonist morphiceptin (Tyr-Pro-Phe-Pro-NH2). Very little binding was found to enkephalin and morphiceptin fragments and analogues, indicating that the entire molecules are necessary. Serotonin binding peptides do not bind the catecholamines. Morphine and apomorphine, however, do bind these catecholamines (with a binding constant for morphine of c. 4 X 10(4) per mole). The opiate antagonist naloxone and a number of other drugs do not bind catecholamines. Morphine, morphiceptin, and the enkephalins also retard the formation of colored reaction products by catecholamines in vitro. These results may help to explain observations that the enkephalins are co-stored and co-transmitted with dopamine and norepinephrine, and may provide a basis for the elucidation of other known cases of peptide-monoamine co-transmission. Possible implications for understanding opiate effects on catecholamines during addiction and withdrawal are discussed, and suggestions concerning drug design are made.

Catecholamines↗
PubMed1987

Harmony and beauty in medical research.

We too often report the results of biomedical research as if there were no people involved in producing those results. However, without physicians and PhD's there would be no medical research. Moreover, reference to the history of medicine and science reveals that very often the men and women who have created the most important medical breakthroughs and perceived the most significant facts of medicine have also been unusually talented in other disciplines as well: music, the arts, poetry and literature. I do not believe that this correlation of talents is an accident. Rather, I argue that the kind of medicine and science that a person accomplishes is a reflection of the personality and skills that the person brings to his or her work. Thus, those doctors who have been most sensitive to their culture, and most inventive in their everyday lives, have also been the most insightful and original in their work. Music, the arts, poetry, and literature actually contribute in essential ways to the training of eminent doctors, and influence the way in which they perceive medicine. I therefore argue that it is not enough that we do our utmost to push back the veils of ignorance in our clinics and laboratories: we must also begin to push back the veils of ignorance that surrounds the questions of who does the best biomedical research and why. We must recognize the intricate ways in which the who, the how, and the what of research are inextricably entwined.

Art↗
PubMed1986

Clinical suppression of experimental allergic encephalomyelitis by muramyl dipeptide "adjuvant".

Experimental allergic encephalomyelitis (EAE) is a model for several human diseases including multiple sclerosis and post-vaccinal encephalopathies. EAE is generally thought to be an autoimmune response to the antigen myelin basic protein (MBP). Oddly, MBP can also suppress EAE, and many observations suggest that an independent immune response to so-called "adjuvant" material is also necessary to EAE induction. Thus, EAE may be a result of a pair of interactive immune responses, one against MBP, and one against adjuvant. If so, the adjuvant should, like MBP, suppress EAE. We present data from experiments on strain 13 guinea pigs demonstrating EAE suppression by muramyl dipeptide, an active component of complete Freund's adjuvant. These results are striking because classically adjuvants are defined as immunopotentiators, not immunosuppressants. Our results, therefore, suggest that a revaluation of the role of adjuvants in inducing autoimmune diseases may be necessary.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1986

Bovine pineal antireproductive tripeptide binds to luteinizing hormone-releasing hormone: a model for peptide modulation by sequence specific peptide interactions?

We report results of chromatographic, pH titration and nuclear magnetic resonance (NMR) spectroscopy studies demonstrating that the bovine pineal antireproductive tripeptide, Thr-Ser-Lys (BPART), binds to luteinizing hormone-releasing hormone (LHRH) at a site comprised of LHRH 2-5 (His-Trp-Ser-Tyr). BPART and LHRH have been shown to be antagonists in vitro. The binding constant is ca. 2 X 10(3)/mole. An NMR study of fifty other peptide pairs demonstrates that the binding is sequence and residue specific. The binding provides evidence of the amino acid pairing hypothesis, and suggests the possibility of modulation of one peptide by directly binding with another peptide.

Amino Acid Sequence↗