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T J Matthews

Publications and source records attributed to T J Matthews.

At least 91 records · Page 5Linked to original sources
PubMed1990

Human immunodeficiency virus-1 disease progression in hemophiliacs.

A retrospective study of 153 hemophiliacs infected with human immunodeficiency virus-1 (HIV-1) was performed to determine the clinical and immunological consequences of HIV-1 infection and the markers and cofactors associated with these changes. Nearly 80% of HIV-1-infected hemophiliacs have developed a significant reduction in their CD-4+ counts (less than 400 CD-4+ cells/mm3) with 40% having less than 200 CD-4+ cells/mm3 by the end of 1987. The rate of CD-4+ cell count decline was slightly greater in patients who have already developed the acquired immunodeficiency syndrome (AIDS) compared to those who have not (50 vs. 31 cells/mm3/6 months). Thrombocytopenia and older age were associated with a more rapid CD-4+ count deterioration, but the quantity of clotting factor utilized did not affect immunologic progression. In patients with less than 200 CD-4+ cells/mm3, the incidence of AIDS was significantly higher in adults (greater than 21 years old) compared to children/adolescents. Cytomegalovirus (CMV) seroprevalence increased with age but did not correlate with the amount of concentrated clotting factor used. Although there was no relationship between CMV status and progression to AIDS, CMV-seropositive patients were older and had a lower CD-4+ count. Thus the majority of HIV-1-infected hemophiliacs are developing progressive immune dysfunction measured by CD-4+ count decline. This drop in CD-4+ count significantly correlates with a risk for the development of AIDS in adults but not in children (less than 21 years old).

Acquired Immunodeficiency Syndrome↗
PubMed1990

HIV-1 neutralizing monoclonal antibodies induced by a synthetic peptide.

We have developed a series of murine monoclonal antibodies to a region of the 120 kD envelope glycoprotein (gp120) of human immunodeficiency virus type 1 (HIV-1). This region has previously been implicated as a site for virus neutralization by antisera raised to recombinant proteins and by antibodies made to full-length gp120 purified from virus. The antigen employed was a synthetic peptide containing 15 amino acids, representing amino acid residues 308-322, RIQRGPGRAFVTIGK, of env gp120 (HTLV-IIIB isolate). Five of the monoclonal antibodies raised to this antigen have reactivity with gp120 from divergent strains of HIV-1 in Western blot assays. The two of these five which were tested with live cells infected with the divergent HIV-1 isolates IIIB, MN, and RF were specifically reactive by fluorescence analyses with cells infected with the MN and IIIB isolates. Four of the five monoclonal antibodies blocked the fusion of IIIB-infected cells with uninfected MOLT-4 target cells. The monoclonal antibody most reactive with MN-infected cells by fluorescence, #5025A, blocked the fusion of MN-infected cells with uninfected MOLT-4 cells. Four of the five monoclonal antibodies neutralized the IIIB isolate of HIV-1 in vitro, but none neutralized the MN or RF isolates at the levels of antibody tested (less than or equal to 50 micrograms/ml). Taken together these data indicate that monoclonal antibodies to the immunodominant neutralizing domain of HIV-1 gp120 display different levels of group reactivity depending on the assay system being examined.

Amino Acid Sequence↗
PubMed1990

C-terminal fragments of gp120 and synthetic peptides from five HTLV-III strains: prevalence of antibodies to the HTLV-III-MN isolate in infected individuals.

The immunoreactivity of HTLV-III-infected individuals and virus-inoculated chimpanzees with gp120 synthetic peptides of the HTLV-III gp120 envelope principle neutralizing domain (amino acid 301-324 sequences), derived from the HTLV-III isolates 3B, RF, MN, WMJ2, and SC were determined. Sequential bleeds from an infected lab worker and chimpanzees, both infected with the HTLV-IIIB, were immunoreactive only with the 3B peptide. In contrast, 33 HTLV-III-infected individuals were immunoreactive with the HTLV-III(MN) peptide. Of these 33 individuals, 23 were also immunoreactive with the HTLV-III(SC) peptide, and 18 with the HTLV-III(WMJ2) peptide. The data suggest that HTLV-III strains related to MN are most prevalent among HTLV-III-infected individuals. The binding specificities of goat sera generated against either of these synthetic peptides or the C-terminal fragment of gp120 (PB-1, amino acid 287-467, derived from the HTLV-III isolates 3B, RF, MN, WMJ2, and SC) were also determined. Four different ELISA formats (peptide sera/peptide antigens, peptide sera/PB-1 antigens, PB-1 sera/PB-1 antigens, and PB-1 sera/peptide antigens) were utilized to determine the cross-reactivity patterns of goat sera with the antigens. Goat sera generated against MN and SC sequences (PB-1 proteins, as well as synthetic peptides) were highly cross reactive. Thus, patient sera cross reactivity to multiple strains of the principal neutralizing domain may reflect the antigenic relatedness of the virus isolates rather than multiple infection events or strains generated during disease progression.

Amino Acid Sequence↗
PubMed1990

Effects of d-amphetamine, diazepam, and pentobarbital on the schedule-controlled pecking and locomotor activity of pigeons.

Pigeons were trained on a variant of the autoshaping procedure devised by Matthews and Lerer (1987) in which a keylight stimulus ramp of increasing brightness signaled the passing of a 30-s interfood interval. This procedure generates two distinct behavioral components: key pecking and locomotor activity. The effects of three psychoactive drugs on these behavior classes were measured. d-Amphetamine had negligible effects on both types of behavior, whereas diazepam and pentobartital increased key pecking and decreased activity in a dose-dependent fashion. In Experiment 2, the possibility that drug effects were suppressed by excessively strong stimulus control exerted in Experiment 1 was tested by decreasing the discriminability of the stimulus ramp. The direction of the effects of diazepam and pentobarbital was the same as in Experiment 1 but the magnitude of the effects tended to be larger. The effects of d-amphetamine, however, remained quite small, suggesting that, under these conditions, locomotor activity and key pecking are less sensitive to d-amphetamine. In Experiments 3 and 4, key pecking was eliminated by removing the keylight. Reinforcers were presented at fixed intervals in Experiment 3 and at variable intervals in Experiment 4. The drug effects on activity observed in Experiments 1 and 2 disappeared in both Experiments 3 and 4. The results suggest that diazepam and pentobarbital affect activity indirectly by increasing key-pecking behavior, which, in turn, competitively decreases activity.

Animals↗
PubMed1990

Schedule-induced kinesic and taxic behavioral stereotypy in the pigeon.

Two experiments explored the functional character of 2 schedule-induced interim behaviors (pacing and retreat) and 1 terminal behavior (keypecking) that developed on fixed-time (FT) schedules of food delivery with a keylight that increased in brightness throughout the interstimulus interval. In Experiment 1, this ramp procedure was compared with a less discriminable ramp, and FT and Random Time (RT) procedures without a signal. Decreased discriminability expanded keypecking in the trial. The FT schedule eliminated only keypecking and the RT procedure eliminated keypecking and retreat while pacing remained. In Experiment 2, predictive and unpredictive ramps were added to the RT procedure. The data suggest that schedule-induced stereotypy can be divided into kinesic stereotypy (pacing), which arises from repeated reinforcer presentations, and taxic stereotypy, which is tied to an increase (keypecking) or decrease (retreat) in the momentary probability of reinforcement.

Animals↗
PubMed1989

Polyvalent human immunodeficiency virus synthetic immunogen comprised of envelope gp120 T helper cell sites and B cell neutralization epitopes.

In previous studies, we have used antisera raised to envelope (env)-gene-encoded synthetic peptides to identify a region of (HIV) glycoprotein (gp) 120 env protein designated SP10 that contains a type-specific neutralizing determinant. To develop a polyvalent, synthetic peptide inoculum that can evoke both neutralizing antibodies and T cell proliferative responses to more than one HIV isolate, synthetic peptides containing type-specific neutralizing determinants of gp120 from HIV isolates HTLV-IIIB (IIIB), HTLV-IIIMN (MN) and HTLV-IIIRF (RF) were coupled to a 16 amino acid T cell epitope (T1) of HIV-IIIB gp120 and used to immunize goats. Goat antisera to each T1-SP10 peptide derived from the SP10 region of gp120 of IIIB, MN, and RF neutralized HIV isolates IIIB, MN and RF in a type-specific manner. Moreover, peripheral blood T cells from immunized goats also proliferated in a type-specific manner to peptides derived from gp120 of IIIB, MN, and RF. When combined in a trivalent inoculum, T1-SP10 peptides from HIV-1 isolates IIIB, MN, and RF evoked a high titered neutralizing antibody response to isolates IIIB, MN, and RF in goats and as well induced immune T cells to undergo blast transformation in the presence of peptides derived from gp120 of all three HIV isolates. The T1 portion of the T1-SP10 construct was shown to induce a B cell antibody response against determinants within the T1 peptide in addition to inducing T cell proliferative responses in immune goat T cells. Moreover, the SP10 portion of the T1-SP10 constructs not only induced B cell antibody production but also induced type-specific T cell proliferative responses localized to the C-terminal variable sequences of the SP10 peptides. Finally, the T1-SP10 peptide construct induced memory T cell proliferative responses to native gp120 env protein. Thus, combinations of homologous SP10 region synthetic peptides containing type-specific neutralizing determinants and T cell epitopes of HIV gp120 may be useful in man to elicit high titered neutralizing B cell responses and, as well, T cell responses to more than one HIV isolate.

Amino Acid Sequence↗
PubMed1989

HIV-1 GP120-mediated immune suppression and lymphocyte destruction in the absence of viral infection.

The magnitude of immunologic defects observed in HIV-1-infected individuals before the development of overt AIDS is disproportionately high in comparison to the levels of infectious virus in these patients--suggesting that factors other than direct virus-induced cytopathology may be involved. With this in mind, we investigated the immunologic consequences of the interaction between purified HIV-1 gp120 and the CD4 molecules expressed by uncommitted as well as Ag-specific lymphocytes. HIV-1 gp120 exhibited a dose-dependent immunosuppressive effect on: 1) Ag-driven proliferation of cloned CD4+ lymphocytes, 2) OKT3-driven proliferation of cloned CD4+ lymphocytes, and 3) cytolytic activity of CD4+, EBV-specific CTL. Thus, HIV-1 gp120 can, in a manner similar to OKT4A antibodies, suppress T cell activation and the expression of cytolytic activities through its interaction with CD4. Additionally, activated CD4+ lymphoblasts can be rendered susceptible to immune cytolysis by virtue of their binding of purified gp120. This "targeting" of activated lymphoblasts can occur with levels of gp120 far below that which is needed to saturate all OKT4A-defined CD4 epitopes. Adsorbed gp120 could be demonstrated on the surface of these cells for up to 12 h, a sufficient time for interaction with host cytolytic elements. The data from these in vitro modeling experiments highlight one of many potential mechanisms of HIV-1 induced immunosuppression and lymphocyte destruction that can occur in the absence of infectious virus and that is based on the unique interaction between HIV-1 gp120 and its cellular receptor, CD4.

Acquired Immunodeficiency Syndrome↗
PubMed1989

GP120 specific cellular cytotoxicity in HIV-1 seropositive individuals. Evidence for circulating CD16+ effector cells armed in vivo with cytophilic antibody.

Fresh circulating PBMC from HIV-1 seropositive individuals have been found to mediate specific, non-MHC restricted lysis of targets expressing the major envelope glycoprotein of HIV-1, gp120, in 6-h 51Cr release assays. This gp120 specific cell-mediated cytotoxicity (CMC) is broadly reactive against target cells infected with a wide range of viral isolates, is IL-2 augmentable, and is mediated by a CD16+, Leu-7+, CD15-, CD3- population of NK/K cells. The presence of FcR (CD16) on these cells suggested that the lytic specificity for gp120 might be directed by cytophilic antibody bound to the cell surface. Affinity purified F(ab')2 antibody fragments specific for the Fc and F(ab')2 portions of human IgG were used in attempts to block gp120 specific lysis. A 1/50 dilution of these antibodies inhibited gp120 specific cytolytic activity by more than 90% while exhibiting a minimal effect on NK/K cell lysis of K562 targets. The blocking activity of these fragments demonstrates the direct involvement of cytophilic antibody in CMC. In attempts to isolate this cytophilic anti-HIV-1 antibody, short 56 degrees C incubations were used to dissociate antibodies from the surface of PBMC of seropositive individuals. The supernatants generated in this manner exhibited specific gp120 activity in antibody-dependent cellular cytotoxicity assays. The ability of Staphylococcal protein A to remove this activity confirms the presence of cytophilic antibody on freshly isolated PBMC. Selective enrichment of specific cell subpopulations revealed the origin of the cytophilic antibody to be CD16+ NK/K cells and not B cells, T cells, or monocytes/macrophages. These studies show that the gp120-specific CMC seen in HIV-1 seropositive individuals is directed by cytophilic antibody bound to circulating CD16+ NK/K cells and represents a form of direct antibody-dependent cellular cytotoxicity which may provide a primary cytotoxic host defense.

Antibody Specificity↗
PubMed1989

Antibodies from human immunodeficiency virus-infected individuals bind to a short amino acid sequence that elicits neutralizing antibodies in animals.

A total of 18 overlapping peptides were synthesized that covered envelope amino acid sequences (amino acids 288-472 of the III-B isolate) of the human immunodeficiency virus type 1 (HIV-1). Antibodies from human immunodeficiency virus-1-infected individuals bound to three of the peptides tested. Guinea pigs were immunized with each of the overlapping peptides and the resultant sera analyzed for biologic activity. One of the peptides elicited antibodies that had both neutralizing and fusion blocking activities that were type specific. This peptide, designated 1-69, was also one of the peptides reactive with the human immunodeficiency virus type 1-positive human sera.

Acquired Immunodeficiency Syndrome↗
PubMed1989

Isolate- and group-specific immune responses to the envelope protein of human immunodeficiency virus induced by a live recombinant vaccinia virus in macaques.

The immune responses produced by four macaques inoculated intradermally with a recombinant vaccinia virus that expresses the envelope gene of human immunodeficiency virus (HIV) were analyzed. Antibody capable of immunoprecipitating the glycosylated envelope protein precursor gp160 was detected in all animals within 3 weeks after the primary intradermal vaccination. The level of antibody was increased following a booster inoculation, and the sera from three of the four animals were then capable of immunoprecipitating gp120. Sera from two of the macaques with anti-gp120 antibody were able to prevent syncytium formation mediated by the parent HIV but not that induced by an unrelated HIV isolate. The fusion-inhibiting antibody was directed toward the highly variable central portion of the gp120 molecule since the effect was abrogated by incubation with PB1. The latter is a recombinant protein produced in Escherichia coli containing amino acids 295-474, a major neutralizing epitope. Sera from the three macaques with anti-gp120 neutralized HIV infectivity in an isolate-specific manner. The serum with highest neutralizing activity was also best at inhibiting syncytium formation. In contrast to the isolate-specific nature of the neutralizing antibody, T lymphocytes from immunized animals proliferated in response to divergent HIV isolates as well as to purified gp120. These studies provide baseline immunologic information for further development of recombinant vaccinia virus vectors.

Animals↗
PubMed1989

Oligosaccharide-mediated interactions of the envelope glycoprotein gp120 of HIV-1 that are independent of CD4 recognition.

In this study carbohydrate-mediated interactions of the envelope glycoprotein, gp120, of HIV-1 were investigated. Oligosaccharide probes (neoglycolipids), prepared from the N-glycosidically-linked chains of the natural and recombinant forms of gp120, were used in conjunction with the intact glycoprotein to investigate reactivities with a soluble carbohydrate-binding protein (lectin) known as mannose-binding protein in human serum. Evidence is presented that the high-mannose-type oligosaccharides with seven, eight and nine mannose residues from both forms of gp120 are recognized by the serum lectin, and that these reactivities are unrelated to CD4 recognition. Reactivities of the two forms of envelope glycoprotein with macrophages derived from human blood monocytes and with the mannose-specific macrophage endocytosis receptor isolated from human placental membranes were also investigated. Evidence is presented that both forms of gp120 bind to the macrophage surface by multiple interactions in addition to CD4 binding, and that among these interactions is a carbohydrate-mediated binding to the endocytosis receptor. We propose that such carbohydrate-mediated interactions could form the basis of viral attachment to a variety of healthy and diseased tissues.

CD4 Antigens↗
PubMed1988

Phenotypic variation in the response to the human immunodeficiency virus among derivatives of the CEM T and WIL-2 B cell lines.

Derivatives of the CEM T and WIL-2 B cell lines showed striking diversity in their responses to the HTLV-IIIB strain of the human immunodeficiency virus (HIV). Several stable phenotypic patterns could be defined, based on whether cells were permissive (P+, P-) for virus production, were sensitive or insensitive to cytopathic effects after infection by free virus (C+, C-), and whether they underwent fusion on contact with virus-infected cells (F+, F-). Although expression of CD4 was essential for infection by HTLV-IIIB, very low levels were sufficient for productive infection of WIL-2 derivatives. Conversely, some CEM T cell lines that expressed ample CD4, and which were able to bind virus gp120 and undergo fusion, did not support productive infection by free virus. One nonpermissive, CD4+ derivative of CEM could bind gp120 but failed to undergo fusion, suggesting an alteration in some membrane protein other than CD4 that is essential for virus entry and HIV-induced cell fusion. The AA2 derivative of the WIL-2 cell line is also described, which is remarkably permissive for HIV replication and exquisitely sensitive to virus cytopathic effect. The panel of related cell lines with different host-virus phenotypes could be useful for more precisely defining steps in the infectious cycle of HIV, and for identifying host cell genes and gene products that determine the outcome of HIV infection.

Antigens, Surface↗
PubMed1988

Cellular anti-GP120 cytolytic reactivities in HIV-1 seropositive individuals.

Forty-one patients seropositive for human immunodeficiency virus type 1 (HIV-1) were assessed for cell-mediated cytotoxicity (CMC) against autologous target cells bearing the major envelope glycoprotein of HIV-1, gp120. Effector lymphocytes from over 85% of seropositive patients showed CMC specific for gp120-coated targets, whereas seronegative individuals had no detectable CMC. As a group, symptomless individuals had the highest levels of CMC; patients with AIDS-related complex and AIDS showed progressively diminished reactivity. The gp120-specific CMC was mediated by a population of non-T-cell effectors phenotypically resembling NK/K cells. Cytolysis was not restricted by major histocompatibility complex determinants, as shown by killing of heterologous gp120-adsorbed targets and of HIV-1-infected cell-lines. Gp120-specific CMC was highly augmented in the presence of interleukin 2, so it may be possible to develop therapeutic strategies aimed at destruction of virus-producing cell reservoirs in infected individuals through stimulation of HIV-specific host CMC.

Antibodies, Monoclonal↗
PubMed1988

Transmission of human immunodeficiency virus to sexual partners of hemophiliacs.

To examine the variables associated with heterosexual transmission of human immunodeficiency virus (HIV), we studied 32 couples in our hemophilia center who had steady sexual relationships for periods more than 1 year. Of the 32 sexual partners of the hemophiliacs, five (15.6%) were HIV seropositive. All five hemophiliacs with HIV transmission to their sexual partners had measurable immunologic deficiencies, as shown by their lower median T-helper (CD-4+) lymphocyte count of 172 cells/mm3. The hemophiliacs without transmission had a slightly higher median CD-4+ count of 297 cells/mm3 (P = .26). To determine if factors other than the degree of immunologic deficiency in the hemophiliac might contribute to HIV transmission, 18 of the 32 couples were studied more intensively by confidential, coded questionnaires. Regular condom use was reported by nine couples (50%). Two of nine women (22%) without condom usage acquired HIV. One of nine women (11%) using condoms was seropositive; she also reported eight needlestick injuries while assisting her spouse with clotting factor treatments. Intravenous drug abuse was reported in two of the five couples with HIV transmission. Thus, hemophiliacs are at risk for transmitting HIV parenterally as well as venereally. Despite various risk behaviours associated with HIV transmission, the prevalence of infection in our cohort of hemophiliacs' sexual partners is low and within the range (6.8-22%) reported by others. This study underscores the need for comprehensive education and counseling in what previously appeared to be a homogeneous clinic population at risk for transmitting HIV to others.

Acquired Immunodeficiency Syndrome↗
PubMed1988

Human T-cell lymphotropic virus I and adult T-cell leukemia: report of a cluster in North Carolina.

PURPOSE: Human adult T-cell leukemia-lymphoma is a malignant, proliferative disease of CD4+ lymphocytes associated with infection with human T-cell lymphotropic virus type I (HTLV-I). Following the presentation of a patient who was infected with the virus, we undertook a study of his family members and sexual contacts to see if a cluster of infected persons could be identified. CASE REPORT: A black heterosexual North Carolina native with a history of drug abuse presented with jaundice, and pancytopenia subsequently developed. He then became hypercalcemic and leukemic, with high numbers of circulating, morphologically abnormal CD4+ lymphocytes. RESULTS: As determined by radioimmunoassay and immunoblot analyses, the serum of the index case contained antibodies against core proteins (p19 and p24) of HTLV-I. When cultured in vitro with interleukin-2, the lymphocytes expressed HTLV-I specific core proteins. The virus recovered from these T cells was transmitted to cord blood T cells, which became immortalized for continuous growth in vitro, expressed HTLV-I p19 protein, and displayed characteristic C-type particles by electron microscopy. Studies of family members and sexual contacts, all of whom were black, heterosexual central North Carolina natives, revealed five of 28 whose serum had anti-HTLV-I antibodies as determined by radioimmunoassay and immunoblot. Neither the patient nor the seropositive family/contacts had antibodies against human immunodeficiency virus proteins. Four of the six people with HTLV-I infection had no history of intravenous drug abuse. Three of the five seropositive family/contacts had circulating, morphologically abnormal lymphocytes suggestive of "preleukemic" or "smoldering" human adult T-cell leukemia-lymphoma.

Adult↗
PubMed1988

AIDS vaccines.

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Acquired Immunodeficiency Syndrome↗
PubMed1988

Binding site for human immunodeficiency virus coat protein gp120 is located in the NH2-terminal region of T4 (CD4) and requires the intact variable-region-like domain.

The external segment of the T4 (CD4) glycoprotein functions as the T-cell surface receptor for human immunodeficiency virus by binding the major viral coat protein (gp120) with relatively high affinity. To more precisely define the region of T4 involved in gp120 interaction, we used purified, soluble forms of T4 anchor-minus polypeptides (produced in a baculovirus system) in conjunction with proteolytic fragmentation, microsequencing, and a specific T4-gp120 binding assay. The results indicate that the NH2-terminal region of T4 including the immunoglobulin variable-region-like domain is required for gp120 interaction. In contrast, the COOH-terminal half of the molecule, containing the two potential N-linked glycosylation sites, is not necessary. Furthermore, reduction of intrachain disulfide bonds in the T4 molecular abrogates gp120 binding, thereby strongly implying that the binding site for gp120 is dependent on the stabilized domain structure of the active binding region.

Amino Acid Sequence↗