Dilemma of neutralization resistance of HIV-1 field isolates and vaccine development.
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AIDS Vaccines↗
Biomedical subjects
T J Matthews
Publications and source records attributed to T J Matthews.
Human immunodeficiency virus (HIV)-infected human blood monocytes and peritoneal macrophages have reduced anticryptococcal activity whereas HIV-infected alveolar macrophages retain normal activity.
Human immunodeficiency virus type 1 (HIV-1) infection causes immune dysfunction. Mononuclear phagocytes (MNP) are immune effector cells against some intracellular pathogens and reservoirs for HIV-1. This study determined effects of HIV-1 on MNP-mediated antifungal function. MNP from seronegative volunteers were inoculated with HIVBal or HIVIIIB. MNP were infected with an avirulent clone of Cryptococcus neoformans; 48 h later, MNP were lysed and yeasts were counted. Viral replication was determined by reverse transcriptase and by visualization of cytopathic effects. Monocytes and peritoneal macrophages exhibited reduced anticryptococcal activity 14 days after infection with HIVBal but retained normal activity when infected with HIVIIIB. Loss of anticryptococcal activity correlated with viral replication. Alveolar macrophages retained normal anticryptococcal activity whether infected with HIVBal or HIVIIIB. In vitro MNP-mediated antifungal activity may be altered by HIV-1 infection; this altered activity appears to depend on viral tropism, viral replication, and MNP tissue origin.
Cell Survival↗
Determinants of antibody response after recombinant gp160 boosting in vaccinia-naive volunteers primed with gp160-recombinant vaccinia virus. The National Institute of Allergy and Infectious Diseases AIDS Vaccine Clinical Trials Network.
Priming with a live recombinant vector followed by subunit boosting is a promising strategy for human immunodeficiency virus (HIV) immunization. Twenty-nine vaccinia-naive volunteers were primed with gp160-recombinant vaccinia virus (HIVAC-1e) and boosted with recombinant (r) gp160 to define factors associated with the magnitude and specificity of antibody response after booster immunization. A longer interval between inoculation and boost, two inoculations of HIVAC-1e with lesion formation occurring after the first, and Western blot-detectable antibody to gp160 after inoculation were significantly associated with higher neutralizing antibody titers and fusion-inhibiting activity after boosting. HIVAC-1e-primed vaccinees were more likely to have antibody to V3- and CD4-binding regions of gp120 and less likely to have antibody to constant regions 2 and 3 than vaccinees immunized with rgp160 alone. Priming volunteers with HIVAC-1e was a key determinant of the epitope specificity and magnitude of functional antibody responses induced by rgp160 boosting.
AIDS Vaccines↗
HIV-1 recombinant gp160 vaccine given in accelerated dose schedules. NIAID AIDS Vaccine Clinical Trials Network.
The purpose of this randomized, double-blind study was to test the safety and immunogenicity of an HIV-1LAI recombinant gp160 (rgp160) vaccine in healthy, uninfected volunteers using accelerated dosing schedules. Thirty volunteers were randomly assigned to receive 50-micrograms doses of rgp160 in one of two immunization schedules. Group 1 received rgp160 at times 0, 1, 2 and 5 months; and group 2 received rgp160 at times 0, 1, 2, 3 and 4 months. The vaccine was safe and stimulated high levels of HIV-1 envelope-specific binding antibody and T cell memory. There was a trend (P < 0.10) suggesting neutralizing antibodies were better induced by the regimen incorporating a rest period before the final immunization in group 1 volunteers. Both accelerated immunization schedules induced immune responses at levels similar to or better than those achieved by four rgp160 vaccine injections given over 12-18 months in other studies.
AIDS Vaccines↗
Structural rearrangements in the transmembrane glycoprotein after receptor binding.
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CD4 Antigens↗
Leiomyosarcoma of soft tissue and pulmonary metastasis, both with osteoclast-like giant cells.
A case is described of leiomyosarcoma with osteoclast-like giant cells in soft tissues which metastasised to the lung. The secondary tumour also contained abundant osteoclast-like giant cells, which raises the question of whether they were locally induced or whether they metastasised with the tumour.
Aged↗
Conversion of an immunogenic human immunodeficiency virus (HIV) envelope synthetic peptide to a tolerogen in chimpanzees by the fusogenic domain of HIV gp41 envelope protein.
The fusogenic (F) domain of human immunodeficiency virus (HIV) gp41 envelope (env) protein has sequence similarities to many virus and mediates the fusion of HIV-infected cells. During a survey of the immunogenicity of HIV env peptides in chimpanzees, we have observed that HIV peptide immunogenicity was dramatically altered by the NH2-terminal synthesis of the gp41 F domain to an otherwise immunogenic peptide. We compared two hybrid peptide types comprised of T helper (Th) and B cell epitopes of HIV gp120 env protein for their immunogenicity in chimpanzees. The Th-B epitope hybrid peptides contained the HIV gp120 Th cell determinant, T1 (amino acids [aa] 428-440)-synthesized NH2 terminal to gp120 V3 loop peptides, which contain B cell epitopes that induce anti-HIV-neutralizing antibodies (SP10IIIB [aa 303-321] and SP10IIIB [A] [aa 303-327]). The F-Th-B peptide contained the HIV gp41 F domain of HIVIIIB gp41 (aa 519-530)-synthesized NH2 terminal to the Th-B peptide. Whereas Th-B peptides were potent immunogens for chimpanzee antibody and T cell-proliferative responses, the F-Th-B peptide induced lower anti-HIV gp120 T and B cell responses. Moreover, immunization of chimpanzees with F-Th-B peptide but not Th-B peptides induced a significant decrease in peripheral blood T lymphocytes (mean decrease during immunization, 52%; p < 0.02). Chimpanzees previously immunized with F-Th-B peptide did not respond well to immunization with Th-B peptide with T or B cell responses to HIV peptides, demonstrating that the F-Th-B peptide induced immune hyporesponsiveness to Th and B HIV gp120 env determinants. These observations raise the hypothesis that the HIV gp41 env F domain may be a biologically active immunoregulatory peptide in vivo, and by an as yet uncharacterized mechanism, promotes primate immune system hyporesponsiveness to otherwise immunogenic peptides.
Amino Acid Sequence↗
A hidden region in the third variable domain of HIV-1 IIIB gp120 identified by a monoclonal antibody.
The third variable domain (V3 domain) of HIV-1 gp120 is involved in virus neutralization by antibody, in determination of cell tropism, and in syncytium-inducing/non-syncytium-inducing capacity. Antibodies are highly specific tools to delineate the role of different V3 amino acid sequences in these processes, and to dissect events occurring during synthesis of gp120/160, gp120-CD4 interaction, cellular infection, and syncytium formation. We describe here an IgG1 murine monoclonal antibody (MAb), coded IIIB-V3-01, that was raised with a synthetic peptide (FVTIGKIGNMRQAHC) derived from the carboxy-terminal flank of the HIV-1 IIIB V3 domain. The binding site of this antibody was mapped to the sequence IGKIGNMRQ, using Pepscan analysis. In ELISA, this antibody binds to E. coli-derived gp120 from HIV-1 IIIB, which is denatured and not glycosylated. The antibody showed no neutralizing activity against HIV-1 IIIB, MN, SF2, or RF in a virus neutralization assay and in a syncytium formation inhibition assay. In addition, this antibody did not react with gp120 expressed on the surface of IIIB-infected MOLT-3 cells in FACS analysis. To assess whether the epitope defined by MAb IIIB-V3-01 is hidden on native gp120, reactivity of the antibody with SDS-DTT-denatured or DTT-denatured glycosylated gp120 (CHO cell produced) was tested. Both these treatments exposed the epitope for binding. From these data we conclude that the epitope defined by MAB IIIB-V3-01 is hidden on glycosylated recombinant gp120, and is not accessible on gp120 expressed on the membrane of HIV-1, IIIB-infected cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Amino Acid Sequence↗
Augmentation of human immunodeficiency virus type 1 neutralizing antibody by priming with gp160 recombinant vaccinia and boosting with rgp160 in vaccinia-naive adults. The NIAID AIDS Vaccine Clinical Trials Network.
Twelve vaccinia-naive volunteers were inoculated with recombinant vaccinia virus expressing the human immunodeficiency virus type 1 (HIV-1) strain IIIB (HIV-1IIIB) envelope glycoprotein gp160 and subsequently immunized with 640 micrograms of recombinant (r) gp160 protein produced in baculovirus. After booster immunization with rgp160, the sera of all vaccinees showed strong antibody responses detected by Western blot and ELISA; 8 had neutralizing activity and 5 had fusion inhibition activity against the homologous strain; 5 blocked binding of CD4 cells to gp120. Cross-reactive neutralization of HIV-1MN was detected in 3 of 8 sera that neutralized HIV-1IIIB. The combination of live recombinant vaccinia followed by subunit booster immunization was more immunogenic than either product alone and represents a promising approach for HIV-1 immunoprophylaxis. Further definition of recombinant vaccinia safety and augmentation of immune responses to geographically prevalent HIV-1 strains will be necessary before expanding clinical trials to high-risk groups.
AIDS Vaccines↗
Human immunodeficiency virus type 1 infection of human monocytes and macrophages does not alter their ability to generate an oxidative burst.
Human immunodeficiency virus type 1 (HIV-1) infects mononuclear phagocytes, cells that may serve as a reservoir for viral persistence. Infection with HIV-1 leads to progressive compromise of the immune system, resulting in infections with opportunistic pathogens and eventual death. Experiments were designed to determine if in vitro HIV-1 infection of mononuclear phagocytes would diminish their oxidative capabilities, thus decreasing their antimicrobial effectiveness. Blood monocytes and peritoneal macrophages were obtained from uninfected donors and inoculated with a monocytotropic strain of HIV-1. Hydrogen peroxide production and reduction of nitroblue tetrazolium were measured after acute stimulation of cells with PMA or a phagocytic stimulus. Despite vigorous virus production, no difference was seen in oxidative burst between uninfected cells and infected cells or between monocyte-derived and peritoneal macrophages. In conclusion, reduced antimicrobial activity of HIV-infected mononuclear phagocytes is probably not secondary to decreased ability to generate reactive oxygen species.
Cells, Cultured↗
Comparison of the use of antibodies to alpha smooth muscle actin and desmin in pulmonary lymphangioleiomyomatosis.
To establish if antibodies to alpha smooth muscle actin (ASMA) are better than desmin as a tumour marker in pulmonary lymphangioleiomyomatosis both antisera were applied to five cases. ASMA strongly stained the muscle in all cases but desmin was negative. Five cases of cryptogenic fibrosing alveolitis showed that mature smooth muscle embedded in fibrous tissue surrounding cysts was positively stained with ASMA but the interstitial fibrous tissue was negative. ASMA is a consistent and better marker than desmin for the detection of immature smooth muscle in pulmonary lymphangioleiomyomatosis.
Actins↗
Constraints on communication in classrooms for the deaf.
One explanation for the relatively low scholastic achievement of deaf students is the character of communication in the classroom. Unlike aural communication methods, line-of-sight methods share the limitation that the receiver of the message must look at the sender. To assess the magnitude of this constraint, we measured the amount of time signers were looked at by potential receivers in typical secondary school classes for the deaf. Videotaped segments indicated that on average the messages sent by teachers and students were seen less than half the time. Students frequently engaged in collateral conversations. The constraints of line-of-sight communication are profound and should be addressed by teaching techniques, classroom layout, and possibly, the use of computer-communication technology.
Adolescent↗
Use of synthetic peptides in primates to induce high-titered neutralizing antibodies and MHC class I-restricted cytotoxic T cells against acquired immunodeficiency syndrome retroviruses: an HLA-based vaccine strategy.
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AIDS Vaccines↗
Changes in bioactive lipids, alkylacylglycerol and ceramide, occur in HIV-infected cells.
The mass levels of bioactive lipids known to modulate signal transduction or to possess other biological activities were measured in HIV-infected CEM cells. The levels of diacylglycerol, an activator of protein kinase C, as well as of alkylacylglycerol were elevated. A more drastic increase was observed in the ceramide levels after HIV-infection, whereas sphingosine levels were hardly influenced. Interestingly, the magnitude of the changes was related to the infection time, being higher at 8 days after infection then at 4 days. The possible role of these lipids in the cytopathic effects of HIV-infection is discussed. In addition, an improved methodology to quantitate simultaneously diacylglycerol and alkylacylglycerol in crude lipid extracts, based upon their phosphorylation by E. coli diacylglycerol kinase, is presented.
Cell Line↗
The ability of certain SIV vaccines to provoke reactions against normal cells.
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Acquired Immunodeficiency Syndrome↗
V3 loop region of the HIV-1 gp120 envelope protein is essential for virus infectivity.
The mechanism by which HIV-1 mediates cell fusion and penetrates target cells, subsequent to receptor (CD4) binding, is not well understood. However, neutralizing antibodies, which recognize the principal neutralizing determinants of the gp120 envelope protein (the V3 loop region, residues 296 to 331), have been shown to effectively block cell fusion and virus infectivity independent of the initial gp120-CD4 binding. To investigate the role of the V3 loop in an HIV infection, a series of site-specific mutations were introduced into the HIV-1 envelope gene. Specifically, each residue (312 to 315) in the strongly conserved tetrapeptide sequence, GPGR, which is positioned in the center of the V3 loop domain was individually altered. The processing, transport, and CD4 binding properties of the mutant envelope proteins were comparable to those of the wild-type protein, however, none of the mutants were able to form syncytia in the HeLa-T4 assay. Molecular HIV-1 clones containing mutations altering the G312, G314, or R315 residues produced noninfectious virions, whereas a clone with a P313A mutation was found to be infectious. These results demonstrate that certain V3 loop mutations can be lethal and clearly indicate that this region of the HIV-1 gp120 protein is essential for virus infectivity.
Amino Acid Sequence↗
Detection of anti-human cell antibodies in sera from macaques immunized with whole inactivated virus.
More than 200 sera from macaques immunized with several different vaccine preparations were tested in various assays with cells of human and macaque origin. Only in instances where whole inactivated SIV preparations were used for immunization, were reactivities found with normal human cells, and this was the case in every instance. Such sera produced a marked clumping of several normal human cell lines and exhibited strong staining of the cell surface in FACS analysis. In the presence of SIVDeltaB670, these sera also enhanced infectivity and fusion formation. When similar tests were performed with macaque cells as targets, such phenomena were not easily discernible. Likewise, there was no trace of such activities in sera from normal animals, animals chronically infected with SIV, or in those from animals which received recombinant viral subunits as vaccines. Finally, we show that in several instances where whole inactivated virus was used as a vaccine, there is a strong correlation between the titer of anticellular activity with protection.
Animals↗
Cross-neutralization of human immunodeficiency virus type 1 and 2 and simian immunodeficiency virus isolates.
In contrast to infrequent and low-titer cross-neutralization of human immunodeficiency virus type 1 (HIV-1) isolates by HIV-2- and simian immunodeficiency virus (SIV)-positive sera, extensive cross-neutralization of HIV-2NIH-Z, SIVMAC251, and SIVAGM208K occurs with high titer, suggesting conservation of epitopes and mechanism(s) of neutralization. The V3 regions of HIV-2 and SIV isolates, minimally related to the HIV-1 homolog, share significant sequence homology and are immunogenic in monkeys as well as in humans. Whereas the crown of the V3 loop is cross-reactive among HIV-1 isolates and elicits neutralizing antibodies of broad specificity, the SIV and especially HIV-2 crown peptides were not well recognized by cross-neutralizing antisera. V3 loop peptides of HIV-2 isolates did not elicit neutralizing antibodies in mice, guinea pigs, or a goat and together with SIV V3 peptides did not inhibit serum neutralization of HIV-2 and SIV. Thus, the V3 loops of HIV-2 and SIV do not appear to constitute simple linear neutralizing epitopes. In view of the immunogenicity of V3 peptides, the failure of conserved crown peptides to react with natural sera implies a significant role of loop conformation in antibody recognition. Our studies suggest that in addition to their grouping by envelope genetic relatedness, HIV-2 and SIV are neutralized similarly to each other but differently from HIV-1. The use of linear peptides of HIV-2 and SIV as immunogens may require greater attention to microconformation, and alternate subunit approaches may be needed in exploiting these viruses as vaccine models. Such approaches may also be applicable to the HIV-1 system in which conformational epitopes, in addition to the V3 loop, participate in virus neutralization.
Acquired Immunodeficiency Syndrome↗