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PubMed1988

Membrane penetration of Sendai virus glycoproteins during the early stages of fusion with liposomes as determined by hydrophobic photoaffinity labeling.

The hydrophobic photoaffinity label 3-(trifluoromethyl)-3-(m-[125I]iodophenyl)diazirine was used to label Sendai virus proteins during fusion with cardiolipin and phosphatidylserine liposomes. Preferential labeling of the viral fusion protein during the initial stages of fusion demonstrated that this protein interacts with the hydrophobic core of the target membrane as an initiating event of virus-liposome fusion. Labeling showed time, temperature, and pH dependence consistent with earlier fluorescent measurements of fusion kinetics. The present method provides conclusive evidence supporting the hypothesis that hydrophobic interaction of the fusion protein with the target bilayer is an initial event in the fusion mechanism of viral membranes.

Affinity Labels↗
PubMed1991

Identification of 1,4-dihydropyridine binding regions within the alpha 1 subunit of skeletal muscle Ca2+ channels by photoaffinity labeling with diazipine.

To identify regions that are involved in the formation of the dihydropyridine receptor site of skeletal muscle L-type Ca2+ channels, the alpha 1 subunit of the channel complex was specifically labeled with the 1,4-dihydropyridine-receptor-selective photoaffinity probe [3H]diazipine. Photoaffinity-labeled regions were identified by probing labeled proteolytic fragments with several anti-peptide antibodies recognizing different segments of the alpha 1 sequence. Forty to 50% of the alpha 1-associated [3H]diazipine label was contained in the tryptic fragment between Arg-988 and Ala-1023 derived from the loop between segments S5 and S6 in domain III. This region corresponds to a portion of the channel that is believed to contribute to formation of the transmembrane pore. Twenty to 30% of the labeling occurred in a V8 protease fragment between Glu-1349 and Trp-1391. This fragment contains transmembrane segment S6 of domain IV and has previously been shown to form part of the drug receptor for phenylalkylamine Ca2+ antagonists. Our data suggest that the dihydropyridine receptor is formed by close apposition of two discontinuous regions of the alpha 1 subunit sequence in domains III and IV. In light of previous work localizing this receptor site to the extracellular surface of the lipid bilayer, it is proposed that amino acid residues at the extracellular surface in the loop connecting segments IIIS5 and IIIS6 and at the extracellular end of segment IVS6 contribute to formation of the dihydropyridine receptor site.

Affinity Labels↗
PubMed1996

Ceramide-binding and activation defines protein kinase c-Raf as a ceramide-activated protein kinase.

Interleukin 1 is the prototype of an inflammatory cytokine, and evidence suggests that it uses the sphingomyelin pathway and ceramide production to trigger mitogen-activated protein kinase (MAPK) activation and subsequent gene expression required for acute inflammatory processes. To identify downstream signaling targets of ceramide, a radioiodinated photoaffinity labeling analog of ceramide ([125I] 3-trifluoromethyl-3-(m-iodophenyl)diazirine-ceramide) was employed. It is observed that ceramide specifically binds to and activates protein kinase c-Raf, leading to a subsequent activation of the MAPK cascade. Ceramide does not bind to any other member of the MAPK module nor does it bind to protein kinase C-zeta. These data identify protein kinase c-Raf as a specific molecular target for interleukin 1 beta-stimulated ceramide formation and demonstrate that ceramide is a lipid cofactor participating in regulation of c-Raf activity.

Affinity Labels↗
PubMed1996

Synthesis and characterization of a photoactivatable analog of corticotropin-releasing factor for specific receptor labeling.

A novel photoactivatable analog of ovine corticotropin-releasing factor (ovine photoCRF) has been synthesized and characterized. A diazirine group, the 4-(1-azi-2,2,2-trifluoroethyl)benzoyl residue, was covalently bound to the amino terminus of ovine CRF (oCRF), which was N-terminally extended by a tyrosyl residue for radioactive labeling with 125I. Under mild conditions, photolysis yielded highly reactive carbenes, responsible for the formation of covalent bonds to the CRF receptor. Ovine photoCRF was shown to bind to the high-affinity site of the CRF receptor with a similar Kd value as oCRF. When radioactively iodinated ovine photoCRF (ovine 125I-photoCRF) was covalently linked to rat CRF receptor, type 1 (rCRFR1), permanently transfected into human embryonic kidney (HEK) 293 cells, a highly glycosylated 75-kDa protein was identified with SDS/PAGE. The specificity of ovine 125I-photoCRF was demonstrated by the finding that this analog could be displaced from the receptor by oCRF, but not other unrelated peptides such as vasoactive intestinal peptide. The observed size of the 75-kDa cross-link was in agreement with the molecular weight reported earlier for native CRFR1 from rat brain. Deglycosylation of the 75-kDa cross-link with peptide:N-glycosidase (PNGase) yielded a 46-kDa protein, in agreement with the molecular weight estimated from cDNA coding for rat CRFR1. The developed CRF analog, photoCRF, is expected to facilitate future biochemical and physiological analysis of CRF receptors and--by analogous strategies--of other peptide receptors.

Affinity Labels↗
PubMed1997

Direct and GTP-dependent interaction of ADP ribosylation factor 1 with coatomer subunit beta.

A site-directed photocrosslink approach was used to elucidate components that interact directly with ADP- ribosylation factor (ARF)-GTP during coat assembly. Two ARF mutants were generated that contain a photolabile amino acid at positions distant to each other within the ARF molecule. Here we show that one of the two positions specifically interacts with coatomer subunit beta both on Golgi membranes and in isolated coat protein complex type I (COPI)-coated vesicles. Thus, a direct and GTP-dependent interaction of coatomer via beta-coat protein complex (COP) with ARF is involved in the coating of COPI-coated vesicles. These data implicate a bivalent interaction of the complex with the donor membrane during vesicle formation.

ADP-Ribosylation Factors↗
PubMed1999

NADH-quinone oxidoreductase: PSST subunit couples electron transfer from iron-sulfur cluster N2 to quinone.

The proton-translocating NADH-quinone oxidoreductase (EC 1.6.99.3) is the largest and least understood enzyme complex of the respiratory chain. The mammalian mitochondrial enzyme (also called complex I) contains more than 40 subunits, whereas its structurally simpler bacterial counterpart (NDH-1) in Paracoccus denitrificans and Thermus thermophilus HB-8 consists of 14 subunits. A major unsolved question is the location and mechanism of the terminal electron transfer step from iron-sulfur cluster N2 to quinone. Potent inhibitors acting at this key region are candidate photoaffinity probes to dissect NADH-quinone oxidoreductases. Complex I and NDH-1 are very sensitive to inhibition by a variety of structurally diverse toxicants, including rotenone, piericidin A, bullatacin, and pyridaben. We designed (trifluoromethyl)diazirinyl[3H]pyridaben ([3H]TDP) as our photoaffinity ligand because it combines outstanding inhibitor potency, a suitable photoreactive group, and tritium at high specific activity. Photoaffinity labeling of mitochondrial electron transport particles was specific and saturable. Isolation, protein sequencing, and immunoprecipitation identified the high-affinity specifically labeled 23-kDa subunit as PSST of complex I. Immunoprecipitation of labeled membranes of P. denitrificans and T. thermophilus established photoaffinity labeling of the equivalent bacterial NQO6. Competitive binding and enzyme inhibition studies showed that photoaffinity labeling of the specific high-affinity binding site of PSST is exceptionally sensitive to each of the high-potency inhibitors mentioned above. These findings establish that the homologous PSST of mitochondria and NQO6 of bacteria have a conserved inhibitor-binding site and that this subunit plays a key role in electron transfer by functionally coupling iron-sulfur cluster N2 to quinone.

Azirines↗
PubMed1996

Photolabeling of prostaglandin endoperoxide H synthase-1 with 3-trifluoro-3-(m-[125I]iodophenyl)diazirine as a probe of membrane association and the cyclooxygenase active site.

Previous studies of the crystal structure of the ovine prostaglandin endoperoxide H synthase-1 (PGHS-1)/S-flurbiprofen complex (Picot, D., Loll, P. J., and Garavito, R. M. (1994) Nature 367, 243-249) suggest that the enzyme is associated with membranes through a series of four amphipathic helices located between residues 70 and 117. We have used the photoactivatable, hydrophobic reagent 3-trifluoro-3-(m-[125I]iodophenyl)diazirine ([125I]TID) which partitions into membranes and other hydrophobic domains to determine which domains of microsomal PGHS-1 are subject to photolabeling. After incubation of ovine vesicular gland microsomes with [125I]TID, ovine PGHS-1 was one of the major photolabeled proteins. Proteolytic cleavage of labeled PGHS-1 at Arg277 with trypsin established that [125I]TID was incorporated into both the 33-kDa tryptic peptide containing the amino terminus and the 38-kDa tryptic peptide containing the carboxyl terminus. This pattern of photolabeling was not affected by the presence of 20 mM glutathione, indicating that the photolabeling observed for PGHS-1 was not due to the presence of [125I]TID in the aqueous phase. However, nonradioactive TID as well as two inhibitors, ibuprofen and sulindac sulfide, which bind the cyclooxygenase active site of PGHS-1, prevented the labeling of the 38-kDa carboxyl-terminal tryptic peptide. These results suggest that [125I]TID can label both the cyclooxygenase active site in the tryptic 38-kDa fragment and a membrane binding domain located in the 33-kDa fragment. Cleavage of photolabeled PGHS-1 with endoproteinase Lys-C yielded a peptide containing residues 25-166 which was labeled with [125I]TID. This peptide contains the putative membrane binding domain of ovine PGHS-1. Our results provide biochemical support for the concept developed from the crystal structure that PGHS-1 binds to membranes via four amphipathic helices located near the NH2 terminus of the protein.

Affinity Labels↗
PubMed1996

Receptor and membrane interaction sites on Gbeta. A receptor-derived peptide binds to the carboxyl terminus.

The functional organization of Gbetagamma is poorly understood. Regions of bovine brain Gbetagamma that interact with a photoaffinity derivative of an alpha2-adrenergic receptor-derived peptide from the third intracellular loop (diazopyruvoyl-modified peptide Q (DAP-Q)) and a hydrophobic membrane probe (3-trifluoromethyl-3-(m-iodophenyl)diazirine (TID)) were examined. We previously showed that DAP-Q cross-links to specific, competable sites on both the alpha and beta subunits of Go/Gi but not on the gamma subunit and that betagamma subunit was required for stimulation of Go/Gi GTPase activity (Taylor, J. M., Jacob Mosier, G. G., Lawton, R. G., Remmers, A. E., and Neubig, R. R. (1994) J. Biol. Chem. 269, 27618-27624). Similarly, we show here that the membrane-associated photoprobe [125I]TID labels alpha and beta but not gamma. We have now mapped the sites of incorporation of DAP-Q and TID into the beta subunit. TID labels both the 14-kDa amino-terminal and the 23-kDa carboxyl-terminal fragments from a partial tryptic digest of beta while DAP-Q labels only the carboxyl-terminal fragment. Further mapping with endopeptidase Lys C reveals substantial labeling of multiple fragments by TID while DAP-Q labels predominantly a approximately 6-kDa fragment within the carboxyl-terminal 60 amino acids of beta1. Thus, regions within the 7th (or possibly 6th) WD-40 repeat of the beta subunit of G protein interact with the receptor-derived peptide while membrane interaction involves multiple sites throughout the beta subunit.

Animals↗
PubMed1997

Molecular interactions of cyclosporin A with P-glycoprotein. Photolabeling with cyclosporin derivatives.

The interaction between P-glycoprotein (140-180 kDa) from the multidrug-resistant Chinese hamster ovary cell line CHRC5 and cyclosporin A was characterized using three different photoactivable cyclosporin A analogs. Two monoclonal antibodies, which are able to discriminate between two major domains of cyclosporin A (the cyclophilin and calcineurin binding domains), were used to detect the photolabeled proteins. A protein of 155 kDa corresponding to P-glycoprotein was much more strongly photolabeled in membranes of CHRC5 cells than in membranes of their drug-sensitive parent cell line AuxB1. The antitumor drug vinblastine and the reversal agents verapamil and cyclosporin A inhibited the photolabeling, and the nonimmunosuppressive derivative PSC-833 caused a stronger inhibition than cyclosporin A. P-glycoprotein photolabeled with cyclosporin A analogs was only detected with the monoclonal antibody that recognizes cyclosporin A and its metabolites, indicating that the calcineurin binding domain recognized specifically by the other antibody is not exposed. These results suggest that the portion of cyclosporin A that binds to calcineurin plays a role in the interaction of cyclosporin A with P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

The membrane binding domains of prostaglandin endoperoxide H synthases 1 and 2. Peptide mapping and mutational analysis.

Prostaglandin endoperoxide H synthases 1 and 2 (PGHS-1 and -2) are the major targets of nonsteroidal anti-inflammatory drugs. Both isozymes are integral membrane proteins but lack transmembrane domains. X-ray crystallographic studies have led to the hypothesis that PGHS-1 and -2 associate with only one face of the membrane bilayer through a novel, monotopic membrane binding domain (MBD) that is comprised of four short, consecutive, amphipathic alpha-helices (helices A-D) that include residues 74-122 in ovine PGHS-1 (oPGHS-1) and residues 59-108 in human PGHS-2 (hPGHS-2). Previous biochemical studies from our laboratory showed that the MBD of oPGHS-1 lies somewhere between amino acids 25 and 166. In studies reported here, membrane-associated forms of oPGHS-1 and hPGHS-2 were labeled using the hydrophobic, photoactivable reagent 3-trifluoro-3-(m-[(125)I]iodophenyl)diazirine, isolated, and cleaved with AspN and/or GluC, and the photolabeled peptides were sequenced. The results establish that the MBDs of oPGHS-1 and hPGHS-2 reside within residues 74-140 and 59-111, respectively, and thus provide direct provide biochemical support for the hypothesis that PGHS-1 and -2 do associate with membranes through a monotopic MBD. We also prepared HelA, HelB, and HelC mutants of oPGHS-1, in which, for each helix, three or four hydrophobic residues expected to protrude into the membrane were replaced with small, neutral residues. When expressed in COS-1 cells, HelA and HelC mutants exhibited little or no catalytic activity and were present, at least in part, as misfolded aggregates. The HelB mutant retained about 20% of the cyclooxygenase activity of native oPGHS-1 and partitioned in subcellular fractions like native oPGHS-1; however, the HelB mutant exhibited an extra site of N-glycosylation at Asn(104). When this glycosylation site was eliminated (HelB/N104Q mutation), the mutant lacked cyclooxygenase activity. Thus, our mutational analyses indicate that the amphipathic character of each helix is important for the assembly and folding of oPGHS-1 to a cyclooxygenase active form.

Amino Acid Sequence↗
PubMed2000

Examining the noncompetitive antagonist-binding site in the ion channel of the nicotinic acetylcholine receptor in the resting state.

3-Trifluoromethyl-3-(m-[(125)I]iodophenyl)diazirine ([(125)I]TID) has been shown to be a potent noncompetitive antagonist (NCA) of the nicotinic acetylcholine receptor (AChR). Amino acids that contribute to the binding site for [(125)I]TID in the ion channel have been identified in both the resting and desensitized state of the AChR (White, B.H., and Cohen, J.B. (1992) J. Biol. Chem. 267, 15770-15783). To characterize further the structure of the NCA-binding site in the resting state channel, we have employed structural analogs of TID. The TID analogs were assessed by the following: 1) their ability to inhibit [(125)I]TID photoincorporation into the resting state channel; 2) the pattern, agonist sensitivity, and NCA inhibition of [(125)I]TID analog photoincorporation into AChR subunits. The addition of a primary alcohol group to TID has no demonstrable effect on the interaction of the compound with the resting state channel. However, conversion of the alcohol function to acetate, isobutyl acetate (TIDBIBA), or to trimethyl acetate leads to rightward shifts in the concentration-response curves for inhibition of [(125)I]TID photoincorporation into the AChR channel and a progressive reduction in the agonist sensitivity of [(125)I]TID analog photoincorporation into AChR subunits. Inhibition of [(125)I]TID analog photoincorporation by NCAs (e.g. tetracaine) as well as identification of the sites of [(125)I]TIDBIBA photoincorporation in the deltaM2 segment indicate a common binding locus for each TID analog. We conclude that relatively small additions to TID progressively reduce its ability to interact with the NCA site in the resting state channel. A model of the NCA site and resting state channel is presented.

Animals↗
PubMed2000

A conformational intermediate between the resting and desensitized states of the nicotinic acetylcholine receptor.

The structural changes induced in the nicotinic acetylcholine receptor by two noncompetitive channel blockers, proadifen and phencyclidine, have been studied by infrared difference spectroscopy and using the conformationally sensitive photoreactive noncompetitive antagonist 3-(trifluoromethyl)-3-m-([(125)I]iodophenyl)diazirine. Simultaneous binding of proadifen to both the ion channel pore and neurotransmitter sites leads to the loss of positive markers near 1663, 1655, 1547, 1430, and 1059 cm(-)(1) in carbamylcholine difference spectra, suggesting the stabilization of a desensitized conformation. In contrast, only the positive markers near 1663 and 1059 cm(-)(1) are maximally affected by the binding of either blocker to the ion channel pore suggesting that the conformationally sensitive residues vibrating at these two frequencies are stabilized in a desensitized-like conformation, whereas those vibrating near 1655 and 1430 cm(-)(1) remain in a resting-like state. The vibrations at 1547 cm(-)(1) are coupled to those at both 1663 and 1655 cm(-)(1) and thus exhibit an intermediate pattern of band intensity change. The formation of a structural intermediate between the resting and desensitized states in the presence of phencyclidine is further supported by the pattern of 3-(trifluoromethyl)-3-m-([(125)I]iodophenyl)diazirine photoincorporation. In the presence of phencyclidine, the subunit labeling pattern is distinct from that observed in either the resting or desensitized conformations; specifically, there is a concentration-dependent increase in the extent of photoincorporation into the delta-subunit. Our data show that domains of the nicotinic acetylcholine receptor interconvert between the resting and desensitized states independently of each other and suggest a revised model of channel blocker action that involves both low and high affinity agonist binding conformational intermediates.

Animals↗
PubMed2001

Evidence for a central apolipoprotein A-I domain loosely bound to lipids in discoidal lipoproteins that is capable of penetrating the bilayer of phospholipid vesicles.

Previous evidence indicated that discoidal reconstituted high density lipoproteins (rHDL) of apolipoprotein A-I (apoA-I) can interact with lipid membranes (Tricerri, M. A., Córsico, B., Toledo, J. D., Garda, H. A., and Brenner, R. R. (1998) Biochim. Biophys. Acta 1391, 67-78). With the aim of studying this interaction, photoactivable reagents and protein cleavage with CNBr and hydroxylamine were used. The generic hydrophobic reagent 3-(trifluoromethyl)-3-(m-[125I]iodophenyl)diazirine gave information on the apoA-I regions in contact with the lipid phase in the rHDL discs. Two protein regions loosely bound to lipids were detected: a C-terminal domain and a central one located between residues 87 and 112. They consist of class Y amphipathic alpha-helices that have a different distribution of the charged residues in their polar faces by comparison with class A helices, which predominate in the rest of the apoA-I molecule. The phospholipid analog 1-O-hexadecanoyl-2-O-[9-[[[2-[125I]iodo-4-(trifluoro-methyl-3-H-diazirin-3-yl)benzyl]oxy]carbonyl]nonanoyl]-sn-glycero-3-phosphocholine, which does not undergo significant exchange between membranes and lipoproteins, was used to identify the apoA-I domain directly involved in the interaction of rHDL discs with membranes. By incubating either rHDL or lipid-free apoA-I with lipid vesicles containing 125I-TID-PC, only the 87-112 apoA-I segment becomes labeled after photoactivation. These results indicate that the central domain formed by two type Y helices swings away from lipid contact in the discoidal lipoproteins and is able to insert into membrane bilayers, a process that may be of great importance for the mechanism of cholesterol exchange between high density lipoproteins and cell membranes.

Amino Acid Sequence↗
PubMed1985

Time scale of radiation damage by 2,4-dinitrophenyl-aziridine (CB 1954) in Chinese hamster cells: a rapid-mix study.

A rapid-mix device was used to study the time-scale of radiation sensitization of hypoxic cells by CB 1954, a monofunctional alkylating agent. It has an electron affinity (E1(7)-385 mV) similar to that of misonidazole but its effectiveness as a sensitizer occurs at a five-fold lower concentration under stationary-state conditions. In the rapid-mix study, the enhancement ratio (e.r.) value of 1 mmol dm-3 CB 1954 rapidly rises to 1.75 within 120 ms, with no further rise by 500 ms. The e.r. obtained is lower than that observed under stationary-state conditions for a similar concentration. The data suggests that CB 1954 sensitizes by at least two independent mechanisms.

Aminoimidazole Carboxamide↗
PubMed1987

Radiosensitization by the 2,4-dinitro-5-aziridinyl benzamide CB 1954: a structure/activity study.

CB 1954 (2,4-dinitro-5-aziridinyl benzamide) is a radiosensitizer which is up to 10 times more efficient in vitro than would be predicted on the basis of its electron affinity. In order to determine the contribution of the various functional groups comprising the molecule to overall sensitizing efficiency, nine structural analogues have been studied. The redox potential, E7(1), and sensitizing efficiency, C1.6, were obtained for each compound. The value of C1.6 depends on both redox potential and the magnitude of an additional component defined by C1.6/C1.6, where C1.6 is derived from a structure/activity relationship (Adams et al. 1979 b, Wardman 1982) described by the equation: log (C1.6/mol dm-3) = (6.96 +/- 0.22) + (9.54 +/- 0.56)E7(1)V. The magnitude of C1.6/C1.6 for CB 1954 and its analogues depends on alkyl substitution of the amide, the presence/absence and position of the nitro groups and is independent of the presence of the aziridine group. Holding cells in the presence of the drug post-irradiation marginally enhanced sensitization by CB 1954, CB 10-107 and by CB 10-092 but the largest effect was seen with the mononitro compound CB 7060 which also has a value of 26 for C1.6/C1.6. This compound was also interesting in that when combined with 2-phenyl-4(5)amino-5(4)-imidazole carboxamide (phenyl AIC) an enhancement of sensitization was obtained. In contrast, phenyl AIC protected against radiosensitization by CB 1954. Taken together, the data suggest that multiple mechanisms of radiosensitization may contribute to the abnormal radiosensitizing efficiency of CB 1954 and its analogues. This has implications for the further design and development of novel radiosensitizing drugs.

Aminoimidazole Carboxamide↗
PubMed1987

Direct probing of the interaction between the signal sequence of nascent preprolactin and the signal recognition particle by specific cross-linking.

We have studied the interaction between the signal sequence of nascent preprolactin and the signal recognition particle (SRP) during the initial events in protein translocation across the endoplasmic reticulum membrane. A new method of affinity labeling was used, whereby lysine residues, carrying the photoreactive group 4-(3-trifluoromethyldiazirino) benzoic acid in their side chains, are incorporated into a protein by means of modified lysyl-tRNA, and cross-linking to the interacting component is induced by irradiation. SRP interacts through its Mr 54,000 polypeptide component with the signal sequences of nascent preprolactin chains containing about 70 residues, and with decreasing affinity with longer chains as well; it causes inhibition of elongation. Binding of SRP is reversible and requires the nascent chain to be bound to a functional ribosome. SRP cross-linked to the signal sequence still inhibits elongation but does not prevent it completely. We conclude that SRP does not block the exit site of the polypeptide chain on the ribosome. The SRP receptor of the endoplasmic reticulum membrane displaces the signal sequence from SRP and, even if SRP is cross-linked, releases elongation arrest.

Animals↗
PubMed1986

Effect of azimexon therapy on host defense parameters and disease-associated symptoms in the acquired immune deficiency syndrome (AIDS) and AIDS-related complex (ARC).

Azimexon, a 2-cyan-aziridinyl immune modulator, was given at a dose of 250 mg/m2/day for 10 days IV to 12 patients with AIDS and 16 with AIDS related complex (ARC). A decrease in total number of AIDS related symptoms from 43 to 24 and in mean number from 2.6 to 1.5 was observed among ARC patients (p less than .01). The most commonly improved symptoms were diarrhea, fatigue, and weight loss with the least frequently improved being lymphadenopathy. The following improvements in immune parameters were observed among ARC patients. DTH to recall antigens improved with an increase in number of positive tests from 35 to 47 and in mean number of positive skin tests from 2.2 on day 0 to 2.9 on day 14 (P less than .05). The geometric mean of the absolute lymphocyte count was 1.395 X 10(3)/microliter on day 0 with a significant increase of 18.0 percent on day 5 (P less than .01) and a 7.7 percent increase on day 21. The geometric mean of the OKT4+ cells on day 0 was 0.250 X 10(3)/microliter with a 33.3 percent increase on day 5 (P less than .07) and a 14.1 percent increase on day 21. T4/T8 ratio increased by 32.7 percent on day 5 (P less than .05) and by 19.4 percent on day 21 from an initial geometric mean of 0.339 X 10(3)/microliter on day 0. The geometric mean of GVH responses increased by 18.2 percent on day 5 (P less than .05) and by 24.0 percent on day 21 (P less than .07) from an initial value of 41.04 mm3. No symptomatic or immunologic improvements were observed among AIDS patients, but rather a significant decrease in mitogenic responses. PHA responses decreased by 70.3 percent on day 5 (P less than .05) and 42.2 percent on day 21 from an initial geometric mean of 4.02 X 10(3) cpm/10(3). Con-A responses decreased by 75.1 percent on day 5 (P less than .05) and increased by 20.3 percent on day 21 from an initial value of 1.14 X 10(3)/10(5) cells. Pretreatment number of absolute OKT4+ cells was the most significant prognostic survival variable. Thus, 8/9 patients with less than 0.10 X 10(3) OKT4+ blood cell/microliter subsequently died as compared to only 1/17 with greater than or equal to 0.10 X 10(3) OKT4+ cells (p less than .001). The only toxic effect of this treatment was mild hemolysis which disappeared upon cessation of treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

AIDS-Related Complex↗