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Biomedical subjects

J Goudsmit

Publications and source records attributed to J Goudsmit.

At least 253 records · Page 14Linked to original sources
PubMed1991

Low number of functionally active B lymphocytes in the peripheral blood of HIV-1-seropositive individuals with low p24-specific serum antibody titers.

The in vitro synthesis of HIV-1, p24-, reverse transcriptase (RT)- and gp120-specific immunoglobulin (Ig) G by unstimulated peripheral blood mononuclear cells (PBMC) from 38 asymptomatic and 10 symptomatic HIV-1-seropositive individuals was analysed. In the majority of these individuals, spontaneous production of HIV-1- and gp120-specific IgG from PBMC cultures was demonstrated. In addition, in the majority of the PBMC cultures from individuals with high serum antibody titers to p24, spontaneous production of p24-specific IgG was shown. In contrast, no p24-specific IgG production was detected in PBMC cultures from seropositive individuals with low or no serum antibody titers to p24. A similar relationship between low or absent RT-specific serum antibody titers and the absence of in vitro RT-specific IgG synthesis was not demonstrated. Furthermore, it was shown that the number of p24-specific B lymphocytes in circulation, as calculated by a spot enzyme-linked immunosorbent assay, were significantly lower in individuals with low serum antibody titers to p24. These results suggest that the decline in p24-specific serum antibodies observed during progression towards AIDS is not merely a reflection of the clearance via immune complexes, but may also be attributable, at least in part, to a reduction of p24-specific antibody-producing active B lymphocytes.

Antibody-Producing Cells↗
PubMed1991

Neutralizing activity of anti-peptide antibodies against the principal neutralization domain of human immunodeficiency virus type 1.

Monoclonal antibodies (MAbs) raised against a 15-mer peptide representing the centre of the principal neutralization domain of human immunodeficiency virus type 1 (strain BH10) showed wide variations in neutralizing activity against the homologous strain. The nature of this difference in neutralizing activity was studied by measuring antibody concentration, their affinity for peptide and specificity, by reaction with peptides which differed in the extent of sequence overlap, length and the presence of single amino acid replacements. All MAbs bound to approximately the same region in the principal neutralization domain, within the sequence RIQRGPGRAFV. The peptides with which each antibody was able to react differed by only a few amino acids. The neutralizing activity of each MAb preparation was related to its affinity and concentration; the affinity is related in part to the fine structure of the epitope recognized. MAbs with high affinity for the peptide tended to react only with peptides in which amino acid replacements did not affect the beta-turn potential of the peptide, whereas the reactivity of MABs with low affinity was relatively insensitive to amino acid replacements affecting the beta-turn potential.

Amino Acid Sequence↗
PubMed1991

Characterization of human antibody-binding sites on the external envelope of human immunodeficiency virus type 2.

Antibody-reactive peptide scanning (Pepscan) using overlapping nonapeptides and human sera as probes allows the identification of amino acids contributing significantly to antigen-antibody interaction. Five-hundred and two overlapping nonapeptides derived from the human immunodeficiency virus type 2 strain Rod (HIV-2Rod) external envelope glycoprotein gp125 were synthesized to serve as probes for reactivity with eight sera of HIV-2-infected individuals. Fifteen antibody-binding regions were identified, among which two amino-terminal regions [E3, amino acids (aa) 118 to 132; E4, aa 125 to 141] and four carboxy-terminal regions (E11, aa 303 to 324; E12, aa 340 to 358; E14, aa 436 to 452; E15, aa 486 to 507) were the most antigenic. The amino acids in binding sites E3 and E4 were highly variable among simian immunodeficiency virus (SIV), HIV-2 and HIV-1. The antibody-binding domains E14 and E15 were highly conserved among HIV-2 strains (94% and 86% identity of HIV-2Rod to HIV-2Isy and HIV-2NIHZ, respectively). Both domains had more amino acids in common with SIV (88% for E14, 64% for E15) than with HIV-1 (41% for E14, 45% for E15). Epidemiological studies revealed that the sera of African HIV-2-infected individuals bound the E11 and E15 peptides best (31%, 8/26). The sera of African HIV-1-infected individuals showed significant levels of cross-reactivity to the HIV-2 peptides, especially to the E15 peptide, whereas the sera of European HIV-1-infected individuals showed only moderate levels of cross-reactivity. If peptides covering the E15 epitope were used, African HIV-2-positive sera showed only a low level of cross-reactivity (4%) to E15 of HIV-1 and SIV. African HIV-1-positive sera bound the HIV-1 E15 peptide best (81%, 52/64), but showed high levels of cross-reactivity to SIV E15 (17%, 11/64) and HIV-2 E15 (25%, 16/64). European HIV-1-positive sera showed a high level of reactivity of HIV-1 E15 (91%, 50/55) and a low level of cross-reactivity to the HIV-2 (2%, 1/55), and none to the SIV E15 (0/55) peptide. These results indicate that the immunodominant regions of the HIV-2 external envelope (E11 and E15) align with the most immunodominant regions of HIV-1.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Serum beta 2-microglobulin levels in asymptomatic HIV-1-infected subjects during long-term zidovudine treatment.

beta 2-microglobulin levels were determined in the serum of 18 initially asymptomatic HIV-1 p24 antigenaemic subjects who were treated with zidovudine (+/- acyclovir) and who were followed for 2 1/2 years. The median serum beta 2-microglobulin level at week 0 was 2.5 mg/l and decreased to 2.3 mg/l after 12 weeks of treatment (p = 0.001). A correlation was found between individual changes in serum beta 2-microglobulin levels and individual changes in serum p24 antigen levels during the first 48 weeks of treatment (p less than 0.05). Six out of 18 subjects progressed to AIDS after 60-126 weeks of treatment. In this group during a period of more than one year before disease progression median serum beta 2-microglobulin levels increased from 2.5 mg/l to 3.3 mg/l (p = 0.03) and median CD4+ cell counts decreased from 0.3 x 10(9)/l to 0.08 x 10(9)/l (p = 0.03), while in that period the pattern of serum p24 antigen levels was inconsistent. Although the variability in serum beta 2-microglobulin levels appeared to make this marker unsuitable for management decisions in individuals, a decline in beta 2-microglobulin levels was found to parallel a decline in p24 antigen levels during the early phase of zidovudine treatment. Moreover, after prolonged treatment, rising beta 2-microglobulin levels--in contrast to p24 antigen levels--were shown to have predictive value for disease progression.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Antibody reactivity to deletion mutants of the HIV-1 SF2 envelope.

In human immunodeficiency virus type 1 (HIV-1) infected individuals, the antibody response to the external envelope (gp120) is associated with in vitro neutralization. To further characterize the anti-gp120 response, we examined the IgG reactivity of 75 HIV-1-seroconverted and 200 HIV-1-seropositive individuals to deletion mutants of gp120 in an enzyme immunoassay. We used yeast-derived, non-glycosylated recombinant HIV-1 SF2 gp120 equivalent and-variants deleted in variable regions. We observed two distinctive response patterns: IgG non-responders (SF2-V3-restricted responders) and IgG responders to conserved regions of gp120. This divergence in response pattern occurred soon after gag/env HIV-1 antibody seroconversion and persisted in time within an individual. In addition, the SF2-V3-restricted responders had a higher frequency of HIV-1 core antigen positivity and HIV-1 core antibody negativity than the non-restricted responders. These results suggest that specific and persistent host antibody response patterns to gp120 develop early in HIV-1 infection and that these patterns are associated with differences in HIV-1 expression.

Cohort Studies↗
PubMed1991

Contribution of antibody response to recombinant HIV-1 gene-encoded products nef, rev, tat, and protease in predicting development of AIDS in HIV-1-infected individuals.

The relation between antibody-response profiles to Escherichia coli-produced HIV-1 nef, rev, tat, and protease proteins and the risk of developing AIDS was studied using stored serum samples taken sequentially from a cohort of 195 initially symptom-free men who were seropositive for antibodies to HIV-1 structural proteins and 72 men who seroconverted for such antibodies. The AIDS attack rates at 39 months follow-up were significantly higher in the men with negative versus positive antibody profiles to nef, tat, and protease, respectively. [Difference (D) between attack rates = 11.279, 5.884, and 8.322, respectively]. No significant difference was found between men with negative versus positive antibody profiles to rev. The above differences between AIDS attack rates were clearly lower than those reported from the same cohort for men who were serum HIV-1 antigen positive versus negative, and for men with low versus normal CD4+ lymphocyte counts, but with respect to nef antibody-response profiles, resembled the difference reported between anti-HIV-1 core antibody-negative versus antibody-positive men. In the subgroup of men without any of the markers previously found to be predictive of progression to AIDS in the cohort (persistent HIV-1 p24 antigenemia, low anti-HIV-1 anti-core antibody reactivity, and low CD4+ cell counts), antibody profiles to nef, rev, tat, and protease did not contribute to the prediction of outcome of infection. When used in combination with persistent HIV-1 p24 antigenemia and low CD4+ cell counts, negative antibody profiles to nef and protease, respectively, were equally sensitive and specific in predicting progression to AIDS, as was low anti-HIV-1 anti-core antibody reactivity.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Zidovudine sensitivity of human immunodeficiency viruses from high-risk, symptom-free individuals during therapy.

Human immunodeficiency type 1 isolates from 18 initially symptom-free men who were treated with zidovudine for 2 years were investigated for drug sensitivity. At the start all the men had persistent core antigenaemia; the acquired immunodeficiency syndrome developed in 6 during the study. The polymerase chain reaction was used to detect mutations at residue 215 of reverse transcriptase, a mutation associated with reduced drug sensitivity. After 2 years 16/18 isolates were mutant. However, after about 6 months of treatment the mutation was detected in only 7 isolates, 4 from individuals who subsequently had AIDS. Limited direct virus sensitivity data correlated with the genetic data. The rate of appearance of the 215 mutation seemed to correlate with CD4 counts and viral virulence.

CD4 Antigens↗
PubMed1990

Phosphate-methylated DNA aimed at HIV-1 RNA loops and integrated DNA inhibits viral infectivity.

Phosphate-methylated DNA hybridizes strongly and specifically to natural DNA and RNA. Hybridization to single-stranded and double-stranded DNA leads to site-selective blocking of replication and transcription. Phosphate-methylated DNA was used to interrupt the life cycle of the human immunodeficiency virus type-1 (HIV-1), the causative agent of acquired immunodeficiency syndrome (AIDS). Both antisense and sense phosphate-methylated DNA 20-nucleotide oligomers, targeted at the transactivator responsive region and the primer binding site, caused complete inhibition of viral infectivity at a low concentration. Hybridization of phosphate-methylated DNA with folded and unfolded RNA was studied by ultraviolet and proton nuclear magnetic resonance spectroscopy. The combined results of hybridization studies and biological experiments suggest that the design of effective antisense phosphate-methylated DNA should focus on hairpin loop structures in the viral RNA. For sense systems, the 5' end of the integrated viral genome is considered to be the important target site.

Anticodon↗
PubMed1990

Immune response and epitope mapping of a candidate HIV-1 p17 vaccine HGP30.

A thirty amino acid synthetic peptide (HGP30) representing the conserved region of HIV-1 p17 induced high titer antibodies to the native p17 in rabbits. This immune sera neutralized HIV-1 replication in cell culture and one of the high titer antisera also inhibited CD4-dependent cell fusion. Pepscan analysis with overlapping nonapeptides derived from the sequence of HIV-1 p17 identified the sequence (KE) ALDKIEE (EQ) as the major antibody binding site. Sera of 9% of AIDS patients (7/76) and 18% of HIV-1 seropositive healthy homosexuals (40/223) were positive for HGP30 antibodies. Decline in HIV-1 p17 antibodies has been shown to be related to disease progression in both children and adults, suggesting that HIV-1 p17 antibodies may be protective. Hence, a synthetic HIV-1 p17 peptide, representing the immunodominant epitope, could be useful as a candidate vaccine for immunization of HIV-1 seronegative or seropositive healthy homosexuals.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Speed of progression to AIDS and degree of antibody response to accessory gene products of HIV-1.

Antibodies to E. coli-produced HIV-1 nef, rev, tat, vpu, and vpr proteins were measured by enzyme immunoassay in serial sets of sera from 72 men seroconverting for antibodies to HIV-1 structural proteins, and from 190 initially symptom-free men who were seropositive for these antibodies at entry into the study. In the men seroconverting for antibodies to structural proteins the levels of nef-, rev-, and tat-specific antibodies, but not of vpu-, and vpr-specific antibodies, within 3 months of seroconversion, appeared to be lower in the five men progressing to AIDS, compared with the men remaining symptom-free during follow-up. Analysis of the prevalence of previously described antibody profiles to these accessory gene products was carried out. In all HIV-1 antibody seroconverters and in those HIV-1 antibody seropositive men with 15 or more months of follow-up who progressed to AIDS, there was a shift from predominantly nef- and vpu-specific antibody negative profiles in the men developing AIDS in the early years of the study to predominantly nef- and vpu-specific antibody positive profiles in men who developed AIDS later. Rev- and tat-specific antibody negative profiles were dominant in men progressing to AIDS throughout follow-up. No vpr-specific antibody profile occurred preferentially in the men progressing to AIDS throughout follow-up. Low antibody reactivity to accessory gene products nef, rev, and tat appears, like low anti-core antibody reactivity, to be associated with progression to AIDS relatively rapidly after infection with HIV-1.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Association of antibodies blocking HIV-1 gp 160-sCD4 attachment with virus neutralizing activity in human sera.

Sera, from HIV-1 and HIV-2 seropositive individuals, were tested for the presence of antibodies able to inhibit the binding (BI) of HIV-IIIB gp 160 (produced in mammalian cells using a vaccinia expression system) to the extracellular portion of the CD4 receptor. A competition enzyme immunoassay (EIA) with soluble CD4 (sCD4) was used. BI antibodies were highly prevalent among HIV-1 seropositives but not in HIV-2 infected individuals. Attempts to localize the binding site for these BI antibodies on the primary sequence of gp 120 by using synthetic peptides encompassing the putative CD4 binding site on gp 120 (aa 397-439) were not successful. This study did not reveal a significant correlation between the presence of BI antibodies and disease evolution. BI antibody titres correlated less well with anti-gp 160 titres (r = 0.51, P less than or equal to 0.011) than with neutralizing antibody (NA) titres using either the isolates HIV-SF2 (SF2) (r = 0.77, P less than or equal to 0.000) and HIV-MN (MN) (r = 0.61, P less than or equal to 0.002) or the isolate HIV-IIIB (HX10) (r = 0.89, P less than or equal to 0.000) of which the gp 160 for the assays was derived. An HIV-IIIB neutralizing serum, elicited in a rabbit by immunization with a 17-mer synthetic peptide derived from the third variable domain (V3) of gp 120, did bind gp 160 without inhibiting the subsequent attachment of sCD4 to gp 160.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding, Competitive↗
PubMed1990

Long-term zidovudine treatment of asymptomatic HIV-1-infected subjects.

Eighteen asymptomatic men with persistent human immunodeficiency virus type 1 (HIV-1) p24 antigenemia were treated with zidovudine 250-500 mg (+/- acyclovir 800 mg) 6-hourly for 4-12 weeks, and thereafter with zidovudine 500 mg (+/- acyclovir 1600 mg) 12-hourly for 92 weeks. Six additional HIV-1 p24 antigenemic subjects were treated with zidovudine 500 mg 12-hourly for 76 weeks. Disease progression occurred in 4 subjects, despite sustained reduction of serum HIV-1 p24 antigen levels: Pneumocystis carinii pneumonia was diagnosed after 60, 80, 90 and 93 weeks, respectively. The median CD4+ cell count of these 4 men at study entry was 0.2 x 10(9)/l, and it declined to 0.07 x 10(9)/l at the moment AIDS was diagnosed. In 20 subjects no disease progression occurred. The median CD4+ cell count of these 20 men at study entry was 0.4 x 10(9)/l and it was 0.45 x 10(9)/l at the end of the study period. Median serum HIV-1 p24 antigen levels at the end of the study period were 42% lower than at study entry in these 20 subjects. In 5/20 men, an initial decline was followed by a rise in antigen levels to above pretreatment value. Treatment with zidovudine was well tolerated. Anemia caused symptoms in 3/24 men, but prolonged leucopenia or neutropenia did not occur. None developed clinical or convincing biochemical evidence of zidovudine-associated myopathy.

Acquired Immunodeficiency Syndrome↗