Biomedical subjects

T F Wolfs

Publications and source records attributed to T F Wolfs.

28 records · Page 2Linked to original sources

PubMed1992

HIV-1 genomic RNA diversification following sexual and parenteral virus transmission.

Human immunodeficiency virus type 1 (HIV-1) genomic RNA variation was studied in seven presumed donor-recipient pairs directly following sexual (6/7) or parenteral (1/7) transmission. The first RNA-positive serum sample of each recipient and the serum sample of the virus transmitter, identified by epidemiological history and taken within a time bracket of three months of the recipient seroconversion, were analyzed by polymerase chain reaction amplification followed by sequencing of eight cDNA clones of 276 bp, including the V3 coding region. The sequence populations of the recipients were without exception homogeneous, while the sequence populations of the transmitters showed varying degrees of heterogeneity. Nucleotide distance between consensus sequences of unrelated individuals from the Amsterdam population (interpatient variation) averaged 11% (range 7-15%). The largest distance between two clonal sequences of one individual (intrapatient variation) was also 11%. Consensus sequences of five recipients differed by only 0-1% from the consensus sequence of the presumed transmitter, including two pairs of which the transmission was either proven or highly probable. This contrasted with a difference of 10-12% in two pairs, casting doubt on the epidemiological relatedness. Antibody reactivity to a panel of V3 peptides with varying degrees of similarity to the V3 sequences obtained did not augment the discriminatory power of sequence analysis. Results of the sequential sequencing of samples of one transmitter suggest that this was due to an anamnestic antibody response of the transmitter to early variants. From the loss of sequence heterogeneity following transmission and the consensus sequence similarities observed within five transmitter-recipient pairs, we conclude that HIV-1 transmission results in the selection of a limited number of genomes carrying on the infection in the new host, but does not generally lead to a shift in the sequence population as defined by the consensus sequence.

Amino Acid Sequence↗

PubMed1992

Characterization of the specificity of the human antibody response to the V3 neutralization domain of HIV-1.

The major neutralization domain of HIV-1, contained in the third variable region (V3) of the external envelope, is highly variable at positions flanking a conserved glycine-proline-glycine sequence. We investigated the relation between V3 sequences of HIV-1 variants circulating in a host and that host's antibody specificity. Multiple V3 sequences were obtained directly, via PCR and subsequent cloning, from serum RNA or cellular DNA from 26 individuals (from 12 around seroconversion). Then, specificity of sera from these individuals to a panel of V3 peptides was determined. The specificity (best recognized peptide) of the early antibody response accurately reflected the virus population circulating around seroconversion in 12/12 individuals and 4/4 HIV-1-infected chimpanzees. A change in serum specificity at later stages of infection was rare: five years after seroconversion, only 3 of 46 individuals had a specificity that differed completely from that in the first year. However, the V3 domain of the virus does change over time, as evidenced by the poor correlation between V3 sequences obtained late in infection and V3 antibody reactivity at the same time point. Thus, in contrast to the accurate antibody response to HIV-1 variants early after infection, generally a specific response to variants emerging at later stages seemed to be absent or of low level. Instead, the early response appeared to be preserved. Finally, we made use of the observed accurate reflection to analyze the variation for the V3 domain of HIV-1 in the Netherlands by probing specificities of early sera from 129 Dutch seroconverting individuals. Specific reactivity to RKSIHIGPGRAFYTTG was found in 36%, to RKSINIGPGRAFYTTG in 12% and to RKSIPIGPGRAFYTTG in 18% of these Dutch sera.

Amino Acid Sequence↗

PubMed1991

Antigenic diversity thresholds and the development of AIDS.

Longitudinal studies of patients infected with HIV-1 reveal a long and variable incubation period between infection and the development of AIDS. Data from a small number of infected patients show temporal changes in the number of genetically distinct strains of the virus throughout the incubation period, with a slow but steady rise in diversity during the progression to disease. A mathematical model of the dynamic interaction between viral diversity and the human immune system suggests the existence of an antigen diversity threshold, below which the immune system is able to regulate viral population growth but above which the virus population induces the collapse of the CD4+ lymphocyte population. The model suggests that antigenic diversity is the cause, not a consequence, of immunodeficiency disease. The model is compared with available data, and is used to assess how the timing of the application of chemotherapy or immunotherapy influences the rate of progress to disease.

Acquired Immunodeficiency Syndrome↗

PubMed1991

Naturally occurring mutations within HIV-1 V3 genomic RNA lead to antigenic variation dependent on a single amino acid substitution.

In a study on the evolution of genomic diversity of HIV-1, genomic RNA was isolated from serum of two individuals. Starting at the time of primary infection we collected six samples of serum from each patient over a period of 5 years. Ninety-four cDNA clones (50 of patient 1 and 44 of patient 495) of part of the envelope coding region including the principal neutralization domain (PND) were sequenced. Around the time of antibody seroconversion, genomic RNA levels reached a peak and the population of sequences was highly homogeneous. In the course of the infection, the number of amino acid substitutions accumulated, which led to a higher genomic diversity within successive samples and a drift in the consensus sequence, progressively differing from the first found consensus sequence. Fixation of a substitution at glycoprotein 120 amino acid 308 was observed in both patients between two time points (patient 1, H----P; patient 495, P----H). With the use of 16-meric synthetic peptides, differing only at the 308 position (H308 versus P308), antibody binding specificity was found to be dependent on this difference. In patient 495, the nonconservative (P308----H) substitution reduced the binding affinity with the patient's antibodies. Furthermore, antibody competition assays showed that the observed substitution at position 308 elicited a new antibody population, indicating antigenic variation. After the decline of V3-specific antibodies, the simultaneous increase in genomic RNA levels and progression to AIDS in patient 495, a new variant with major changes in the PND emerged, again forming a homogeneous population of sequences.

Acquired Immunodeficiency Syndrome↗

PubMed1991

Immunodominance and antigenic variation of the principal neutralization domain of HIV-1.

The principal neutralization domain (PND) of HIV-1 is located in the third variable region (V3) of the envelope glycoprotein gp 120. Cross-reactivity of experimental and natural sera with recombinant proteins containing the V3 region of four HIV-1 variants showed that a group of viruses (among which HIV-1 MN) had antigenically similar V3 regions. The V3 regions of HIV-1 IIIB and HIV-1 RF were antigenically distinct. Antibodies raised to V3 domains of two isolates from the "MN group" neutralized HIV-1 MN (and not HIV-1 IIIB), thus confirming the antigenic similarity of V3 of these isolates to that of HIV-1 MN. Human antibodies to the V3 region were shown to be mainly directed to the central area in V3, where the neutralization domain is. In addition, antibody reactivities in sera of 397 Dutch and 39 Tanzanian HIV-1-infected individuals show that the V3 neutralization domain is highly antigenic, and that viruses from the MN group predominate in The Netherlands and to a lesser extent in Tanzania. Thus, if the protective value of antibodies to the PND can be established, then PND (poly)peptides derived from the MN group may be important components of a subunit vaccine against HIV-1.

Amino Acid Sequence↗

PubMed1990

Evolution of sequences encoding the principal neutralization epitope of human immunodeficiency virus 1 is host dependent, rapid, and continuous.

The principal neutralization epitope of human immunodeficiency virus 1 is localized in the third variable (V3) domain of the external envelope and has been shown to bind isolate-specific antibodies. Therefore, the extent of variation within the nucleic acid sequence encoding this epitope was studied in DNA directly obtained from peripheral blood mononuclear cells of six children and their plasma donor. This revealed that the quasi-species distribution of sequences obtained after cloning varied from recipient to recipient and that the distance from the donor sequences increased over time. V3 nucleotide evolution rates averaged 9.5 x 10(-3) per site per year for silent sites and 11.4 x 10(-3) per site per year for nonsilent sites (vs. 9.7 and 9.8 x 10(-3) per site per year for a control region 5' adjacent to the V3 region) and, although individual differences were observed, did not correlate with the serum antigen levels or disease progression. Sequences of both the epitope coding region itself (V3) and the control region upstream diverted more from the donor sequence among children not progressing to AIDS than among children progressing to AIDS. The evolution of V3 sequences is apparently host dependent, rapid, and independent of the level of antigen expression.

Acquired Immunodeficiency Syndrome↗

PubMed1989

Serum capacity to inhibit reverse transcriptase in vitro distinguishes HIV-1 infection from HIV-2 or SIV infection.

The inhibition of HIV-1 and SIV reverse transcriptase by human and rhesus macaque serum positive for HIV-1 or HIV-2/SIV antibodies was studied. The domain to which reverse transcriptase-inhibiting antibodies were elicited appeared to be highly antigenic. A total of 67% (48 of 72) of individuals had HIV-1 reverse transcriptase-inhibiting (RTI) antibodies 1 year after seroconversion for HIV-1, 90% (9 of 10) of HIV-2 antibody positive persons had SIV RTI antibodies, and all four experimentally SIV-infected rhesus macaques developed SIV RTI antibodies. Low cross-reactivity between HIV-1 and HIV-2/SIV RTI antibodies was observed. Of 10 HIV-1 RTI sera, 2 reduced SIV RT activity by more than 50% (mean reduction 85 versus 24%). Only 1 of 9 SIV RTI human sera reduced HIV-1 RT (mean reduction 74 versus 25%). This serum, however, showed a shared reactivity against both HIV-1 and HIV-2. These results indicate that the HIV-1 domain inducing RTI antibodies is antigenically different from the HIV-2/SIV domain.

Acquired Immunodeficiency Syndrome↗

PubMed1989

Low AIDS attack rate among Dutch haemophiliacs compared to homosexual men: a correlate of HIV antigenaemia frequencies.

A cohort of 180 haemophiliacs followed between 1983 and 1986 and a cohort of 961 homosexual men followed between 1984 and 1986 were compared for the prevalence and incidence of HIV-1 antibody (HIV-1-Ab) seropositivity, the incidence of AIDS-related complex (ARC) and AIDS and the prevalence and incidence of serological and immunological markers for HIV-related disease progression. Among the haemophiliacs 23 (12.8%) patients were HIV-1-Ab seropositive at entry and 20 (12.7%) of the remaining 157 seroconverted for HIV-1-Ab during follow-up. Of the homosexual men 238 (24.8%) were HIV-1-Ab seropositive at entry and 68 (9.4%) of the 723 at entry seronegatives seroconverted during follow-up. Clinical follow-up of the HIV-1-Ab seropositive and seroconverted men was 59 months in the haemophiliac cohort and 60 months in the homosexual cohort. Among the HIV-1-Ab seropositive and seroconverted haemophiliacs and homosexual men the cumulative ARC/AIDS incidence was 2 and 18%, respectively. Occurrence of HIV-1-antigenaemia was more frequent among seropositive and seroconverted homosexual men (28%) than among haemophiliacs (7%) (p = 0.001). The groups did not differ significantly for the absence or loss of anti-HIV core antibodies or the occurrence of low CD4+ cell numbers. These data indicate a slower progression of HIV-related disease in seropositive haemophiliacs compared to seropositive homosexual men.

AIDS-Related Complex↗

PubMed1989

Antibody response to human immunodeficiency virus type 1 protease according to risk group and disease stage.

Three groups with different routes of human immunodeficiency virus type 1 (HIV-1) transmission (homosexual men, hemophiliacs, and children) were studied for serum antibodies to a recombinant form of the HIV-1 protease using an enzyme-linked immunoassay. At 1 year after seroconversion, defined as the moment antibodies to HIV-1 proteins were first detected, 56% (34/61) of the homosexual men had antibodies to protease, and 2 years after seroconversion this percentage was 63% (24/38). Within this 2-year period these antibodies were no longer detected in 16% (9/56). A similar pattern was observed in 20 hemophiliacs who seroconverted after exposure to HIV-1-contaminated blood products. We found that 63% (160/255) of homosexual men in Centers for Disease Control stage II or III, 60% (9/15) of patients with acquired immunodeficiency syndrome (AIDS)-related complex, and 36% (14/39) of patients with AIDS had antibodies to protease. In 255 homosexual men in Centers for Disease Control stage II or III, antibodies to protease were significantly more frequently found in samples lacking HIV-1 antigen (P less than 0.001) and possessing antibodies to HIV-1 core proteins (P less than 0.001). Twenty-four persons who developed AIDS were studied longitudinally: 58% (14/24) had antibodies to protease 1 year before developing symptoms; 29% (7/24) showed a decline and 29% (7/24) showed a loss of antibodies to protease at the onset of symptoms. Within a group of 47 HIV-1-infected children, 90% (18/20) with a stable disease course were persistently protease antibody positive, versus 4 of 27 children (15%) with an unstable disease course (P = 0.0001). These data indicate that HIV-1 protease is expressed and antigenic in most HIV-1-infected individuals and that a decline or absence of antibodies to protease is strongly associated with unstable disease in children and AIDS in adults.

Acquired Immunodeficiency Syndrome↗

PubMed1988

HIV-antibody seroconversions in Dutch haemophiliacs using heat-treated and non heat-treated coagulation factor concentrates.

A national multicentre study was performed to investigate the effects of donorselection and the use of heat-treated plasma products on seroconversion to HIV in 157 Dutch haemophiliacs. All patients included in the study were seronegative for HIV antibodies in 1983. Thirteen percent (20/157) seroconverted between 1983 and 1986. Nineteen of 20 seroconversions could be related to the use of non heat-treated products in the year preceding HIV antibody seroconversion. One seroconversion occurred in a person using heat-treated non donor screened product. Seroconversion rate decreased as a result of the policy to discourage high risk blood donors and no seroconversions were observed following the introduction of donor screening in 1985.

Blood Coagulation Factors↗