Viral phenotype and immune response in primary human immunodeficiency virus type 1 infection.

Nineteen individuals were studied for virologic and immunologic events during primary human immunodeficiency virus type 1 (HIV-1) infection. In 16 individuals only non-syncytium-inducing (NSI) isolates were detected; syncytium-inducing (SI) isolates were obtained from 3. Studies of transmitter-recipient pairs indicated that both NSI variants and SI variants were transmitted and that SI variants may be suppressed in the recipient.

HIV-1 biological phenotype in long-term infected individuals evaluated with an MT-2 cocultivation assay.

Objective: We have previously demonstrated that detection of syncytium-inducing (SI) HIV-1 in asymptomatic seropositive individuals is associated with rapid progression to AIDS. In the present study, we sought to develop and evaluate an HIV-1 phenotyping assay for the screening of large numbers of individuals.

Methods: Efficiency of HIV-1 isolation from patient peripheral blood mononuclear cells (PBMC) was studied with donor PBMC or seven different CD4+ T-cell lines as target cells.

Immunological abnormalities in the natural history of HIV infection: mechanisms and clinical relevance.

Infection with the human immunodeficiency virus (HIV) ultimately results in profound immunodeficiency characterized by severe depletion of CD4+ T helper cells. In symptomatic infection a general perturbance of immune function is observed. Here recent insights in the sequence of events in progression to AIDS is reviewed.

Regulation of T-cell differentiation by CD2 and CD28 accessory molecules.

It was analysed to what extent the functional T-cell responses that result from T-cell receptor (TcR)/CD3 triggering differ from responses that are induced after simultaneous ligation of CD2 and CD28 accessory molecules. To allow a quantitative comparison of these activation pathways, purified lymphocytes were stimulated with either graded densities of immobilized anti-CD3 monoclonal antibodies (mAb) or with increasing amounts of anti-CD28 mAb in the presence of a constant concentration of anti-CD2 mAb. Both activation systems were sensitive to the regulatory properties of CD11a/CD18 molecules.

Immunological and virological markers in individuals progressing from seroconversion to AIDS.

Six men were selected from a large cohort of homosexual men participating in a study on HIV infection that was followed from seroconversion to AIDS. The patients were studied retrospectively for immunological functions of T cells, T-cell subset distribution and biological phenotype of HIV. A severe decrease in anti-CD3 monoclonal antibody (MAb)-induced T-cell proliferation at seroconversion was observed in two out of six men.

Allo-cross-reactivity of a human neuraminidase-specific T cell clone dependent on presentation of an endogenous B cell-specific antigen.

T cells specific for foreign antigen recognize a complex of peptides and self-major histocompatibility complex (MHC) molecules and can also cross-react with allo-MHC molecules. It remains controversial, however, what alloreactive T cells exactly recognize. It has been proposed that alloreactive T cells recognize endogenous peptides presented by allo-MHC molecules.

Human CD8+ T lymphocytes can be divided into CD45RA+ and CD45RO+ cells with different requirements for activation and differentiation.

The functional distinction between CD45RA+ and CD45RO+ cells within the human CD4+ T cell subset is well established. This study was undertaken to investigate whether a similar division can be made within the CD8+ T cell population. A quantitative comparison was made of the requirements for activation and differentiation of CD8+CD45RA+ and CD8+CD45RO+ cells.

Monocytotropic human immunodeficiency virus type 1 (HIV-1) variants detectable in all stages of HIV-1 infection lack T-cell line tropism and syncytium-inducing ability in primary T-cell culture.

We previously demonstrated a correlation between the presence of syncytium-inducing (SI) human immunodeficiency virus type 1 (HIV-1) variants showing tropism for cell line H9 and the occurrence of rapid CD4 cell decline and progression to AIDS. In contrast, in stable asymptomatic individuals, we detected only isolates with low replication rates that were non-syncytium-inducing (NSI) and nontropic for the H9 cell line. Here, we investigated the monocytotropism of established HIV-1 isolates with a panel of isolates and with biological HIV-1 clones with distinct phenotypes.

Non-mitogenic T cell activation signals are sufficient for induction of human immunodeficiency virus transcription.

The expression of human immunodeficiency virus type 1 (HIV) is enhanced after T cell activation due to the interaction of cell-encoded nuclear factors with binding sites in the viral long terminal repeats (LTR). We studied the minimal signal transduction requirements for induction of HIV transcription during T cell activation. Monoclonal antibodies (mAb) against the T cell receptor/CD3 complex induced interleukin (IL) 2 production as well as HIV-LTR-directed gene expression in Jurkat T cells.

Frequent injecting impairs lymphocyte reactivity in HIV-positive and HIV-negative drug users.

To investigate whether drug use affected immunological parameters, we conducted a cross-sectional study of 321 drug users. Absolute numbers of CD4+ lymphocytes and the T-cell reactivity were lower in HIV-positive than in HIV-negative people. The functional capacity of the T-cell system as measured after stimulation with a monoclonal antibody directed against CD3 was found to be strongly associated with the frequency of injecting, while no relationship was found between the frequency of injecting and the total number of lymphocytes or T-cell subsets.

Differences in clinical course in zidovudine-treated asymptomatic HIV-infected men associated with T-cell function at intake.

Declining CD4+ T-cell numbers and anti-CD3-induced T-cell responsiveness are prognostic markers for progression of HIV infection. We investigated the effect of long-term (2-year) zidovudine treatment on these immunological markers in a group of nine asymptomatic p24-antigenaemic men, five of whom progressed to AIDS. A group of 10 untreated HIV-infected men, five of whom progressed to AIDS, was studied as a control.

Induction of monocyte proliferation and HIV expression by IL-3 does not interfere with anti-viral activity of zidovudine.

Myelosuppression is a major symptom in the acquired immunodeficiency syndrome (AIDS). Moreover zidovudine, an anti-retroviral drug used to treat AIDS patients has myelosuppressive side effects. Therefore treatment with IL-3, a multi-lineage hemopoietic growth factor may be beneficial for zidovudine-treated individuals.

Generation of alloreactive cytolytic T lymphocytes by immobilized anti-CD3 monoclonal antibodies. Analysis of requirements for human cytolytic T-lymphocyte differentiation.

Requirements for the induction of human cytolytic T-lymphocyte (CTL) activity were studied in a monocyte-free T-cell activation system that uses immobilized anti-CD3 monoclonal antibodies (mAb) as a stimulus. Alloreactive CTL with specificity for HLA-A and -B locus antigens could be demonstrated within 2 days after the initiation of activation. CTL induction in purified T cells initiated by an optimal concentration of immobilized anti-CD3 mAb was not enhanced by the addition of monocytes or exogeneous cytokines, whereas addition of anti-CD25 mAb largely blocked the response.

Functional and phenotypic evidence for a selective loss of memory T cells in asymptomatic human immunodeficiency virus-infected men.

In addition to a well-documented depletion of CD4+ T helper cells in later stages of human immunodeficiency virus (HIV) infection, evidence has been provided for a specific unresponsiveness to triggering either by specific antigen in the context of autologous major histocompatibility molecules (self + X) or anti-CD3 monoclonal antibodies (MAb) in both CD4 and CD8 cells from asymptomatic HIV-infected individuals. In the present study we analyzed this unresponsiveness using mitogenic antibodies to distinct T cell membrane receptors. T cells from HIV-infected men who had normal numbers of CD4+ T cells responded poorly to activation signals via the CD3 membrane antigen in both accessory cell-dependent as well as accessory cell-independent culture systems.

Selective loss of T cell functions in different stages of HIV infection. Early loss of anti-CD3-induced T cell proliferation followed by decreased anti-CD3-induced cytotoxic T lymphocyte generation in AIDS-related complex and AIDS.

To investigate the effects of persistant human immunodeficiency virus (HIV) infection on T cell reactivity, functional properties of peripheral blood T cells from HIV-seropositive homosexual men in various stages of infection were studied. T cell activation via CD3 resulting in proliferation and differentiation was measured in a model system independent of accessory cells, using immobilized anti-CD3 monoclonal antibodies (mAb). T cells from HIV-infected asymptomatic men had a decreased proliferative response compared to HIV-negative controls.

Analysis of the role of leukocyte function-associated antigen-1 in activation of human influenza virus-specific T cell clones.

The role of leukocyte function-associated Ag-1 (LFA-1) in intercellular adhesion is well documented. Previously, we demonstrated that the LFA-1 molecule (CD11a/CD18) can also regulate the induction of proliferation of peripheral blood T cells. In these studies, we observed opposite effects of antibodies against CD11a (LFA-1-alpha-chain) or CD18 (LFA-1-beta-chain).

Low T-cell responsiveness to activation via CD3/TCR is a prognostic marker for acquired immunodeficiency syndrome (AIDS) in human immunodeficiency virus-1 (HIV-1)-infected men.

In a cohort of 300 HIV-1-infected homosexual men, studied longitudinally, the prognostic value of T-cell proliferative responses for development of AIDS was analyzed. In 15 persons we observed that, at seroconversion, T-cell reactivity to anti-CD3 monoclonal antibody (Mab) and phytohemagglutinin (PHA) was decreased to 20 and 60% of the normal values, respectively. After seroconversion, within 3 months, the response to anti-CD3 Mab and PHA returned to 60 and 80%, respectively, of the normal magnitude and declined thereafter.

Requirements for induction of activation and proliferation of human B cells analysed with anti-idiotype monoclonal antibodies.

We have produced five monoclonal antibodies (MoAb) directed against idiotypic determinants of surface immunoglobulins (sIg) expressed on malignant B cells from a patient suffering from prolymphatic leukaemia (B-PLL). The anti-idiotype MoAb were characterized by immunofluorescence-binding studies, allotype reactivity, and immunoprecipitation studies and were found to recognize at least two distinct epitopes on the sIg of the neoplastic B cells. Differential effects of the soluble anti-idiotype MoAb on phorbol myristate acetate (PMA)-induced B-PLL-cell proliferation were found; three types of anti-idiotype MoAb could be distinguished: (1) MoAb that enhanced the PMA-induced B-PLL-cell proliferation, (2) MoAb without effect, and (3) MoAb that inhibited the PMA-induced B-PLL-cell proliferation.

Detection and subtyping of HIV-1 isolates with a panel of characterized monoclonal antibodies to HIV p24gag.

A panel of monoclonal antibodies (Mabs) was used to analyze the number and localization of B-cell epitopes on human immunodeficiency virus (HIV) p24gag and the variability of these epitopes in sequential HIV isolates and in isolates from different geographical origin. The specificity of these Mabs was demonstrated by immunoblotting and radioimmunoprecipitation assays. Cross-inhibition experiments indicated the presence of at least five different epitopes on p24.