Impaired T-lymphocyte-dependent immune responses to microbial antigens in patients with HIV-1-associated persistent generalized lymphadenopathy.

T-cell mediated and humoral responses directed to microbial antigens were investigated, at the time of the initial visit, in a group of 139 patients with HIV-1-related persistent generalized lymphadenopathy (PGL) enrolled in a longitudinal study. In vivo and in vitro cell-mediated responses to tuberculin were lower in patients than in controls. Differences were not significant for candidin and streptococcal antigen in vitro, whereas higher responses were observed in the patient group for cytomegalovirus antigen. Following immunization, a subgroup of patients did not have a significantly raised serum antitetanus antibody level, whereas in vitro lymphocyte proliferative responses to tetanus toxoid were lower than in controls. No association was found between these abnormalities and other immunological parameters, including the blood level of CD4+ lymphocytes. Lower responses to most microbial antigens were observed in patients with HIV-1-related symptoms in addition to lymphadenopathy, or the patients who progressed to AIDS in the 2 years following the study. Moreover, intravenous drug users showed higher responses than homosexual patients, possibly because of the influence of previous infections on immunological responses to microbial antigens.

Progression to AIDS in the majority of asymptomatic HIV-infected people.

Sixty-eight asymptomatic HIV-seropositive people with a CD4 lymphocyte count above 400/mm3 at the first examination were followed up every year over a 3-year period, by monitoring the biological markers of AIDS (CD4 lymphocyte decrease, loss of anti-p24 or anti-p17 antibodies, positive p24 antigenemia, increase of erythrocyte sedimentation rate, and of serum levels of immunoglobulin G. immunoglobulin A, neopterin and beta 2-microglobulin). The percentages of subjects positive for at least one marker at the first, second, third and fourth examinations were 66, 88, 94 and 97%, respectively. The increase in the number of markers with time was significant (chi-square test; P less than 0.001). This increase suggests a progression to AIDS in the majority of asymptomatic seropositive subjects, even those without a decreased CD4 lymphocyte count.

Appearance of predictors of disease progression in relation to the development of AIDS.

To study the natural history of HIV-1 infection in relation to serological and immunological profiles, 199 asymptomatic HIV-1-antibody (HIV-1-core-antibody)-seropositive and 76 seroconverted homosexual men were followed prospectively for 39 months. AIDS was diagnosed in 38 men. The AIDS attack rate was 20.8% after 39 months. The AIDS attack rate in the HIV-I-core-antibody positives was 12.1, versus 30.1% in the HIV-1-core-antibody negatives (P less than 0.001), and it was 13.3% in the HIV-1-antigen (HIV-1-Ag) negatives versus 53.9% in the HIV-1-Ag positives (P less than 0.001). The AIDS attack rate after 39 months was 10.9% in men with counts greater than or equal to 0.5 x 10(9)/l and 49.9% in those with CD4+ lymphocyte counts less than 0.5 x 10(9)/l. AIDS attack rates after 30 months in the same cohort have been previously reported [1], and were as follows: 6.8% in the core-antibody positives versus 35.7% in the core-antibody negatives. 6.9% in the HIV-1-Ag negatives versus 43.9% in the HIV-1-Ag positives, and 6.1% in those with CD4+ lymphocyte counts greater than or equal to 0.5 versus 51.9% in those with CD4+ lymphocyte counts less than 0.5 x 10(9)/l. The disappearance of core antibody, the appearance of antigen and the occurrence of low CD4+ lymphocyte counts preceded AIDS by a mean (s.d.) of 21.3 (8.9), 17.7 (8.8) and 15.7 (8.9) months, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Fluorescence intensity analysis through simplex optimization in flow cytometry.

Fluorescence intensity analysis in flow cytometric surface immunophenotyping has recently been appreciated in clinical applications. A curve fitting method to estimate the mean and SD values of fluorescence intensity is described in this report. A Gaussian distribution is aimed to be adapted for a specified distribution in logarithmically scaled histogram data through the simplex optimization, one of the non-linear least squares methods. In comparison with the conventional methods which include the detection of peak point and the direct calculation, this fitting method has demonstrated exceeding precisions in the estimation of both parameters with limited involved cell counts in typical lymphocytic phenotyping. The actual estimation for a precise SD value will develop the quality control approaches based on the fluorescence intensity analysis. While this method is not suitable for distributions that involve extremely small cell counts or that deviate markedly from a symmetric Gaussian, it has additional advantages of loose requirements, namely, narrow fitting regions, ordinarily small cell counts, practical computational periods and a simple programming.

Progression to AIDS in patients with lymphadenopathy or AIDS-related complex: reappraisal of risk and predictive factors.

PURPOSE: In 1985, we reported that acquired immunodeficiency syndrome (AIDS) developed in 14 of 81 (17%) men with generalized lymphadenopathy followed prospectively for an average of 13 months. The presence of oral thrush or constitutional symptoms, or both, or severely impaired T4+ cell responses to specific antigen (interferon-gamma production) accurately identified patients at immediate risk for AIDS. The purpose of the current report is to describe the progress of these 81 patients during the three and a half years since enrollment and to include new data on initial serum levels of beta 2 microglobulin and human immunodeficiency virus (HIV) p24 antigen. PATIENTS AND METHODS: The mean age of the 81 patients was 35.4 years; 79 were homosexuals and two were drug abusers. Immunologic testing was performed once at the time of enrollment in all patients. Seventy-seven of the 81 patients were seropositive for HIV antibody. Frozen samples of serum, also obtained at initial study, were assayed in 1988 for beta 2 microglobulin and HIV p24 antigen. The clinical status of patients was determined six, 14, and 36 months after enrollment was closed (June 1984) by either interview and examination or telephone contact with private physicians. RESULTS: After three and a half years of follow-up, 42 patients have developed AIDS, including (1) 77% who had had thrush or symptoms, or both, (2) 80% to 88% of those who originally demonstrated marked immunologic abnormalities (skin test anergy, less than 200 T4+ cells/mm3, T4/T8 cell ratio of less than 0.5, severely impaired interferon-gamma production [less than 25 U/mL], or elevated serum beta 2 microglobulin level [greater than 3.0 mg/L], and (3) 95% of patients with HIV p24 antigenemia. However, AIDS also developed in 51% of patients who had had more apparently benign initial manifestations (lymphadenopathy alone, herpes zoster), in 41% to 54% despite normal initial results for either T4+ cell number, interferon-gamma secretion, beta 2 microglobulin, or skin testing, and in 44% of those whose sera did not contain HIV antigen. CONCLUSION: These updated results demonstrate the remarkably poor prognosis of patients with generalized lymphadenopathy or AIDS-related complex irrespective of initial clinical, immunologic, and serologic findings, and suggest that essentially all such persons may be candidates for antiviral therapy.

Activation antigens expressed on T-cells of the peripheral blood in Sjögren's syndrome and rheumatoid arthritis.

We analyzed activated T-cells in the peripheral blood (PB) of 29 patients with Sjögren's syndrome (SS: 13 I degrees-SS and 16 II degrees-SS patients) and 11 patients with rheumatoid arthritis (RA) by two-color flowcytometry using antibodies to antigens serially expressed on the cell surface after activation--interleukin-2 receptor (IL-2R), HLA-DR, T-lineage specific antigen (TLiSA-1) and very late antigen (VLA-1). The early and intermediate activation antigens, DR and TLiSA-1, were significantly increased in the PB of SS and/or RA patients. The proportions of activated T-cells were higher in CD8+ cells than those in CD4+ cells. T-cells expressing IL-2R or VLA-1, which appear in the very early or late stages of activation, were also increased in SS and/or RA patients. The results suggest that activated T-cells in the PB of both diseases might be recruited from continuously activated lymphoid organs, and that the activated cells migrate from PB into target tissues. In addition, the increase of activated T-cells in PB might be one of the causes of the deficient cell-mediated immunity reported in these patients.

Asymptomatic patients with HIV infection. Keeping them well.

Primary care physicians need to be prepared to counsel and manage patients with human immunodeficiency virus (HIV) infection. Asymptomatic seropositive patients should be seen quarterly, and T4 lymphocyte counts should be followed. Other serologic markers that may detect disease progression are p24 antigen and beta 2 microglobulin. Abnormalities in the levels of these markers may influence the decision to initiate early antiretroviral therapy. Therapeutic regimens are now available for delaying progression of HIV disease and for preventing Pneumocystis carinii pneumonia, the most common opportunistic infection to develop in patients with HIV infection. Whether antiretroviral therapy should be initiated in all asymptomatic HIV-positive patients remains to be seen. Physicians can do their part by educating themselves about HIV infection so they can provide competent, nonjudgmental care to patients and by supporting legislation to protect the rights of HIV-infected persons.

[T4 and T8 lymphocytic populations after total hip replacement]. / Etude des populations lymphocytaires CD 4 et CD 8 après chirurgie pour prothèse de hanche.

Immunosuppression is involved in the occurrence of sepsis after surgical trauma. A postoperative lymphocytopenia is a recognised fact. In the opposite, studies on T-lymphocytes helpers (CD 4) and suppressors (CD 8) resulted in conflicting results. The aim of this study was to assess the variations in these two T-lymphocyte sub-populations using strongly standardized conditions in order to minimize the risk of non specific variations: same surgeon, same surgical technique, blood samples collected just before induction, immediately and 24 hours after surgery, automatized measures (Technicon H1). The results confirmed the lymphocytopenia, 24 hours after surgery, but no differences on CD 4 and CD 8 percentages were noted. It is concluded that during the first 24 postoperative hours surgery does not change the relative proportions of T-helpers and T-suppressors. Their measurement is not more useful than total lymphocyte count for assessment of postoperative immunosuppression.

[Zona in 50 patients infected by human immunodeficiency virus. Clinical manifestations and prognostic value]. / Zona chez 50 malades infectés par le virus de l'immunodéficience humaine. Manifestations cliniques et signification pronostique.

Between January 1981 and April 1989, 50 patients infected with HIV were examined for herpes zoster. Herpes zoster enabled HIV infection to be detected in 23 patients (46 percent). It had only one localisation (involving contiguous dermatomes) in 37 patients, two localisations in 6 patients, three or four localisations in 1 patient each, and was disseminated in 5 patients. Localisations were mostly thoracic and cervicofacial. Herpes zoster was treated with acyclovir in 29 patients. All patients, treated or untreated, recovered from herpes zoster, but 9 of them (18 percent) had sequelae: pain in 8 and hypoacousia in 1. Herpes zoster recurred once in 8 patients and twice in 2. Among the patients with AIDS related complex 20 percent developed AIDS after herpes zoster at one year and 30 percent at two years. Among all the patients, the proportion of deaths after herpes zoster was 13 percent at one year and 34 percent at two years.

Clinical and histopathological aspects of Kaposi's sarcoma in Africa: relationship with HIV serology.

From 1983 to 1987, 45 Kaposi's sarcomas (KS) were diagnosed at the University Hospital in Bangui; 37 cases were easily classified as either endemic or AIDS-related KS on clinical grounds and HIV serology. Moreover, probably due to the stage at which patients consulted and lesions were sampled, noticeable histopathological differences were observed between the two clinical presentations. But for 8/45 which we classified as "borderline KS", strong discrepancies occurred between clinical aspects, patient evolution, HIV serology and histopathology. In two cases, HIV-positive patients had typical endemic non-evolutive KS and have survived 15 and 36 months.

PIP: 45 cases of Kaposi's sarcoma diagnosed in Bangui, Central African Republic since 1983 were compared with respect to clinical features, evolution, HIV seroprevalence, immune status and histopathology. 37 cases were categorized as typical endemic KS or atypical aggressive KS, but 8 were found to be "borderline KS" with mixed characteristics. Endemic KS presents as a simple hemangioma with granulations in clusters of capillaries, both in the epidermis and dermis. Later 3 types of tissue damage may be seen: 1) nodular mixed fibroblasts, spindle cells, lymphocytes and histiocytes with vascular slits; 2) fibrocystoma-like; 3) angiosarcoma-like. AIDS-related KS showed scattered spindle cells, vascular slits resembling capillaries, considerable infiltration by plasma cells, lymphocytes and inflammatory cells, PAS-positive eosinophilic tumor cells, and ferric pigmented macrophages. Typical endemic KS lesions are multifocal and limited to the lower extremities. Aggressive AIDS-related KS lesions were infiltrative, edematous or indurated, sometimes located buccally or conjunctively. All 45 patients could be classified as endemic or aggressive KS clinically. None of the patients with clearly endemic KS had antibodies to HIV. The 8 borderline cases had a wide variation in findings. The mean survival times for 6 endemic KS patients was 30 months or more; that of the AIDS-related KS patients was 3.5 months.

Analysis and characterization of the interleukin 2 receptor alpha and beta chain expression in CD4-CD8- cells.

The differential effects that the binding of interleukin 2 (IL-2) to its beta or alpha beta receptors might induce in two different CD4-CD8- T-cell lines were analysed. While LD1.T3b, a double-negative T cell derived from MRL/lpr mice, constitutively expressed high levels of the IL-2R beta chain, YAC-1, a Moloney sarcoma virus-transformed CD4-CD8- T cell, expressed (as an activated T cell) the beta and alpha chains. The presence of IL-2 in the culture medium was lethal for LD1.T3b cells, while it had no effect on the growth of YAC-1 cells. IL-2 increased the expression of the beta chain and, to a lesser extent, of the alpha chain in YAC-1 cells. In addition, other markers such as CD4 and CD5 were induced by IL-2 in this cell line.

[Development of HIV 1 antigenemia during treatment with azidothymidine (AZT): follow-up of 90 patients for a year]. / Evolution de l'antigénémie VIH 1 lors du traitement par l'azidothymidine (AZT): suivi de 90 malades à un an.

VIH 1 antigenaemia has a significant value in the follow-up of patients treated with AZT. This study of 90 patients (55 ARC - 35 AIDS), each receiving AZT for more than a year, 200 mg every 4 hours, demonstrates the prognosis value of antigenaemia at Day 0, as well as its therapeutic indication value. However, at term and under this treatment, the significance of this virological data has to be reconsidered. Various kinetic patterns are described according to the clinical status and the CD4+ cells count.

Evidence for a role of virulent human immunodeficiency virus (HIV) variants in the pathogenesis of acquired immunodeficiency syndrome: studies on sequential HIV isolates.

Sequential human immunodeficiency virus (HIV) isolates, recovered from a panel of longitudinally collected peripheral blood mononuclear cells obtained from 20 initially asymptomatic HIV-seropositive homosexual men, were studied for differences in replication rate, syncytium-inducing capacity, and host range. Eleven individuals remained asymptomatic; nine progressed to acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC) at the time point at which the last HIV isolate was obtained. In 16 individuals, only non-syncytium-inducing (NSI) isolates, with a host range restricted to mononuclear cells, were observed. From four individuals, high-replicating, syncytium-inducing (SI) isolates that could be transmitted to the H9, RC2A, and U937 cell lines were recovered. From two of these four individuals, SI isolates were obtained throughout the observation period. In the two others, a transition from NSI to SI HIV isolates was observed during the period of study. Three of these four individuals developed ARC or AIDS 9 to 15 months after the first isolation of an SI isolate. With the exception of the two individuals in whom a transition from NSI to SI isolates was observed, within a given individual the replication rate of sequential HIV isolates was constant. A significant correlation was found between the mean replication rate of isolates obtained from an individual and the rate of CD4+ cell decrease observed in this individual. In individuals with low-replicating HIV isolates, no significant CD4+ cell loss was observed. In contrast, recovery of high-replicating isolates, in particular when these were SI isolates, was associated with rapid decline of CD4+ cell numbers and development of ARC or AIDS. These findings indicate that variability in the biological properties of HIV isolates is one of the factors influencing the course of HIV infection.

A longitudinal study of serum beta 2-microglobulin levels in haemophilia.

Serum beta 2-microglobulin (beta 2-m) levels were measured in 75 adults with haemophilia A. Beta 2-microglobulin was found to be significantly elevated in haemophiliacs compared with the non-haemophiliac population. There was a greater rise in beta 2-m in HIV antibody-positive haemophiliacs. No further significant increase occurred in the subgroup with HIV-related disease but all these patients had beta 2-m levels greater than or equal to 3 mg/l. Over the study period of 18 months no significant increase in beta 2-m was documented in either HIV antibody-negative or -positive groups. Beta 2-microglobulin was elevated in HIV antibody-negative subjects with raised transaminase levels. No correlation was found between beta 2-m and the amount of factor VIII concentrate infused, T-cell subsets, thrombocytopenia or age. It is concluded that probable reasons for elevated beta 2-m levels in haemophiliacs include infection with HIV and other viruses, chronic liver disease, and repeated antigenic challenge from multiple infusions of factor VIII. The role of serial measurement of beta 2-m in haemophiliacs with a view to predicting the onset of HIV-related disease warrants further study.

Efficacy of intravenous immunoglobulins in patients with advanced HIV-1 infection. A randomized clinical study.

40 adults with symptomatic HIV-1 infection (AIDS related complex [ARC] WR 2B-4B or AIDS WR 5-6) were randomized into two groups, receiving either 200 mg of an i.v. immunoglobulin preparation (ivIg)/kg body weight every other week or no such treatment. Medical care and antibiotic therapy were comparable in the two groups. Frequency of opportunistic infections, "B"-symptoms, number of T-helper cells, change of disease stage (Walter Reed Classification, WR), delayed cutaneous hypersensitivity, onset and clinical course of Kaposi's sarcoma, neurological manifestations and proportion of patients alive at the end of the observation period were evaluated. After an average observation period of 13.8 months, decreased mortality was observed in ivIg treated patients of WR 5-6 (p less than 0.004). Frequency and microbial spectrum of opportunistic infections, the most frequent cause of death, were not influenced significantly by ivIg treatment. No statistically relevant differences concerning the other parameters were observed. A similar beneficial effect of ivIg in WR 2B-4 patients has not become apparent so far.

[Pathophysiological analysis of rapidly progressive periodontitis].

Pathophysiological features were studied on 7 patients with rapidly progressive periodontitis but without any evidence of systemic disease, to analyse the clinical pathogenesis. The patients consisted of 5 females, 2 males, between the ages of 32 and 42 years. All patients had severe and rapid alveolar bone destruction on the basis of radiographic measurement. Abnormal serum levels of IgG and IgM were detected in some patients. Higher IgG level was found in 4 patients and higher IgM level was found in 2 patients. The proportion of lymphocyte subsets was calculated in mononuclear cells from peripheral blood of patients. Higher OKT4/OKT8 ratio was found in all patients. The percentage of OKT4 positive cells in 2 patients was higher than that in normal subjects while the percentage of OKT8 positive cells in 4 patients was lower than that in the healthy controls. Microorganisms from periodontal pockets were examined in 5 patients. Bacteriodes was isolated in all 5 patients and Haemophilus actinomycetemcomitans in 2 patients.

High levels of oral yeasts in early HIV-1 infection.

Ten human immunodeficiency virus-1 (HIV-1) infected homosexual or bisexual individuals (ages 24-45) with no history of opportunistic infection were examined, by culture, for the presence of yeasts in whole saliva and on oral mucosa. All were HIV-1 antibody-positive men, non-smokers, non-denture wearers, and taking no medication. The mean salivary level of yeast was four logs higher in the HIV-1 infected group compared to a control group of normal, unmedicated, non-smoking men (ages 20-41) who denied any risk behavior for HIV-1 infection. Identification of the yeast in these HIV-1 positive individuals established that Candida albicans was the predominant species found in whole saliva and on buccal mucosa and tongue. Distinct hyphae were observed with only one mucosal sample. No significant correlation was found between whole saliva yeast concentration and the T4/T8 lymphocyte ratios or absolute number of T4 cells. No correlation was observed between oral yeast concentration and anti-C. albicans IgA titers. The high level of oral yeast in these individuals prior to the development of opportunistic infections is consistent with the suggestion that oral defense mechanisms are compromised in individuals following HIV-1 infection.

Detection of HIV-1 DNA in different subsets of human peripheral blood mononuclear cells using the polymerase chain reaction. Rapid communication.

The presence of HIV-1 proviral DNA was determined in CD4 cells, CD8 cells and macrophages/monocytes obtained from peripheral blood of 8 HIV-1 infected persons. Using the polymerase chain reaction (PCR) we were able to detect proviral DNA in the extracts of only 10(2)-10(3) CD4 (T4) cells. In contrast, 10(5) CD8 cells did not contain detectable amounts of proviral DNA. Surprisingly, in four of our eight patients studied no HIV-1 DNA was found in macrophages. In peripheral blood, every hundred T4 cell may be infected with HIV-1.

Analysis of human lymphocyte protein expression. I. Identification of subpopulation markers by two-dimensional polyacrylamide gel electrophoresis.

This study provides new knowledge on the changes in protein expression that differentiate the functionally and phenotypically different cells of the human immune system. Purification by flow cytometry of normal lymphocytes (both T and B cells), monocytes and granulocytes, combined with high-resolution two-dimensional polyacrylamide gel electrophoresis, revealed reproducible qualitative and quantitative changes between these cell populations. Characteristic profiles of marker proteins for each cell type were identified. Determination of markers for T lymphocyte subpopulations was achieved by the comparative analysis of normal T cells separated on the basis of CD4 and CD8 expression in combination with the analysis of cells from patients with T cell chronic lymphocyte leukemia. These results suggest that the modulation or regulation of proteins is very strictly controlled in lymphoid differentiation, and that several quantitative and a few qualitative differences can give rise to completely different phenotypes. Thus, instead of detecting numerous random differences among lymphocyte protein patterns, rather stringent regulation of protein expression in each subpopulation was found.