The Vancouver Lymphadenopathy - AIDS Study: 2. Seroepidemiology of HTLV-III antibody

Testing for antibody to human T-lymphotropic retrovirus (HTLV-III) was carried out in 448 participants in the Vancouver Lymphadenopathy-AIDS (acquired immune deficiency syndrome) Study. The overall prevalence rate of seropositivity was 34%. Of 130 seronegative subjects followed for an average of 8.5 months, 14 became seropositive; thus, the approximate annual seroconversion rate was 15%. More than 100 male sexual partners in one''s lifetime, frequent receptive anal intercourse, fisting, a history of gonorrhea or hepatitis, and frequent sexual contact in clubs were found to be independent risk factors for HTLV-III seropositivity.     

The Vancouver Lymphadenopathy-AIDS Study: 5. Antecedent behavioural,clinical and laboratory findings in patients with AIDS and HIV-seropositive controls.

In a group of homosexual men in Vancouver studied prospectively since November 1982, 26 cases of acquired immune deficiency syndrome (AIDS) have arisen. To identify behavioural, clinical and laboratory findings that might predict the development of AIDS in people with antibody to human immunodeficiency virus (HIV), we compared data for 25 patients with AIDS with corresponding data for 80 controls serologically positive for HIV selected from the cohort. The clinical and laboratory data for the patients with AIDS preceded the diagnosis of the syndrome by a mean of 17.5 months. The controls had been both seropositive and AIDS-free for a mean of 16.7 months after acquisition of their data. We detected significant differences between the patients with AIDS and the controls in IgG and IgA levels, absolute number of helper T cells and ratio of helper to suppressor T cells but not in lifetime number of male sexual partners, frequency of receptive anal intercourse or receptive fisting, illicit drug use or history of infectious disease. We also detected an increased risk of AIDS among those who had an elevated number of sexual contacts in AIDS-endemic areas in the 5 years before enrollment. A history of increased early sexual contact in AIDS-endemic areas is likely to be associated with early infection and with an increased risk of AIDS among men with HIV infection of unknown duration. Thus, although our analysis had limited statistical power, we conclude that most lifestyle variables appear to act as exposure factors in HIV infection but not as cofactors in the development of AIDS.     

Diagnostic utility of lymphocyte subset analysis in AIDS case finding.

Abnormalities of lymphocyte subsets, especially low absolute number of helper T cells, are characteristically present in acquired immune deficiency syndrome (AIDS). Similar abnormalities can be found in patients with persistent generalized lymphadenopathy (PGL) or AIDS-related complex (ARC) and, to a lesser degree, in asymptomatic people who have been exposed to human T-lymphotropic virus type III (HTLV-III). Nevertheless, there appears to be a widespread perception that lymphocyte subset analysis may be useful in AIDS case finding within high-risk groups. We evaluated the diagnostic utility of absolute number of helper T cells and ratio of helper to suppressor T cells in 33 patients with AIDS, 43 patients with PGL who had been referred for lymph node biopsy, 90 patients with PGL and 195 male homosexual controls. At conventional cutoff levels the tests did not appear to revise the probability of AIDS upward to any clinically significant degree when the pretest probability of AIDS was low. Lymphocyte subset analysis does not appear to be a cost-effective method of AIDS case finding in identified groups at risk in which the prevalence of AIDS is low.     

Seroepidemiology of HTLV-III antibody in Danish homosexual men: prevalence,transmission, and disease outcome.

Sera taken from 250 Danish homosexual men in December 1981 as part of a prospective study of the acquired immunodeficiency syndrome (AIDS) were examined for the presence of HTLV-III antibody with an enzyme-linked immunosorbent assay. Antibody was present in 22 (8.8%) of the men. Seropositivity was most strongly associated with sexual exposure to men in the United States (relative risk 3.5; p less than 0.007). Increased frequency of anal receptive intercourse was also independently associated with seropositivity (p less than 0.05), but age, years of homosexual experience, number of homosexual partners, and use of nitrite inhalant were not independent risk factors. The frequency of seroconversion from absence to presence of HTLV-III antibody appeared to be about 1% a month in this community during December 1981 to February 1983. Of the 22 men who were originally seropositive, two (9%) subsequently developed AIDS as defined by the Centre for Disease Control and two (9%) others the AIDS related complex. Blood was taken in addition from two of the men to develop AIDS earliest in Denmark (diagnosed 1981) at the same time as the initial survey in 1981; both were seropositive. The spread of HTLV-III from high to low risk areas and the subsequent appearance of illnesses related to AIDS in the seropositive group support the hypothesis that HTLV-III is causally related to the development of AIDS.     

Immunomodulating properties of MDMA alone and in combination with alcohol: a pilot study

Cell-mediated immune response after the administration of MDMA alone and in combination with alcohol was evaluated in a randomized, double-blind, double-dummy, cross-over pilot clinical trial conducted in four healthy MDMA consumers who received single oral doses of 75 mg MDMA (n = 2) or 100 mg MDMA (n = 2), alcohol (0.8 mg/kg), MDMA and alcohol, or placebo. Acute MDMA treatment produced a time-dependent immune dysfunction associated with MDMA plasma concentrations. Although total leukocyte count remained unchanged, there was a decrease in the CD4 T/CD8 T-cell ratio as well as in the percentage of mature T lymphocytes, probably because of a decrease in both the percentage and absolute number of T helper cells. The decrease in CD4 T-cell counts and in the functional responsiveness of lymphocytes to mitogenic stimulation was dose-dependent. The correlation between MDMA pharmacokinetics and the profile of MDMA-induced immune dysfunction suggests that alteration of the immune system may be mediated by the central nervous system. Alcohol consumption produced a decrease in T helper cells, B lymphocytes, and PHA-induced lymphocyte proliferation. Combined MDMA and alcohol produced the greatest suppressive effect on CD4 T-cell count and PHA-stimulated lymphoproliferation. Immune function was partially restored at 24 hours. These results provide the first evidence that recreational use of MDMA alone or in combination with alcohol alters the immunological status.     

The relationship of abnormalities of cellular immunity to antibodies to HTLV-III in homosexual men

A comprehensive evaluation of the cellular immune system (total T-cell, helper cell, suppressor cell, and natural killer cell numbers; in vitro interleukin-2 production, T-cell responses to mitogens and antigens, serum beta 2 microglobulin levels, and delayed hypersensitivity skin tests) was performed on 36 HTLV-III seronegative and 16 HTLV-III seropositive healthy homosexual men, 48 asymptomatic homosexual men with the chronic lymphadenopathy syndrome, 41 patients with AIDS, and 29 heterosexual controls without any known risk factors for AIDS. Our studies demonstrate that HTLV-III seronegative homosexual men have normal cellular immunity and are comparable to heterosexual controls. The abnormalities of lymphocyte subsets observed in HTLV-III seropositive healthy homosexual men are comparable to subjects with chronic lymphadenopathy. Assays of lymphocyte function, with the exception of delayed type hypersensitivity (DTH) skin tests, are similar in each group except patients with AIDS. Subjects with chronic lymphadenopathy were less responsive to DTH skin tests and HTLV-III seropositive healthy homosexuals were comparable to chronic lymphadenopathy subjects. We conclude that immunologic abnormalities in homosexual men are attributable to infection with HTLV-III.     

Markers of HTLV-III in patients with end stage renal failure treated by haemodialysis.

Patients and members of staff from a haemodialysis unit were tested for markers of infection with human T cell lymphotropic virus type III (HTLV-III), the virus associated with the acquired immune deficiency syndrome (AIDS). An enzyme linked immunosorbent assay showed eight of 100 patients to have antibodies to HTLV-III. In five of these patients past or present infection with HTLV-III was confirmed by Western blot analysis or detection of HTLV-III antigens in lymphocyte cultures, or both. Investigation of other risk factors for AIDS showed that the putative source of HTLV-III was unrelated to dialysis in two patients whereas blood transfusion was the most likely cause of contamination in the others. No member of staff gave a positive result in the enzyme linked immunosorbent assay. Nosocomial transmission of HTLV-III seems unlikely if precautions similar to those recommended for the control of hepatitis B infection are applied.     

Identification of novel HLA-DR1-restricted epitopes from the hepatitis B virus envelope protein in mice expressing HLA-DR1 and vaccinated human subjects

Helper T lymphocytes that control CD8(+) T-cell and antibody responses are key elements for the resolution of infection by the hepatitis B virus and for the development of effective immunological memory after hepatitis B vaccination. We have used H-2 class II-deficient mice that express the human MHC class II molecule, HLA-DR1, to identify novel hepatitis B virus envelope-derived T helper epitopes. We confirmed the immunogenicity of a previously described HLA-DR1-restricted epitope, and identified three novel epitopes. CD4(+) T-cell immune responses against these epitopes were detected in peripheral blood mononuclear cells from HLA-DR1(+) individuals vaccinated against hepatitis B. We showed that subjects receiving the currently available hepatitis B vaccines do not develop cross-reactive T helper responses against one of the novel epitopes which are structurally variable between different hepatitis B virus subtypes. These findings highlight the need for developing vaccines against a wider range of viral subtypes, and establish humanized mice as a convenient tool for identifying new immunogenic epitopes from pathogens.     

IgM and IgG antibodies to human T cell lymphotropic retrovirus (HTLV-III) in lymphadenopathy syndrome and subjects at risk for AIDS in Italy.

A study was performed to assess the prevalence of specific antibodies to human T cell lymphotropic retrovirus (HTLV-III) in patients with lymphadenopathy syndrome, patients with the acquired immune deficiency syndrome (AIDS), and those at risk of AIDS. Serum samples were obtained from these groups and from healthy controls in selected cities in Italy, and antibodies to HTLV-III were measured by immunofluorescence assay and, in a few patients, by Western blotting. In addition, IgM antibody values were measured in 82 of those positive for HTLV-III. Altogether, 235 out of 320 patients with lymphadenopathy syndrome had antibodies to HTLV-III, the proportions being highest in haemophiliacs, homosexuals, and drug addicts from Rome; 11 out of 12 patients with AIDS had antibodies; 78 out of 439 subjects at risk for AIDS had antibodies; and six out of 30 patients with lymphadenopathy syndrome and positive for HTLV-III antibodies and nine of 52 patients at risk of AIDS had a detectable titre of IgM. HTLV-III is widespread in groups at risk of AIDS in Italy, and antibodies to HTLV-III are highly prevalent in patients with lymphadenopathy syndrome. A higher proportion of drug abusers were positive for antibodies than in previous studies. HTLV-III "infection" would appear to be spread mainly in compromised hosts, as none of the controls were positive for antibodies.     

Longitudinal study of HTLV-III-infected chimpanzees by lymphocyte subpopulation analysis

Following inoculation with plasma from human patients with AIDS, two chimpanzees demonstrated specific antihuman T-cell leukemia virus type 3 (HTLV-III) antibodies. One of the two chimpanzees also developed massive lymphadenopathy that persisted for 32 weeks and demonstrated a concurrent and more frequent depression of total T cells (T3) and T helper cells (T4) with a decrease in the ratios of T4 to T suppressor cells (T8). These results indicate that chimpanzees demonstrate a range of T-cell subpopulations during infection and disease induced by HTLV-III.     

Clinical and epidemiologic characteristics of hepatitis C in a gastroenterology/hepatology practice in Ottawa.

OBJECTIVE: To examine the clinical and epidemiologic features of hepatitis C virus (HCV) infection in a gastroenterology/hepatology practice in Ottawa. DESIGN: Retrospective chart review. PATIENTS: Sixty-three consecutive patients found to be anti-HCV positive. Their charts were analysed with respect to risk factors, history of hepatitis, serum aspartate aminotransferase (AST) levels and the presence of hepatitis B markers. The long-term sexual partners of 29 patients agreed to undergo HCV antibody testing. RESULTS: Of the patients 48 (76%) had been exposed to HCV parenterally: 27 used intravenous drugs, and 21 had received blood or blood products. Eleven patients did not have any known risk factor (sporadic infection), but eight of them had lived in countries where hepatitis C may be more prevalent; the other three had locally acquired infection. The mean serum AST level at the first visit was 140 (normally less than 40) IU/L. At least one hepatitis B marker was identified in 33% of the patients. None of the sexual partners who were tested were anti-HCV positive. CONCLUSION: Most cases of hepatitis C in Ottawa are acquired through parenteral exposure; sexual transmission is rare. Sporadic infection in the Ottawa region is rare but may be more common in people from countries with a higher prevalence rate of hepatitis C. Most cases of hepatitis C are asymptomatic.     

Cellular changes during the infusion of high dose intravenous immunoglobulin

With the ever widening group of autoimmune conditions that are beneficially affected by infusions of high dose immunoglobulin the possible mechanisms of action of such therapy appear increasingly complex. Fc mediated blockade of the mononuclear phagocyte system is an acknowledged early effect. This is, however, accompanied by a decrease of neutrophil counts which suggests that IgG binding to the neutrophil may be a mechanism of action. The decrease of neutrophil counts is transient but in immune thrombocytopenia is inversely proportional to the platelet response observed. In parallel to the effect on the neutrophil there are changes in the lymphocyte subsets with reversal of the T helper/suppressor ratio and alterations in the individual cellular constituents of each subset that correlate with the clinical response. The observed changes in B cell numbers and function suggest that T dependent and independent antibody production is effected by intravenous immunoglobulin. It is increasingly clear that in ITP at least the clinical response to IV IgG is a summation of several cellular events and their balance reflects the ultimate outcome. It may eventually be possible to use these observations to predict the likely outcome in the individual patient of this mode of therapy.     

Sexual transmission of hepatitis C virus and its relation with hepatitis B virus and HIV.

OBJECTIVE--To determine the extent of transmission of hepatitis C virus in sexual partners of intravenous drug misusers and to examine the relation between the prevalences of HIV, hepatitis B virus, and hepatitis C virus infections in homosexual men and intravenous drug misusers and their sexual partners. DESIGN--Serum samples collected between 1984 and 1988 were tested for hepatitis B virus markers and antibodies against hepatitis C virus by enzyme linked immunosorbent assay (ELISA) and for HIV antibody by enzyme immune analysis and western blotting. SETTING--Large referral university hospital with an external AIDS clinic in the metropolitan area of Barcelona, Spain. SUBJECTS--243 Intravenous drug misusers, 143 of their regular heterosexual partners, and 105 homosexual men. MAIN OUTCOME MEASURES--Prevalences of hepatitis C virus, hepatitis B virus, and HIV infections. RESULTS--In all, 178 of the 243 (73%) intravenous drug misusers, 16 out of 143 (11%) of their partners, and 17 of the 105 (16%) homosexual men had antibodies against hepatitis C virus. The presence of hepatitis C virus infection was unrelated to sex, age, the presence of HIV or hepatitis B virus infections, or the Centers for Disease Control stage of HIV. In sexual partners of intravenous drug misusers there were strong correlations between the presence of hepatitis C virus infection and that of HIV (p = 0.001) and hepatitis B virus (p = 0.013) infections. CONCLUSIONS--Intravenous drug misusers have a high risk of acquiring hepatitis C virus, hepatitis B virus, and HIV infections, but the presence of hepatitis C virus infection seems to be unrelated to the presence of the other two viruses. Homosexual men have a high prevalence of HIV and hepatitis B virus infections with a low prevalence of hepatitis C virus infection, the presence of which is not related to that of the other two infections. Conversely, heterosexual partners of intravenous drug misusers have low prevalences of the three virus infections, but the presence of hepatitis C virus infection correlates significantly with the presence of HIV and hepatitis B infections. The rate of sexual transmission of hepatitis C virus seems to be low, even in partners of people known to be seropositive for this virus.     

Defective helper T-cell activity in LPS-unresponsive C3H/HeJ mice

C3H/HeJ mice, unresponsive to LPS, exhibit a defective ability to mount antibody responses to T-dependent immunogens. The anti-TNP antibody response to TNP-HRBC, a T-dependent immunogen, was found to be lower in these mice as compared to LPS-responsive C3H/HeN mice, whereas the anti-TNP antibody response to TNP-Ficoll, a T-independent immunogen, was of the same magnitude in C3H/HeJ and C3H/HeN mice. An impaired helper activity of C3H/HeJ HRBC-primed spleen cells was demonstrated in a titration assay in which graded numbers of C3H/HeJ or C3H/HeN HRBC-primed spleen cells were added to cultures containing a constant number of unprimed spleen cells from either C3H/HeJ or C3H/HeN mice and the immunogen TNP-HRBC. The reduced helper T-cell activity of C3H/HeJ HRBC-primed spleen cells appears to be independent of macrophage defects, since C3H/HeJ and C3H/HeN macrophages were found equally effective in antigen presentation as evaluated by an in vitro antigen-specific T-cell proliferation assay. The difference in helper T-cell activity between these two substrains probably reflects a lower number and/or proliferation rate of antigen-responsive T cells in C3H/HeJ mice.     

Studies on the control of antibody synthesis. XIV. Role of T cells in regulating antibody affinity.

The effect of limiting the number of helper T cells on the affinity of the primary antibody response to a T-dependent antigen (DNP-BGG) was evaluated in a cell transfer system. Lethally irradiated, thymectomized mice were reconstituted with either bone marrow or anti-brain θ antiserum plus complement-treated spleen as the source of B cells. In addition, they received various numbers of thymus cells as a source of helper T cells. The animals were immunized with DNP-BGG 1 day after cell transfer and their splenic anti-DNP PFC response was assayed for magnitude and affinity 3 weeks later. A marked restriction in helper T-cell activity resulted in a primary response which was of low magnitude, which lacked indirect PFC, and which had a very low affinity and restricted heterogeneity. When sufficient thymus cells were given to permit a switch to indirect plaque formation, a highly heterogeneous, high-affinity primary response was elicited. Further increase in the number of thymic cells resulted in a progressive increase in the magnitude of the primary response but had no effect on affinity. Thus, a reduction of 50% in the magnitude of the response as a consequence of limiting the number of T-helper cells had no effect on the affinity of the PFC. The results are consistent with the interpretation that the effect of restriction in T-cell help on antibody affinity is not due to a direct effect on precursors of high-affinity PFC but is secondary to inefficient selection for high-affinity cells when the degree of cell proliferation is markedly reduced.     

Human immunodeficiency virus infection,hepatitis B virus infection,and sexual behaviour of women attending a genitourinary medicine clinice

During the six months immediately after a public information campaign about the acquired immune deficiency syndrome 1115 women who attended a genitourinary medicine clinic in west London were tested for antibodies to the human immunodeficiency virus (HIV). Three women (0·27%) were positive, and all three were regular sexual partners of men with high risk lifestyles—two intravenous drug users and one bisexual. A consecutive series of 647 women from the cohort was tested for antibodies for hepatitis B core antigen: 27 were positive, of whom six had been born in the United Kingdom and were not known to have been at risk. The two women who were seropositive for HIV who completed a questionnaire on their sexual behaviour before they were tested reported both anal and oral receipt of semen and were in the upper fifth percentile for lifetime sexual partners. More than half (53%) of 424 women who reported that they had non-regular sexual partners never used a condom.It is concluded that heterosexual women in London are at a low risk of becoming infected with HIV.     

Risk factors for male to female transmission of HIV. European Study Group.

OBJECTIVE--To identify risk factors for sexual transmission of HIV from infected men to their female sexual partners. DESIGN--Cross sectional analysis as part of a continuing study. Data were obtained by interviewing heterosexual couples in which the man was infected with HIV. Risks were assessed by comparing couples in which transmission had occurred (woman infected with HIV) with those in which it had not (woman not infected) and estimated by independent odds ratios and their 95% confidence intervals. SETTING--Infectious disease and public health departments from nine centres in six European countries. PARTICIPANTS--153 Male index patients (mean age 30.4 years) and their 155 female partners (mean age 27.8 years). INTERVENTIONS--Women were tested to determine their HIV antibody state. Women with a risk of infection with HIV other than sexual contact with their infected partner were excluded. END POINT--Three risk factors for male to female transmission of HIV. MEASUREMENTS AND MAIN RESULTS--Three risk factors were identified: a history of sexually transmitted disease in the previous five years for the female partner (odds ratio 3.1, 95% confidence interval 1.1 to 8.6); index patient with full blown AIDS (5.4, 1.2 to 25.2); and practice of anal intercourse (5.8, 2.3 to 14.8). The proportion of women positive for HIV antibody was 27% (42/155), ranging from 7% (1 to 13%) (4/60) for couples with none of the three risk factors to 67% (45 to 89%) (12/18) for those with two or three of the risk factors. Duration of the relationship (median three years), frequency of sexual contacts, sexual practices other than anal intercourse, and contraceptive behaviour were not associated with infection of the partner. CONCLUSIONS--The risk of sexual transmission of HIV from an infected man to his female partner varies considerably according to the characteristics of the couple. The differences in rates of transmission in high risk groups may be considerably reduced if the risk factors are taken into account during individual and public health counselling.     

A model for the selective loss of major histocompatibility complex self-restricted T cell immune responses during the development of acquired immune deficiency syndrome (AIDS)

Functional analyses of peripheral blood leukocytes (PBL) from high risk HTLV-III antibody-negative and antibody-positive donors, as well as from patients with acquired immune deficiency syndrome (AIDS), lymphadenopathy syndrome (LAS), and AIDS-related complex (ARC) were performed by the in vitro generation of cytotoxic T lymphocyte (CTL) and proliferative responses to the HLA self-restricted antigens of influenza virus (S + X) and to nonself restricted HLA alloantigens (ALLO). All 40 antibody-negative donors tested responded to both S + X and ALLO in the CTL response, whereas six of 14 antibody-positive, two of three LAS, four of five ARC, and seven of 17 AIDS patients exhibited a selective absence of CTL to S + X, but generated normal or elevated CTL responses to ALLO. Of the remaining 10 AIDS patients, nine did not respond to either S + X or ALLO, and one responded to both S + X and ALLO. A similar selective loss of the proliferative response to S + X was found. We also observed antibody-positive donors who initially generated CTL responses to S + X and ALLO, but lost the S + X response as a function of time. We were able to restore the selective loss of S + X CTL activity in vitro by the addition of IL 2 and, to some extent, by co-stimulation with S + X plus ALLO. Depletion of CD4+ T helper cells and removal of autologous antigen-presenting cells from the PBL of healthy antibody-negative donors indicated that distinct T helper cell subsets exist in human PBL, and that S + X responses must use a CD4+ T helper population, whereas ALLO responses can utilize an alternate CD4- T helper pathway. A model is presented indicating the selective depletion of CD4+ T helper function in the developmental stages of AIDS. The functional test for T helper activity to self restricted antigens may be the earliest indicator of immune functional loss in the development of AIDS, and may precede a reduction in the absolute number of CD4+ cells.     

Sera from HTLV-III/LAV antibody-positive individuals mediate antibody-dependent cellular cytotoxicity against HTLV-III/LAV-infected T cells

The causative agent of the acquired immunodeficiency syndrome (AIDS) has been shown to be a human retrovirus called human T lymphotropic virus (HTLV)-III or lymphadenopathy-associated virus (LAV). The nature of the protective immune response against this virus is currently unknown. We report here results using an antibody-dependent cellular cytotoxicity (ADCC) assay which has been developed for measuring a specific immune response against HTLV-III/LAV. Forty-four sera were examined for their ability to mediate ADCC against HTLV-III/LAV-infected T cells. Sera from healthy HTLV-III/LAV seropositive individuals in the presence of mononuclear cells from healthy HTLV-III/LAV seronegative donors exhibited significantly higher levels of ADCC activity compared to sera from patients with AIDS. Western blot analysis of serum samples indicated that antibody reactivity with the p24 protein of HTLV-III/LAV correlated with higher levels of ADCC activity than did reactivity with Gp120/160. The observation that sera from healthy HTLV-III/LAV seropositive individuals mediated higher levels of ADCC activity than did sera obtained from subjects with AIDS suggests that ADCC may represent a protective immune response to infection with HTLV-III/LAV.     

Frequency and Absolute Number of FoxP3^＋ Regulatory T Cells Correlate with Disease Progression of Chronic HIV-1 Infection

CD4 CD25 Regulatory T cells (Treg) have been found to down-regulate immune activation in HIV-1 infection. However,whether the depletion of Treg benefits to the disease status of HIV infection remains undefined. To address this issue,we enumerated the Treg absolute counts and frequency in 75 antiviral-nave HIV-1-infected individuals in this study. It was found that HIV-infected patients displayed a significant decline in Treg absolute counts but a significant increase in Treg frequency. In addition,with disease progression indicated by CD4 T-cell absolute counts,circulating Treg frequency gradually increased; while Treg absolute counts were gradually decreased,suggesting that the alteration of Treg number closely correlated with disease progression in HIV infection. Functional analysis further showed that Treg efficiently inhibit both CD4 and CD8 T cell proliferation in vitro. Thus,our findings indicates that Treg actively participate in pathogenesis of chronic HIV infection,influencing the disease progression.