'Brown sugar' heroin intoxication and improvement of surrogate immunologic markers in HIV infection.

OBJECTIVE: To report on the unexpected improvement in major biological surrogate markers (CD4 T-cell count, HIV RNA viral load, and apoptosis level) during the periods of 'brown sugar' heroin intoxication (BSI) in 12 HIV-1-infected intravenous drug users, independently of their antiretroviral therapy, compared to the period of 'brown sugar' heroin withdrawal (BSW). METHODS: The patients were followed prospectively for a total of 417 months over 4 years. Twenty-four episodes of BSI and 24 periods of BSW were analyzed. RESULTS: (1) BSI: the mean (+/-SE) duration was 9+/-1.8 months; at onset, the mean +/-SE CD4 T-cell count was 401+/-88/mm3; at the end, an absolute increase of 346 CD4 T-cells/mm3 and a CD4 T-cell count relative variation of +131% was observed. Half of the patients showed an increase of CD4 T-cell count of more than 90% during their follow-up. The mean+/-SE of CD8 T-cell count increased significantly by 108%. (2) BSW: the mean +/- SE duration was 8.4+/-1.3 months; at onset, the mean +/-SE CD4 T-cell count was 695+/-78/mm3; at the end, an absolute decrease of 342 CD4 T-cells/mm3 and a CD4 T-cell count relative variation of -52% was observed. Half of the patients showed a decrease of CD4 T-cell count of more than 51%. (3) Circulating viral load appeared to be significantly higher during BSW (median: 452 000 Eq RNA/mL) than during BSI (median: 52 000 Eq RNA/mL); p<0.01. (4) Similarly, the apoptotic process affecting circulating lymphocytes was significantly lower during BSI than during BSW episodes. (5) The 4-year mortality rate was 7%, compared with 36% in HIV-positive former drug users (p<0.001). CONCLUSIONS: Taken together, these features suggest that 'brown sugar' heroin could have either immunomodulatory or antiretroviral properties. Confirmation of these findings and investigation of the role of the many substances in 'brown sugar' heroin are indicated.

Molecular evidence for nosocomial transmission of human immunodeficiency virus from a surgeon to one of his patients.

We have investigated the molecular evidence in favor of the transmission of human immunodeficiency virus (HIV) from an HIV-infected surgeon to one of his patients. After PCR amplification, the env and gag sequences from the viral genome were cloned and sequenced. Phylogenetic analysis revealed that the viral sequences derived from the surgeon and his patient are closely related, which strongly suggests that nosocomial transmission occurred. In addition, these viral sequences belong to group M of HIV type 1 but are divergent from the reference sequences of the known subtypes.

Efficacy and safety of Buxus sempervirens L. preparations (SPV(30)) in HIV-infected asymptomatic patients: a multicentre, randomized, double-blind, placebo-controlled trial.

The objective of the present study was to compare the efficacy and safety of two doses of SPV(30) in HIV asymptomatic patients. The study was designed as a randomized double-blind multicentre trial of two doses of SPV(30) (990 mg/d and 1980 mg/d) versus placebo. 145 previously untreated subjects with asymptomatic HIV infection (CDC group IV) and CD4 cell counts between 250 and 500 × 10(6)/1 were recruited. There was a statistically significant difference in therapeutic failures between groups in favor of SPV(30) 990 mg including decreases of CD4 cell count < 200 × 10(6)/1 and/or number of clinical aggravations (progression to AIDS or AIDS related complex). The treatment groups differed statistically in the rate of disease progression also in favor of SPV(30) 990 mg/d. Fewer patients receiving SPV(30) 990 mg/d had at the end an increase of viral load greater than 0.5 log (P = 0.029). No severe side-effects were reported in the 3 groups. From these results we conclude that SPV(30) 990 mg/d has beneficial effects in HIV asymptomatic patients and appears to delay the progression of HIV disease.

Human immunodeficiency virus infection and AIDS in a person with negative serology.

A 38-year-old woman resident of Ivory Coast died of AIDS, while remaining human immunodeficiency virus (HIV)-seronegative. She had been regularly tested because her husband was HIV-seropositive. The subject's lack of specific antibodies was assessed using commercial tests and confirmed by a radioimmunoprecipitation assay of the patient's virus. She was unquestionably HIV-1-infected, with a high plasma virus load, and her virus could be isolated. Molecular analyses indicated this retrovirus was clade A, which is common in Africa, and it was highly homologous to the virus isolated from her husband. The subject's seronegative status was thought to be due to rapid depletion of specific CD4+ helper T cells, resulting from accelerated disease progression, and was host-related rather than due to a specific HIV strain.

Gag-specific cytotoxic responses to HIV type 1 are associated with a decreased risk of progression to AIDS-related complex or AIDS.

The duration of human immunodeficiency virus (HIV-1) infection prior to the development of AIDS is variable, and for most patients the exact time of infection is not known. A group of 38 HIV-1-infected subjects was tested while asymptomatic for comparative cytotoxic lymphocyte responses to the Gag and envelope antigens of HIV-1. Twenty of the 38 patients had no detectable primary cytotoxic T lymphocyte (CTL) response to Gag, and this was associated with a relative risk of 1.89 for progression to ARC or AIDS during the subsequent 3 to 40 months of observation when compared with patients who had Gag-specific CTL activity at the beginning of the observation period. In contrast, no significant association was observed between envelope-specific cytotoxic activity and disease progression. Other patient characteristics, including CD4+ T lymphocyte counts and antibody levels to the p24gag protein, measured at the start of observation, did not correlate with disease progression during the observation period. This suggests that the anti-Gag CTL response may be protective during HIV-1 infection.

Isolation and envelope sequence of a highly divergent HIV-1 isolate: definition of a new HIV-1 group.

We report here the isolation and envelope sequence of a divergent HIV-1 isolate from a French woman with AIDS. This virus, HIV-1VAU, is closely related to the recently described Cameroonian viral isolates HIV-1ANT70 and HIV-1MVP5180, until now designated HIV-1 subtype O. Phylogenetic analysis reveals that the three viruses are equidistant from one another and that their mutual divergence is similar to what has been reported between the more conventional HIV-1 subtypes. Therefore, these three viruses could be included in a new viral group, HIV-1 group O (outgroup), distinct from the cluster of other HIV-1 isolates, which we will refer to as group M (Major group). The HIV-1 group O is currently emerging in western central Africa but its spread in Europe has already started.

Idiotypic expression of anti-gp120 antibodies in unrelated human immunodeficiency virus-infected individuals.

Although it is recognized that human immunodeficiency virus (HIV) env genes exhibit a high degree of variability, little is known about the molecular heterogeneity of gp120-specific antibodies in infected individuals. As a first step to approach this issue, we investigated the idiotypic relatedness of anti-gp120 antibodies present in the serum of HIV-infected individuals. Idiotypic determinants (idiotopes) are fingerprints of the variable region of the antibody molecule and, as such, they represent unique probes with which to explore the diversity of the immune response. We isolated IgG anti-gp120 antibodies from the serum of a seropositive asymptomatic individual by affinity chromatography. The purified antibodies were shown to bind gp120 and gp160 by ELISA, Western blotting and radio-immunoprecipitation. They also recognized HIV-infected human T cells as detected by immunofluorescence. Anti-idiotypic reagents were generated against this gp120 idiotype, and one of them was used to study anti-gp120 idiotypic diversity in a panel of 65 sera drawn from AIDS and AIDS-related complex patients, and from HIV seropositive asymptomatic individuals. Sixty normal human sera were used as negative controls. We found no evidence for common idiotopes on anti-gp120 antibodies of unrelated individuals. In contrast, we also noticed that the idiotypic profile expressed sequentially at two different intervals in a persistently infected individual showed little variation. Finally, when the diversity of murine anti-gp120 antibodies with a monoclonal anti-idiotype was analysed, no evidence of cross-reactive idiotopes in the murine system was found.

Autoantibodies typical of non-organ-specific autoimmune diseases in HIV-seropositive patients.

OBJECTIVE: To analyse serological aspects of systemic autoimmunity in HIV-1-seropositive patients and in individuals at risk for AIDS. DESIGN AND METHODS: The reactivity of antibodies in the serum of 100 HIV-1-seropositive patients was investigated by enzyme-linked immunosorbent assay (ELISA) using a series of antigens known to be recognized by antibodies from patients with multisystemic autoimmune diseases, such as systemic lupus erythematosus, mixed-connective tissue disease and Sjögren's syndrome. RESULTS: High levels of immunoglobulin G (IgG) antibodies reacting with double-stranded DNA (dsDNA), synthetic peptides of ubiquitinated histone H2A, Sm-D antigen, U1-A RNP antigen and 60 kD SSA/Ro antigen were found in 44-95% of HIV-infected patients. Among histone antibodies, the most frequent reactions were towards the carboxy-terminal region of histone H1 and to histone H2B and its amino-terminal domain 1-25. Eight HIV-1-seropositive patients at different stages of disease according to the Centers for Disease Control classification were also studied. In most cases, no obvious fluctuations were observed over several years. Antibodies were found early, and their specificity and apparent level of activity remained relatively constant. There was no evidence of such an autoimmune response in the serum of high-risk homosexual seronegative men. CONCLUSIONS: Although the aetiology of AIDS is known, in general the aetiology of multisystemic autoimmune diseases remains to be determined, and the sequence of events taking place remains obscure in both cases. It is possible that the large spectrum of antibodies found in HIV-infected patients reflects a specific stimulation of B-cells by nuclear antigens released by apoptosis during an early stage of disease.

Clinical and virological aspects of HIV2 infection in rhesus monkeys.

To establish an animal model of AIDS, two different "wild" or "adapted" HIV2 Rod and Eho strains were cultivated on monkey cells from different species (baboons, cynomolgus, Rhesus monkeys). Five different available strains were then injected both by intravenous (i.v.) and intracerebral (i.c.) route into ten Rhesus monkeys. Seven animals seroconverted between days 13 and 230. Reverse transcriptase activity in the lymphocyte culture supernatants was detectable in six of the seven animals that seroconverted, and in one animal that remained seronegative. Lymphopenia and a decrease in the CD4+ cell counts were observed in eight animals. One animal, inoculated with HIV2-Rod "wild type," developed a severe cachexia, with dyspnea, and associated neurological symptoms 150 days after inoculation. This animal was sacrificed on day 220. Pathological examination showed typical lesions of actinomycetes infection in the lungs and in the meninges. Another monkey had significant weight loss associated with lymphadenopathies and pancytopenia. These results suggest that in vivo replication of HIV2 in Rhesus monkeys may induce clinical symptoms of immune deficiency. This method is reproducible and may provide a good model for AIDS.

Anti-idiotypic antibodies to human anti-gp120 antibodies bind recombinant and cellular human CD4.

The presence of anti-CD4 antibodies in sera of human immunodeficiency virus (HIV)-seropositive individuals has been recently documented, but its origin remains unknown. To test the hypothesis that anti-idiotypic antibodies to gp120, the HIV envelope glycoprotein with high affinity for CD4, mimic the configuration of gp120 and bind CD4, we performed two sets of experiments. First, we tested the possibility that anti-CD4 antibodies present in sera of a proportion of HIV-positive individuals exhibit variable region complementarity to autologous anti-gp120 antibodies. We show here that affinity-purified human anti-gp160 antibodies recognize specifically autologous affinity-purified anti-CD4 antibodies. We also demonstrate that antibodies to CD4 competitively inhibit anti-gp160 autologous antibodies binding to gp160. This implies that at least some anti-CD4 antibodies are directed towards idiotypic motifs located on anti-gp120 antibodies and that they may result from an anti-idiotypic response to anti-gp120 antibodies. In a second set of experiments, we examined the effect of anti-idiotypic immunization of experimental animals against human anti-gp120 antibodies. We found that anti-idiotypic antibodies produced in a rabbit immunized against affinity-purified human anti-gp120 antibodies specifically recognize recombinant and cellular human CD4, and that this interaction is competitively inhibited by soluble CD4. The data support the concept of idiotypic mimicry whereby anti-idiotypic antibodies produced against anti-gp120 antibodies recognize CD4, the cellular receptor of HIV.

A study of seroprevalence of HIV-1 and HIV-2 in six provinces of People's Republic of Angola: clues to the spread of HIV infection.

A seroepidemiological study was carried out to determine the distribution of the human immunodeficiency viruses type 1 (HIV-1) and type 2 (HIV-2) in the People's Republic of Angola, where HIV-2 existence was previously unknown and HIV-1 seropositivity was only reported to be present in Luanda and Cabinda. A total of 1,695 serum samples were obtained from healthy persons (control group) and from a group of patients in the provinces of Zaire (13), Lunda-Norte (L.N.) (749), Luanda (556), Huambo (154), Kuando-Kubango (K.-K.) (49), and Namibe (119). All samples were tested for HIV-1 and HIV-2 antibodies by enzyme-linked immunosorbent assay and an indirect immunofluorescence assay using MOLT-T4 cells. Positive samples were confirmed by the Western-blot technique. Sera giving cross reactivity at the level of HIV-1 and HIV-2 large glycoproteins were further tested by radioimmunoprecipitation assay and by reactivity against a peptide corresponding to the dominant epitope of the transmembrane protein. The overall seroprevalance was 14.2%, with significantly higher values in the patient group [19.4% (HIV-1 = 8.8%; HIV-2 = 8.4%; HIV-1 + HIV-2 = 2.2%)] than the control group [9.3% (HIV-1 = 3.3%; HIV-2 = 5.3%; HIV-1 + HIV-2 = 0.7%)]. HIV-2 as well as HIV-1 infection is actually present in Angola in all studied provinces. Higher seroprevalence was seen in the provinces of Zaire, Lunda Norte, and Huambo. People displacements, mainly as a consequence of the war, certainly play an important role in spreading HIV infection from the northern frontier areas of the country to the central and southern regions.

[Infectivity inhibition of HIV prototype strains by antibodies directed against a peptide sequence of mycoplasma]. / Inhibition de l'infectiosité de souches prototypes du VIH par des anticorps dirigés contre une séquence peptidique de mycoplasme.

Antibodies prepared against a peptide corresponding to the site of cyto-adherence of Mycoplasma genitalium adhesine inhibit or reduce the infectivity of the HIV-1BRU and HIV-2ROD strains of Human Immunodeficiency Virus in lymphoid cells. These results strengthen the hypothesis that some mycoplasmas may play an important part in HIV replication and pathogenicity.

Antibodies to the nef protein and to nef peptides in HIV-1-infected seronegative individuals.

The silent period that follows infection by the human immunodeficiency virus (HIV-1) and precedes seroconversion remains a problem for the screening of blood supply, and knowledge about the mechanism involved in the maintenance of latency is only fragmentary. Using purified nef recombinant protein and six synthetic nef peptides, antibodies to the product of an HIV-1 regulatory gene, the negative regulatory factor (nef) involved in maintenance of proviral latency, were detected by Western blot and radioimmunoassay techniques in HIV-1-seronegative, viral antigen-negative, and virus culture-negative individuals at risk for HIV infection. This antibody response to nef was correlated in eight individuals with the detection of HIV-1 proviral DNA by oligonucleotide hybridization, following enzymatic amplification of HIV DNA in peripheral blood mononuclear cells. Such latent HIV infections have now been followed for up to 6 or 10 months in five individuals. In addition, retrospective and prospective analysis of HIV-1-seropositive individuals have shown (1) antibodies to nef preceding seroconversion, and (2) the persistence of antibodies to nef and of HIV-1 proviral DNA in a case of spontaneous complete HIV-1 seronegativation. Since DNA amplification cannot be currently considered for routine use, screening for anti-nef antibodies followed by confirmation by DNA amplification could represent a basis for new diagnostic strategies. Beyond their diagnostic implications, these findings, suggesting that regulatory genes of the HIV-1 provirus can be expressed prior to the initiation of virion synthesis, may also be applicable in the design of alternative vaccines against the acquired immunodeficiency syndrome.

HIV 2 infection among blood donors and other subjects in France. The "Retrovirus" Study Group of the French Society of Blood Transfusion.

During a 3 year period, from August 1985 to August 1988, 18 HIV 2-infected blood donors were detected in France as a result of systematic HIV 1 screening. These sera were characterized as HIV 2 by specific Western blot and synthetic peptides. Within the same period, 40 other HIV 2 infected subjects were identified by our study group, independently of blood donations. Thirty of these 58 subjects living in France originate from West Africa (8 blood donors), 3 (I blood donor) are Portuguese men who had lived in West Africa and 25 (9 blood donors) are of French origin; among these, 16 have had a known close contact with West Africa. When HIV 2-infected subjects were asymptomatic, cross reactivity between antibodies to HIV 2 and HIV 1 proteins was generally observed with the two-step ELISA assays using total HIV 1 proteins; it was poor with the competitive assays and variable with the assays using recombinant proteins. When the subjects had signs of immunodeficiency, cross reactivity decreased. The data confirm that HIV 2 is not widespread in France and that most of HIV 2-infected but asymptomatic subjects are recognized by several HIV 1 ELISA assays. Accordingly, systematic screening for HIV 2 with an additional test cannot be recommended at the present time, but a combined HIV 1 and HIV 2 test will be useful when available.

[Inflammatory arthropathies in patients with human immunodeficiency virus infection]. / Arthropathies inflammatoires chez des malades infectés par le virus de l'immunodéficience humaine.

Articular manifestations were observed in 10 patients (8 men, 2 women, aged from 23 to 46 years) with human immunodeficiency virus (HIV) infection. All men were homosexuals, except for an intravenous drug addict. One woman was a native of Gabon and the other had multiple transfusions. The joint diseases were of the polyarthritis and acute oligoarthritis types, affecting mainly the knees and ankles but also the wrist and fingers; the spine was involved in one case. The synovial fluid present in 4 patients contained 5,000 to 27,000 cells per cubic millimeter, with a strong predominance of polymorphonuclears. In 3 cases, infective viral particles were found in the fluid with anti-HIV antibodies. In 2 patients biopsy of the synovial membrane provided evidence of non-specific subacute synovitis. All X-ray films, including those of the sacro-iliac joint, were and remained normal. The course of the joint disease was acute and regressive in 5 cases, chronic and prolonged in the remaining 5 cases. In 5 patients the arthropathies were the first clinical manifestations of the HIV infection. Three patients who had stage IV C AIDS died; the others were in stages II (5), III (1) or IV E (1) and did not progress to a more severe stage. This study shows that various types of inflammatory arthritis may occur in HIV positive patients. In most cases the arthritis is reactive, but certain data suggest that it may be directly related to the virus in some patients.