The safety of the hepatitis B vaccine. Inactivation of the AIDS virus during routine vaccine manufacture.

In the United States, one hepatitis B vaccine (Heptavax-B) has been licensed for the prevention of hepatitis B virus infections. Even though this vaccine has been shown to be highly effective and well tolerated in controlled trials and has been recommended for use in those at risk for acquiring infection by hepatitis B virus, many individuals have been reluctant to be immunized for fear of contracting acquired immunodeficiency syndrome (AIDS). In this study, we demonstrate that each of the three inactivation steps used in the manufacture of Heptavax-B independently will inactivate the infectivity of high-titered preparations of the AIDS virus; recipients of the hepatitis B vaccine do not develop antibodies to the AIDS virus; the hepatitis B vaccine does not contain detectable levels of nucleic acids related to the AIDS virus. These observations clearly demonstrate that vaccination with the currently available hepatitis B vaccine poses no demonstrable risk for acquiring AIDS.

Human T-cell leukemia virus (HTLV-I) p24 antibody in New York City blood product recipients.

Human T-cell leukemia virus (HTLV-I) is known to be associated with certain hematologic malignancies, and a related virus, HTLV-III/LAV, might be the cause of AIDS. Some persons with AIDS have had evidence of HTLV-I infection. Unrelated to these findings, it has been suggested that HTLV-I is transmitted via blood products. We therefore evaluated the serologic status to the HTLV-I core antigen p24 of 48 persons with hemophilia (Hem A) receiving factor concentrate therapy (a group at risk for AIDS), 49 persons with beta-thalassemia major (Thal) receiving frozen packed red blood cells therapy (FPRC), 26 patients with sickle cell anemia (SCA) receiving FPRC, and 18 persons not receiving any blood products. All participants were clinically well; only one had a risk factor other than hemophilia for AIDS, and all were from New York City, an area with a high incidence of AIDS. No Hem A or nontransfused persons had serum antibody to HTLV core p24 antigen; three with Thal and one with SCA were antibody-positive. These results were confirmed by both radioimmunoprecipitation and Western blot techniques. Positive serology did not correlate with any immune findings or quantity of blood products used. These data support that HTLV-I is preferentially transmitted through cellular blood products and that it is an infection for which cellular blood product recipients in at least some areas of the United States are at risk. Concentrate products appear free of transmission risk relative to cellular blood products, but we cannot be certain that this safety is absolute. The public health implications of blood product transmission of HTLV-I merit active, long-term investigation.

Evidence against transmission of human T-lymphotropic virus/lymphadenopathy-associated virus (HTLV-III/LAV) in families of children with the acquired immunodeficiency syndrome.

Six children with the acquired immunodeficiency syndrome (AIDS) and 12 of their household contacts were investigated serologically for evidence of infection with human T-lymphotropic virus/lymphadenopathy-associated virus (HTLV-III/LAV), the presumed etiologic agent of AIDS. All six children had antibody against HTLV-III/LAV, as measured by enzyme-linked immunosorbent assay, in each specimen tested. Of the two mothers studied both were seropositive; one was diagnosed with and died from AIDS. Four of the remaining 10 household members were seropositive, including three adults in groups at high risk for the development of AIDS and one sibling who was younger than the child with AIDS. Among the seronegative household contacts were four foster mothers or grandmothers of the children with AIDS, three of whom had cared for the children since infancy. Household contact with children with AIDS may include persons in groups at high risk for AIDS who have been infected with HTLV-III/LAV. However, the negative findings in household contacts without risk factors for AIDS suggest that horizontal transmission of the virus within households by means other than sexual contact must be infrequent.

Human T-cell leukemia virus type II: primary structure analysis of the major internal protein, p24 and the nucleic acid binding protein, p15.

The 24,000-molecular-weight major internal protein (p24) and the 15,000-molecular-weight nucleic acid binding protein (p15) of human T-cell leukemia virus type II (HTLV-II) were subjected to amino acid composition and amino-terminal amino acid sequence analysis. A comparison of amino acid composition of p24 and p15 of HTLV-II with those of the analogous proteins of HTLV-I revealed that these two proteins share overall similarity. Further, alignment of the amino-terminal amino acid sequence for the first 27 residues of p24 and 34 residues of p15 from HTLV-II showed extensive sequence homology with analogous proteins of HTLV-I. These data suggest that although disease associated with HTLV-I is malignant T-cell leukemia and that associated with HTLV-II is a relatively benign variant of hairy-cell leukemia, HTLV-I and HTLV-II are closely related to each other, at least in their gag-gene-encoded sequences.

HTLV-I antibody status in hemophilia patients treated with factor concentrates prepared from U.S. plasma sources and in hemophilia patients with AIDS.

Serum samples from 85 Austrian hemophilia patients treated with lyophilized factor concentrates prepared from U.S. plasma sources, 24 hemophilia patients from Georgia on a home therapy program with factor concentrates, and 10 U.S. hemophilia patients with acquired immunodeficiency syndrome (AIDS) were analyzed by two different methods for the presence of antibodies to the major internal antigen of human T-cell leukemia virus I (HTLV-I) p24. All but one, a Georgia sample, were negative. The absence of antibody to HTLV-I p24 in the serum of European hemophilia patients, of U.S. hemophilia patients with no symptoms of AIDS, and of U.S. hemophilia patients with AIDS is interpreted as an indication of the lack of ready transmissibility of HTLV-I in lyophilized factor concentrates.

Nucleic acid structure and expression of the human AIDS/lymphadenopathy retrovirus.

The 9,213-nucleotide structure of the AIDS/lymphadenopathy virus has been determined from molecular clones representing the integrated provirus and viral RNA. The sequence reveals that the virus is highly polymorphic and lacks significant nucleotide homology with type C retroviruses characterized previously. Together with an analysis of the two major viral subgenomic RNAs, these studies establish the coding frames for the gag, pol and env genes and predict the expression of a novel gene at the 3' end of the genome unrelated to the X genes of HTLV-1 and -II.

Human T-cell leukemia virus in lymphocytes of two hemophiliacs with the acquired immunodeficiency syndrome.

Fresh and cultured peripheral blood cells from two patients with hemophilia A and the acquired immunodeficiency syndrome were examined for markers of infection with human T-cell leukemia virus (HTLV) type 1. Neither patient had antibody to membrane antigens of HTLV-infected cells at the time of culture. Electron microscopy of peripheral blood cells from Patient 1 and cultured cells from Patient 2 showed type C retrovirus-like particles. Examination of peripheral blood lymphocytes showed other smaller virus-like particles in circulating mononuclear cells from both patients. Indirect immunofluorescence of peripheral mononuclear cells from both patients and of cultured cells from Patient 2 showed staining with antibodies to purified HTLV and to HTLV core proteins p24 and p19.

Antibodies to the core protein of lymphadenopathy-associated virus (LAV) in patients with AIDS.

Lymphadenopathy-associated virus ( LAV ), a human T- lymphotrophic retrovirus isolated from a homosexual man with lymphadenopathy, has been causally associated with acquired immunodeficiency syndrome (AIDS). A sensitive and specific radioimmunoprecipitation test was developed for the detection of antibodies to the major core protein of LAV , p25 (molecular weight 25,000). Antibody to LAV p25 was found in the serum of 51 of 125 AIDS patients, 81 of 113 patients with lymphadenopathy syndrome, 0 of 70 workers at the Centers for Disease Control (some of whom had handled specimens from AIDS patients), and 0 of 189 random blood donors. Of a group of 100 homosexual men from San Francisco whose serum was obtained in 1978, only one had antibody to LAV p25; in contrast, of a group of 50 homosexual men in the same community whose serum was obtained in 1984, 12 had antibodies to LAV p25.

Lymphadenopathy associated virus infection of a blood donor--recipient pair with acquired immunodeficiency syndrome.

A retrovirus isolated from three patients with the acquired immunodeficiency syndrome (AIDS) in the United States was morphologically and antigenically identical to lymphadenopathy associated virus isolated in France. Two of these isolates were from a blood donor-recipient pair, each of whom developed AIDS. Lymphadenopathy associated virus was isolated from the blood donor's lymphocytes 12 months after his onset of AIDS symptoms and from the blood recipient's lymphocytes 1 month after her onset of AIDS symptoms. Two isolates from the blood donor-recipient pair and an isolate from an epidemiologically unrelated homosexual man were examined by competitive radioimmunoassay to determine their antigenic relatedness to each other and to other human retroviruses. The major core proteins (p25) of the isolates were antigenically identical and all three isolates were identical to prototype lymphadenopathy associated virus isolated in France.

Nucleotide sequence and host La protein interactions of rabies virus leader RNA.

Rabies virus leader RNA was detected in infected BHK-21 cell extracts by hybridization to end-labeled genomic RNA. Similar to the leader RNA of vesicular stomatitis virus, the leader RNA of rabies virus was also found to be associated with the La protein by specific immunoprecipitation with antisera from lupus patients. The 3' end of the genomic RNA of rabies virus was sequenced, and the size and termination site of leader RNA were determined. In addition, extension of the sequence into the nucleocapsid gene of rabies virus showed an open reading frame for at least 37 amino acid residues. Sequence relationships between rabies virus and vesicular stomatitis virus leader genes and the possible involvement of the La protein in rhabdovirus biology are discussed.

Transfusion-associated AIDS: serologic evidence of human T-cell leukemia virus infection of donors.

An assay for antibodies to membrane antigens of cells infected by human T-cell leukemia virus was used to examine serum from persons who donated blood to 12 patients with acquired immunodeficiency syndrome (AIDS) associated with blood transfusions. The occurrence of positive results in the assay was significantly greater among donors to the AIDS patients (9 of 117; 7.7 percent) than among random donors (1 of 298; 0.3 percent). Of 12 sets of donors examined, 9 sets included a donor whose serum gave positive results for the presence of the antibodies. In six of these nine sets, the seropositive donor was an individual who was also identified as a possible source of AIDS transmission when epidemiologic and immunologic criteria were used.

Antibodies to human T-cell leukemia virus membrane antigens (HTLV-MA) in hemophiliacs.

Along with homosexual men, Haitians, and intravenous drug abusers, hemophiliacs are at high risk of contracting acquired immunodeficiency syndrome (AIDS). An earlier study revealed that 36 percent of a group of the AIDS patients had antibodies to cell membrane antigens associated with the human T-cell leukemia virus (HTLV-MA), whereas only 1.2 percent of matched asymptomatic homosexual controls had these antibodies. In the present experiments, serum samples from 172 asymptomatic hemophiliacs were examined for the presence of antibodies to HTLV-MA. Such antibodies were detected in 5 to 19 percent of the hemophiliacs examined from four geographical locations, but in only 1 percent or less of laboratory workers, normal blood donors, donors on hemodialysis, or donors with chronic active hepatitis.

Antibodies to human T cell leukaemia virus-associated membrane antigens in haemophiliacs: evidence for infection before 1980.

Human T cell leukaemia virus (HTLV), HTLV proviral DNA, and antibodies to HTLV or a related agent have recently been detected in patients with acquired immunodeficiency syndrome (AIDS). Antibodies against HTLV-related antigens were assayed by means of indirect living cell immunofluorescence of HTLV-infected cells in sera recently collected from Georgia haemophiliacs and in sera collected between 1976 and 1981 from New York haemophiliacs. 5 of 45 Georgia haemophiliacs and 8 of 48 New York haemophiliacs had antibodies to HTLV-associated cell membrane antigen (HTLV-MA). None of the control Georgia patients on haemodialysis or with chronic hepatitis had detectable antibodies. The 5 haemophiliac patients from Georgia with HTLV-MA had significantly fewer T4 lymphocytes than similar HTLV-MA-negative patients. There were no other significant immunological differences between these groups. These data suggest that transfusions with blood products may expose haemophiliacs to a substantial risk of acquiring HTLV or a related virus.

The changing etiology of epidemic keratoconjunctivitis: antigenic and restriction enzyme analyses of adenovirus types 19 and 37 isolated over a 10-year period.

Strains of adenovirus types 19 (Ad-19) and 37 (Ad-37) isolated from cases of epidemic keratoconjunctivitis (EKC) over a 10-year period were analyzed for differences in antigenic and restriction enzyme patterns. By restriction analysis, 35% of the isolates recovered between 1973 and 1981 and typed by hemagglutination-inhibition tests as Ad-19 were in fact Ad-37. This finding was confirmed by comprehensive serologic tests when Ad-37 reagents became available in 1981. All Ad-19 strains isolated between 1973 and 1980 were identical to the previously described genotype Ad-19A, and these Ad-19A strains exhibited a differential hemagglutination profile distinct from that of Ad-19 and Ad-37 prototypes. The earliest Ad-37 case found in the United States occurred in April 1976; Ad-37 then became the major agent of EKC from 1977 to 1983. Intermediate strains between types 19A and 37 were not detected by either antigenic or restriction fragment analyses. Thus, some genetic event appears to generate new genotypes such as Ad-19A and serotypes such as Ad-37.

Molecular cloning and sequencing of the La Crosse virus S RNA.

Complete double-stranded DNA copies of the La Crosse virus (LAC) S genome have been synthesized and cloned into plasmid pBR322. The cloned genome was characterized and sequenced. The LAC S genome consisted of 981 nucleotides and contained two overlapping open reading frames. The first reading frame begins at nucleotide 82 and encodes a protein of 235 amino acids. A polypeptide of 92 amino acids can be translated in a +1 reading frame 16 nucleotides downstream from the start of the first reading frame. This second reading frame is initiated with two AUG codons followed by the serine codon UCG, the same serine codon which immediately follows the AUG of the first reading frame.