Human T-lymphotropic Virus Type III Research Articles

The natural history of human T lymphotropic virus-III infection: the cause of AIDS.

This article reviews current knowledge on the etiology modes of transmission immunologic aspects clinical outcome and prevention of acquired immunodeficiency syndrome (AIDS). The isolation of a human retrovirus as the etiologic agent has facilitated clearer understanding of the natural history of AIDS. Antibodies to human T-lymphotropic virus type III (HTLV-III) have been found in over 90% of AIDS patients 80-100% of those with related conditions such as unexplained persistent generalized lymphadenopathy but only 1% of people outside the defined risk groups. 4-7 weeks seems to be the latency period for the development of antibodies in cases of parenteral exposure whereas the amount of time required for seroconversion after sexual transmission is unknown. HTLV-III has been isolated from lymphocytes in peripheral blood bone marrow cells spinal fluid and brain tissue lymph nodes cell free plasma saliva semen and tears. The risk of infection seems to depend most on the route of exposure i.e. blood and blood products sexual contact parenteral drug use and prostitution perinatal transmission. Full blown AIDS is associated with the depression or aberration of most measurable cellular and humoral immune responses. Among those seropositive to HTLV-III but without clinical signs of AIDS the viral interaction with the immune system is not well understood. Even minor reductions in the rate with which HTLV-III is spread will have a large impact on the total number of infected persons a few years from now suggesting the importance of preventive education and counseling. Promiscuity and anonymous sex should be discouraged. Blood organ and sperm donors should be tested for antibodies. Screening should be offered to women in high risk groups who are considering pregnancy and those who are antibody positive should be advised not to become pregnant at least until more knowledge is available.

HLA antibodies as a cause of false-positive reactions in screening enzyme immunoassays for antibodies to human T-lymphotropic virus type III.

15,680 volunteer blood donors were screened by enzyme-linked immunosorbent assay (EIA) for antibodies to human T-lymphotropic virus Type III (HTLV-III). On at least two of three determinations, 0.37 percent were found to be reactive. When the first 38 of these samples were sent for repeat EIA and Western blot, the EIA was positive in 14. In only three of these 14 samples was the EIA result confirmed by Western blot. Eight of these eleven false-positive samples were from women who were found to have HLA antibodies. In seven of these women, the HLA antibodies were directed to Class II antigens expressed on the cell used to grow HTLV-III in the preparation of screening EIA kits. We conclude that HLA antibodies are an important cause of false-positive reactions in the screening test for HTLV-III antibody.

Narrow host range of AIDS-related retroviruses (YU-1, 2, 3, 4) isolated from Japanese hemophiliacs: inability to infect H9, Molt-4, and MT-4 cells.

Infectivity was assayed by infecting human T-lymphocytes, H9, Molt-4, and MT-4 cells with different strains of AIDS viruses (HTLV-III, LAV, ARV, and YU viruses). Human T-lymphotropic virus type-III (HTLV-III), lymphadenopathy-associated virus (LAV), and AIDS-associated retrovirus (ARV) were able to infect all kinds of target cells tested and to induce virus-specific antigens, whereas Japanese isolates, YU viruses, infected only interleukin-2-dependent human T-lymphocytes. Long-term propagation of the YU viruses and pretreatment of the cells with Polybrene did not allow the YU virus to produce viral antigens by infecting H9, Molt-4, and MT-4 cells. Thus, YU viruses have a rather narrow host range as compared with HTLV-III, LAV, and ARV. These different infectivities may be reflected in the progress and symptoms of AIDS in vivo.

Children with AIDS

The etiologic agent for acquired immune deficiency syndrome (AIDS) has been identified as human T lymphotropic virus type III (HTLV-III). Its distinguishing characteristics and putative receptor, the T4 molecule, are discussed. The Western Blot method has been applied to assess the presence of antibody to HTLV-III in patients as a measure of infection with HTLV-III. The definition of AIDS in children, based on the Centers for Disease Control surveillance criteria, is explored and expanded. Clinical and laboratory manifestations of pediatric AIDS are explained in the context of ‘HTLV-III infection’ through an analysis of prospective and retrospective serologic studies. Transmission of the disease is explored through parental history of infected children. Finally, the rationale for antibody replacement therapy is set forth.

Disease-specific and tissue-specific production of unintegrated feline leukaemia virus variant DNA in feline AIDS

Feline leukaemia viruses (FeLVs) have long been known to be associated with induction of proliferative and anti-proliferative diseases of domestic cats. Strains of FeLV have been recognized which specifically induce lymphosarcoma, aplastic anaemia, myelodysplastic anaemia, and, recently, feline AIDS (acquired immune deficiency syndrome), a naturally occurring immunosuppressive syndrome strikingly similar to human AIDS which is lethal in 100% of inoculated and viraemic specific-pathogen-free (SPF) cats. Here, we have analysed FeLV DNA in tissues of 22 SPF cats that had been inoculated with the feline AIDS strain (FeLV-FAIDS) and we find two classes of viral DNA--a monotypic common form which is detectable in bone marrow regardless of disease state, and variant forms, recognizable by restriction site differences, whose appearance correlates with onset of disease symptoms and persists throughout the course of the disease. FeLV-FAIDS variant DNA is detected at high concentration (10-50 copies per cell) and principally as unintegrated viral DNA (UVD) in bone marrow of cats with feline AIDS. In marked contrast high levels of UVD were not present in cats in the terminal-stages of T-cell lymphosarcoma, aplastic anaemia, or myelodysplastic anaemia induced by other FeLV strains. These results parallel recent observations in humans, where high levels of UVD were sometimes found in cells derived from AIDS patients infected with human T-lymphotropic virus type III (HTLV-III)/lymph-adenopathy-associated virus (LAV), and suggest that persistence of unintegrated variant viral DNA is a crucial indicator of retrovirus-induced cytopathic disease syndromes such as AIDS.

Influence of the human T-lymphotropic virus/lymphadenopathy-associated virus on functions of human lymphocytes: evidence for immunosuppressive effects and polyclonal B-cell activation by banded viral preparations.

The etiologic agent for the acquired immunodeficiency syndrome (AIDS) is now firmly established as the retrovirus termed the human T-lymphotropic virus type III (HTLV-III) or the lymphadenopathy-associated virus, LAV. The disease is characterized by profound and progressive loss of immunity, but molecular evidence indicates that only a few cells in peripheral blood are being productively infected with this virus. In the present study we have investigated a disrupted HTLV-III viral preparation for biologic effects on normal lymphoid cells. Relatively dilute concentrations of this preparation were found to stimulate immunoglobulin secretion by peripheral blood lymphocytes; at the same dosages, the preparation was inhibitory for the B-cell differentiation responses that are induced with other known polyclonal B-cell activators, pokeweed mitogen, Staphylococcus aureus, and Epstein-Barr virus. This preparation was also inhibitory at high concentrations for T-lymphocyte proliferative responses to phytomitogens and antigens and resulted in a reduced expression of Tac antigen on phytohemagglutinin-activated lymphocytes. Paradoxically, incubation of lymphocytes of certain healthy donors with the HTLV-III preparation alone resulted in increased expression of Tac and Leu-12 antigens. These findings show that a disrupted preparation of HTLV-III virus can mimic many of the immunologic abnormalities present in patients with HTLV-III infection. Nonviable viral proteins may be responsible for some of the immunologic perturbations that occur in HTLV-III-infected states.

Human T-cell growth factor (interleukin 2) and gamma-interferon genes: expression in human T-lymphotropic virus type III- and type I-infected cells.

Acquired immune deficiency syndrome (AIDS) is characterized by severe depletion of OKT4+ T lymphocytes and leukemia is associated with abnormal proliferation of maturation-arrested lymphocytes. Human T-lymphotropic virus type III (HTLV-III) or lymphoadenopathy virus (LAV) and type I (HTLV-I) are etiologically linked to AIDS and adult T-cell leukemia/lymphoma, respectively. T-cell growth factor (TCGF, also known as interleukin 2) is required for the growth of activated T-cells, which play an important role in immune regulation. gamma-Interferon (IFN-gamma) is also implicated in immune modulation. It was possible that T-cell depletion in acquired immune deficiency syndrome could be due to an impairment of TCGF synthesis and that adult T-cell leukemia could be due to unregulated production of TCGF. The results reported here show that the transcription of the TCGF gene was not impaired in cultured HTLV-III-infected cells. Paradoxically, the TCGF gene in HTLV-I-infected cells was transcriptionally inactive. The reverse was the case for the gamma-interferon gene--it was actively transcribed in HTLV-I-infected cells but not in the HTLV-III-infected and virus-producing H9 and H4 cell line. No evidence was obtained suggesting abnormal regulation of the TCGF or of the IFN-gamma gene consequent to HTLV-III infection. It thus appears that in both HTLV-III and HTLV-I infection, growth control and immune regulatory mechanisms may bypass a modulatory role of TCGF or of IFN-gamma.

Effects of a Novel Compound (AL 721) on HTLV-III Infectivity in Vitro

This letter reports the results of a study indicating that AL 721 a lipid compound with a demonstrated ability to extract cholesterol from cellular membranes inhibits human T-lymphotropic virus type III (HTLV-III) infection of human peripheral-blood lymphocytes or an immortalized helper T-cell line (H9). When H9 cells were incubated with HTLV-III for 4 days reductions were detected in cell numbers and there were significant levels of reverse transciptase p15 and p24. After H9 cells were infected with HTLV-III in the presence of AL 721 there was a reduction in viral infectivity. The median dose for this effect was 100 mcg/ml of AL 721. It is not clear whether the virucidal effects of AL 721 are due to its actions on the retroviral envelope or on the host cell membrane. In preliminary clinical trials with elderly human subjects daily oral doses of AL 721 over a 6-week period restored diminished lymphocyte proliferative capacity and were well tolerated. AL 721 is considered a promising new candidate for investigation in the treatment of acquired immunodeficiency syndrome (AIDS) especially since it does not produce the side effects that are associated with reverse transcriptase inhibitors.

Licensed tests for antibody to human T-lymphotropic virus type III. Sensitivity and specificity.

Before the discovery of the etiologic agent of the acquired immunodeficiency syndrome (AIDS), substantial epidemiologic evidence suggested that the responsible agent could be transmitted by blood and blood products such as factor VIII. The Public Health Service and the Food and Drug Administration therefore took general steps to increase the safety of the blood supply. With the discovery of the human T-lymphotropic virus type III (HTLV-III) it became possible to test blood for evidence of infection using an antibody detection assay. Currently licensed tests to detect antibody to HTLV-III range in sensitivity between 93% and 99%, and all are above 99% in specificity. The Public Health Service has issued provisional recommendations regarding the voluntary use of the antibody tests to screen blood and plasma donations.

3'-Azido-3'-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro.

The acquired immune deficiency syndrome (AIDS) is thought to result from infection of T cells by a pathogenic human retrovirus, human T-lymphotropic virus type III (HTLV-III) or lymphadenopathy-associated virus (LAV). In this report, we describe the antiviral effects of a thymidine analogue,3'-azido-3'-deoxythymidine (BW A509U), which, as a triphosphate, inhibits the reverse transcriptase of HTLV-III/LAV. This agent blocks the expression of the p24 gag protein of HTLV-III/LAV in H9 cells following exposure to virus. The drug also inhibits the cytopathic effect of HTLV-IIIB (a virus derived from a pool of American patients) and HTLV-III/RF-II (an isolate obtained from a Haitian patient that differs by about 20% in the amino acid sequence of the envelope gene from several isolates of HTLV-III/LAV, including HTLV-IIIB, analyzed so far). 3'-Azido-3'-deoxythymidine also completely blocks viral replication as assessed by reverse transcriptase production in normal human peripheral blood mononuclear cells exposed to HTLV-IIIB. Finally, at concentrations of 3'-azido-3'-deoxythymidine that block the in vitro infectivity and cytopathic effect of HTLV-IIIB, the in vitro immune functions of normal T cells remain basically intact.

The value of haematological screening for AIDS in an at risk population.

The haematological variables measured by automated full blood count in matched homosexual and heterosexual men attending a clinic for sexually transmitted diseases (STD) were compared with those of normal controls and patients infected with the human T lymphotropic virus type III (HTLV-III). Homosexual and heterosexual men were statistically identical for all variables, but both differed noticeably from patients with clinical diagnoses of the acquired immune deficiency syndrome (AIDS) or AIDS related disease. A full blood count as a screening test for AIDS is only interpretable in the context of clinical assessment.

Epidemiological evidence that HTLV-III is the AIDS agent.

Human T-lymphotropic virus type III (HTLV-III) is a recently discovered retrovirus with tropism and cytotoxicity for the OKT4+ lymphocytes that are depleted in the acquired immune deficiency syndrome (AIDS). In addition to the frequent detection of HTLV-III in patients with AIDS and related syndromes, seroepidemiological studies have shown that HTLV-III can be transmitted by sexual contact and blood transfusion in a manner identical to the putative AIDS agent. Analyses of stored sera have revealed that HTLV-III antibodies appeared in high-risk groups some two years before the disease outbreak, which corresponds to the apparent incubation period in patients with transfusion-associated AIDS. The risk of developing AIDS is clearly associated with HTLV-III seropositivity and may be as high as 20% within three years. Strong evidence that HTLV-III is the AIDS agent mandates aggressive efforts to minimize further sexual, maternal-fetal, and blood-borne transmission of this virus while pursuing vaccine development and antiretroviral therapies.

Antibody Seronegative Human T-Lymphotropic Virus Type III (HTLV-III)-Infected Patients With Acquired Immunodeficiency Syndrome or Related Disorders

AbstractThe human T-lymphotropic virus type III (HTLV-III) is the primary cause of the acquired immunodeficiency syndrome (AIDS) and related disorders (ARC). Prior studies have reported that nearly all symptomatic patients with AIDS or ARC manifest antibody to HTLV-III. This observation has engendered efforts to screen for HTLV-III, especially prior to blood donation, with assays for antibody to HTLV-III. We report the first two cases, one with AIDS and one with ARC, that are HTLV-III virus positive but antibody negative. Accurate diagnosis of HTLV-III infection in some cases may require direct virus culture or tests for antigen. In addition, lack of HTLV-III antibody may indicate an atypical clinical course of AIDS.

Antibody seronegative human T-lymphotropic virus type III (HTLV-III)- infected patients with acquired immunodeficiency syndrome or related disorders

The human T-lymphotropic virus type III (HTLV-III) is the primary cause of the acquired immunodeficiency syndrome (AIDS) and related disorders (ARC). Prior studies have reported that nearly all symptomatic patients with AIDS or ARC manifest antibody to HTLV-III. This observation has engendered efforts to screen for HTLV-III, especially prior to blood donation, with assays for antibody to HTLV-III. We report the first two cases, one with AIDS and one with ARC, that are HTLV-III virus positive but antibody negative. Accurate diagnosis of HTLV-III infection in some cases may require direct virus culture or tests for antigen. In addition, lack of HTLV-III antibody may indicate an atypical clinical course of AIDS.

Revision of the Case Definition of Acquired Immunodeficiency Syndrome for National Reporting—United States

The Conference of State and Territorial Epidemiologists (CSTE) approved the following definitions regarding the case definition of acquired immunodeficiency syndrome (AIDS) at its annual meeting in June 1985. 1st, the case definition of AIDS used for national reporting will continue to include only the more severe manifestations of human T-lymphotropic virus type III (HTLV-III) infection. 2nd, Centers for Disease Control (CDC) will develop more inclusive definitions and classifications of HTLV-III infection for diagnosis, treatment, and prevention, as well as for epidemiologic studies and special surveys. 3rd, a number of refinements will be adopted in the case definition of AIDS used for national reporting. In the absense of the opportunistic diseases required by the current case definition, disseminated histoplasmosis, isosporiasis, bronchial or pulmonary candidiasis, non-Hodgkin's lymphoma of high-grade pathologic type, and histologically confirmed Kaposi's sarcoma in patients 60 years or over will be considered indicative of AIDS if the patient has a positive serologic or virologic test for HTLV-III. Also, in the absence of the required opportunistic diseases, a histologically confirmed diagnosis of chronic lymphoid insterstitial pneumonitis in a child under 3 years of age will be considered indicative of AIDS unless HTLV-III antibody tests are negative. Patients who have a lymphoreticular malignancy diagnosed more than 3 months after the diagnosis of an opportunistic disease used as a marker for AIDS will no longer be excluded as AIDS cases. Finally, to increase the specificity of the case definition, patients will be excluded as AIDS cases if they have a negative result on testing for serum antibody to HTLV-III, have no other test for HTLV-III with a positive result, and do not have a low number of T-helper lymphocytes or a low T4:T8 ratio.

ISOLATION OF HUMAN T-LYMPHOTROPIC VIRUS TYPE III FROM THE TEARS OF A PATIENT WITH THE ACQUIRED IMMUNODEFICIENCY SYNDROME

Human T-lymphotropic virus type III (HTLV-III) was isolated from the tears of 1 out of 7 patients with the acquired immunodeficiency syndrome (AIDS) or the AIDS-related complex. The tears from 5 healthy individuals did not show HTLV-III. The recovery of HTLV-III from tears suggests that they may harbour free virus or contain virus-positive cells and is consistent with the recovery of HTLV-III from other body fluids. Although casual contact with such fluids has not been shown to cause AIDS, direct contact with the tears of AIDS patients, including contact during routine ophthalmologic procedures, should be minimised.

Genomic diversity of human T-lymphotropic virus type III (HTLV-III).

The DNA genomes of human T-lymphotropic virus type III (HTLV-III) isolated from 18 individuals with AIDS or who were at risk for AIDS were evaluated for evidence of variation. Although all of the 18 viral DNA's hybridized throughout their entire genomes to a full-length cloned probe of the original HTLV-III isolate, each of the 18 isolates showed a different restriction enzyme pattern. The number of restriction site differences between isolates ranged from only 1 site in 23 to at least 16 sites in 31. No particular viral genotype was associated with a particular disease state and 2 of the 18 patients had evidence of concurrent infection by more than one viral genotype. Propagation of three different viral isolates in vitro for up to 9 months did not lead to detectable changes in their restriction patterns. These findings indicate that different isolates of HTLV-III comprise a spectrum of highly related but distinguishable viruses and have important implications regarding the pathogenicity of HTLV-III and attempts to develop effective diagnostic, therapeutic, and preventive measures for this virus.

Screening Blood: Public Health and Medical Uncertainty

Use of the human T-lymphotropic virus type III (HTLV-III) antibody screening test for reducing the risk of contracting acquired immunodeficiency syndrome (AIDS) through blood transfusion has raised ethical issues regarding notification and confidentiality. It has also raised longterm questions about mass screening mandatory reporting of positive results to public health officials behavioral change and public health interventions under conditions of medical uncertainty. Initially blood banks resisted mandatory notification of antibody-positive donors on the grounds that it established a clinical relationship between donor and blood bank and also might encourage people to come to blood centers solely to get their tests results. Now that other agencies have had time to set up alternative sites for HTLV-III antibody testing blood banks will begin to inform people about their positive antibody status. Names of seropositive individuals will be kept in the American Red Cross confidential national deferral registry. Those who test positive on a single test only will not be notified and their names will not be entered in the national registry but their names will be kept in a local registry and subsequent donations will be discarded. A troubling question concerns whether to notify past recipients of blood from donors who are now seropositive. Most blood banks have adopted a policy of not notifying such recipients since it is not known whether the donor had antibodies at the time of the index donation. Because of the psychological trauma associated with notification blood centers and alternative test sites plan to offer counseling to seropositive persons. More compelling evidence of a public health threat than presently exists will be required to justify mass screening of all those at risk of contracting or spreading AIDS. Such testing would threaten the civil liberties of the persons tested.

Trans -Activator Gene of Human T-Lymphotropic Virus Type III (HTLV-III)

Human T-lymphotropic virus type III (HTLV-III) encodes a trans-acting factor that activates the expression of genes linked to the HTLV-III long terminal repeat. By functional mapping of complementary DNA transcripts of viral messenger RNA's the major functional domain of the gene encoding this factor was localized to a region immediately before the env gene of the virus, a region previously thought to be noncoding. This newly identified gene consists of three exons, and its transcription into messenger RNA involves two splicing events bringing together sequences from the 5' part (287 base pairs), middle (268 base pairs), and 3'part (1258 base pairs) of the HTLV-III genome. A similar messenger RNA with a truncated second exon (70 base pairs) does not encode a trans-acting function. It is proposed that this second messenger RNA is the transcript of a gene (3'-orf) located after the env gene. Messenger RNA's were also identified for the env and gag-pol genes of HTLV-III.

Serologic identification and characterization of a macaque T-lymphotropic retrovirus closely related to HTLV-III.

Human T-lymphotropic virus type III (HTLV-III) is thought to play an etiologic role in the development of the acquired immune deficiency syndrome (AIDS). In this study the serologic characterization of a new simian retrovirus that is related to HTLV-III is described. This new virus, here referred to as STLV-III, was isolated from sick macaques at the New England Regional Primate Research Center. Radioimmunoprecipitation analysis revealed STLV-III-specific proteins of 160, 120, 55, and 24 kilodaltons, all similar in size to the major gag and env proteins of HTLV-III. These antigens were recognized by representative macaque serum samples and human reference serum samples positive for HTLV-III antibodies. Monoclonal antibodies directed to p24, the major core protein of HTLV-III, also immunoprecipitated a 24-kilodalton species in lysates of cells infected with the macaque virus. This HTLV-III-related virus, which naturally infects a nonhuman primate species, may provide a useful model for the study of HTLV-III and the pathogenesis of AIDS.