The human T-cell lines MT-2 and MT-4 carry the human T-cell leukemia virus type I (HTLV-I). When MT-2 and MT-4 were infected with HTLV-III, the probable etiologic agent of the acquired immune deficiency syndrome (AIDS), rapid cytopathogenic effects and cytotoxicity were observed that made it possible to titrate the biologically active virus in a plaque-forming assay. The cytopathogenic effects were preceded by the rapid induction and increase of HTLV-III antigens as revealed by immunofluorescence and immunoprecipitation. Activities of HTLV-III were neutralized by the human antibodies against the virus when immunofluorescence and plaque assays were used. Essentially the same results were obtained with the lymphadenopathy-associated virus (LAV1).

http://science.sciencemag.org/content/sci/229/4713/563.full.pdf

Infection of HTLV-III/LAV in HTLV-I-carrying cells MT-2 and MT-4 and application in a plaque assay

The human T-cell leukemia (lymphotropic) virus type III (HTLV-III) appears to be central to the causation of the acquired immune deficiency syndrome (AIDS). Two full-length integrated proviral DNA forms of HTLV-III have now been cloned and analyzed, and DNA sequences of the virus in cell lines and fresh tissues from patients with AIDS or AIDS-related complex (ARC) have been characterized. The results revealed that (i) HTLV-III is an exogenous human retrovirus, approximately 10 kilobases in length, that lacks nucleic acid sequences derived from normal human DNA; (ii) HTLV-III, unlike HTLV types I and II, shows substantial diversity in its genomic restriction enzyme cleavage pattern; (iii) HTLV-III persists in substantial amounts in cells as unintegrated linear DNA, an uncommon property that has been linked to the cytopathic effects of certain animal retroviruses; and (iv) HTLV-III viral DNA can be detected in low levels in fresh (primary) lymphoid tissue of a minority of patients with AIDS or ARC but appears not to be present in Kaposi's sarcoma tissue. These findings have important implications concerning the biological properties of HTLV-III and the pathophysiology of AIDS and Kaposi's sarcoma.

Molecular characterization of human T-cell leukemia (lymphotropic) virus type III in the acquired immune deficiency syndrome

Human T-cell leukemia virus type III (HTLV-III) was recently identified as the probable etiologic agent of the acquired immune deficiency syndrome (AIDS). Here it is shown that, in human T-cell lines infected with HTLV-III, gene expression directed by the long terminal repeat sequence of this virus is stimulated by more than two orders of magnitude compared to matched uninfected cells. The rate of transcription of the HTLV-III long terminal repeat is more than 1000 times that of the SV40 early promoter in one infected cell line. Thus, HTLV-III, like HTLV-I, HTLV-II, and the bovine leukemia virus, is characterized by trans-activation of transcription in infected cells. The efficiency of trans-activation in the case of HTLV-III may account, at least in part, for the virulent nature of HTLV-III infection.

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Trans-acting transcriptional regulation of human T-cell leukemia virus type III long terminal repeat.

Publisher Summary This chapter reviews the state of knowledge concerning the structure and function of the HIV genome, virus cell tropism, cytotoxic and noncytotoxic effects of HIV on both the immune system and the central nervous system (CNS), latent HIV infection and virus activation, and the immune response to HIV. HIV induced immunosuppression results in the emergence of opportunistic infections and neoplasms that are pathognomonic for the acquired immunodeficiency syndrome (AIDS). Infection with HIV also results in a syndrome of neurological abnormalities, which has been termed the AIDS-dementia complex. Efforts to control AIDS require a fundamental knowledge of the etiological agent itself, the mechanisms by which HIV destroys the immune systems, and the nature of the immune response against HIV. Fortunately, long-standing basic research both on retroviruses and on the immune system laid the groundwork for rapid advances in the accrual of knowledge of HIV and the immunopathogenic mechanisms of HIV infection. In other retroviral systems persistence of unintegrated retroviral DNA has been associated with a cytopathic effect. In HIV infection, a substantial amount of HIV DNA exists in an unintegrated form, potentially contributing to the cytopathicity observed in HIV infection. The interaction of HIV with the CD4 molecule that is present on the surface of the helped inducer subset of T lymphocytes is the critical event in the pathogenesis of HIV infection. The successful control of HIV infection through either therapeutic agents or vaccines requires an extensive understanding of the agent itself and its pathogenesis. The fact that HIV is a member of the lentivirus subfamily of viruses was an immediate clue that the natural history of HIV infection would entail a lengthy latent period and disease progression, despite the generation of an immune response.

The immunopathogenesis of HIV infection.

Peripheral blood leukocytes and saliva from 20 individuals, including four with the acquired immune deficiency syndrome (AIDS), ten with AIDS-related complex (ARC), and six healthy homosexual males at risk for AIDS, were compared as sources of transmissible human T-cell leukemia (lymphotropic) virus type III (HTLV-III), the virus found to be the etiologic agent of AIDS. All of the AIDS and ARC patients and four of the six healthy homosexuals had evidence of prior exposure to HTLV-III as indicated by seropositivity for antibody to HTLV-III structural proteins. Infectious virus was isolated from the peripheral blood of one of the AIDS patients, four of the ARC patients, and two of the healthy homosexual males, consistent with previous reports. HTLV-III was also isolated from the saliva of four of the ARC patients and four of the healthy homosexuals. Virus was also observed by electron microscopy in material prepared by centrifugation of the saliva of one AIDS patient. Although AIDS does not appear to be transmitted by casual contact, the possibility that HTLV-III can be transmitted by saliva should be considered.

https://science.sciencemag.org/content/sci/226/4673/447.full.pdf

HTLV-III in saliva of people with AIDS-related complex and healthy homosexual men at risk for 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.

E H Braff

Papers

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