ADMINISTRATION OF 3'-AZIDO-3'-DEOXYTHYMIDINE, AN INHIBITOR OF HTLV-III/LAV REPLICATION, TO PATIENTS WITH AIDS OR AIDS-RELATED COMPLEX

Peripheral blood lymphocytes from patients with the acquired immunodeficiency syndrome (AIDS) or with signs or symptoms that frequently precede AIDS (pre-AIDS) were grown in vitro with added T-cell growth factor and assayed for the expression and release of human T-lymphotropic retroviruses (HTLV). Retroviruses belonging to the HTLV family and collectively designated HTLV-III were isolated from a total of 48 subjects including 18 of 21 patients wih pre-AIDS, three of four clinically normal mothers of juveniles with AIDS, 26 of 72 adult and juvenile patients with AIDS, and from one of 22 normal male homosexual subjects. No HTLV-III was detected in or isolated from 115 normal heterosexual subjects. The number of HTLV-III isolates reported here underestimates the true prevalence of the virus since many specimens were received in unsatisfactory condition. Other data show that serum samples from a high proportion of AIDS patients contain antibodies to HTLV-III. That these new isolates are members of the HTLV family but differ from the previous isolates known as HTLV-I and HTLV-II is indicated by their morphological, biological, and immunological characteristics. These results and those reported elsewhere in this issue suggest that HTLV-III may be the primary cause of AIDS.

A cell system was developed for the reproducible detection of human T-lymphotropic retroviruses (HTLV family) from patients with the acquired immunodeficiency syndrome (AIDS) or with signs or symptoms that frequently precede AIDS (pre-AIDS). The cells are specific clones from a permissive human neoplastic T-cell line. Some of the clones permanently grow and continuously produce large amounts of virus after infection with cytopathic (HTLV-III) variants of these viruses. One cytopathic effect of HTLV-III in this system is the arrangement of multiple nuclei in a characteristic ring formation in giant cells of the infected T-cell population. These structures can be used as an indicator to detect HTLV-III in clinical specimens. This system opens the way to the routine detection of HTLV-III and related cytopathic variants of HTLV in patients with AIDS or pre-AIDS and in healthy carriers, and it provides large amounts of virus for detailed molecular and immunological analyses.

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.