Publications

Bovine leukaemia virus (BLV) and the human T-cell leukaemia/lymphoma viruses I and II represent a specific group of type-C RNA tumour viruses characterized by the presence between the err gene and the 3'LTR of an "x" region or LOR frame, which codes for a protein that trans-activates the transcription of the viral genome. As BLV can also infect sheep and induces pre B-cell specific tumours in these animals, we were interested in investigating whether suramin, a potent inhibitor of retrovirus-associated reverse transcriptase, may inhibit the in vivo multiplication of BLV in sheep. The sheep were infected with 4 X 10(7) leukocytes from a BLV-infected cow. The animals were maedi-visna virus-negative. Viral p24 antigen and reverse transcriptase appeared at 2 weeks and seroconversion occurred at 4 weeks after infection. Suramin was administered at 20 mg/kg/week from the 10th till the 16th week after infection. During the treatment period the expression of p24 antigen as well as the titre of anti-p24 and anti-gp51 antibodies were followed. Suramin treatment led to a significant, but transient, disappearance of p24 antigen and did not affect the titre of anti-p24 and anti-gp51 antibodies. The BLV-infected sheep may serve as a useful animal model for the investigation of retrovirus inhibitors and the evaluation of different therapeutic regimens.

Abstract Die Verbindung (II) besitzt keine antivirale und antibakterielle Aktivität sowie keine Antitumor‐Wirkung.

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Many HIV-1 isolates at the late stage of disease are capable of using both CXCR4 and CCR5 in transfected cell lines, and are thus termed dual-tropic. Here we asked whether these dual-tropic variants also use both coreceptors for productive infection in a natural human lymphoid tissue microenvironment, and whether use of a particular coreceptor is associated with viral cytopathicity. We used 3 cloned dual-tropic HIV-1 variants, 89.6 and its chimeras 89-v345.SF and 89-v345.FL, which use both CCR5 and CXCR4 in transfected cell lines. In human lymphoid tissue ex vivo, one variant preferentially used CCR5, another preferentially used CXCR4, and a third appeared to be a true dual-tropic variant. The 2 latter variants severely depleted CD4(+) T cells, whereas cytopathicity of the virus that used CCR5 only in lymphoid tissue was mild and confined to CCR5(+)/CD4(+) T cells. Thus, (a) HIV-1 coreceptor usage in vitro cannot be unconditionally extrapolated to natural microenvironment of human lymphoid tissue; (b) dual-tropic viruses are not homogeneous in their coreceptor usage in lymphoid tissue, but probably comprise a continuum between the 2 polar variants that use CXCR4 or CCR5 exclusively; and (c) cytopathicity toward the general CD4(+) T cell population in lymphoid tissue is associated with the use of CXCR4.

The first acyclonucleosides based on the benzothiadiazine dioxide system were synthesized following the silylation procedure. Several acyclic moieties, including acetoxyethoxymethyl, benzyloxymethyl, and propargyloxymethyl groups, were introduced. Two synthetic strategies were designed to selectively obtain the N-1 or N-3 derivatives. Lipase-mediated deacylation was used for the deprotection of the acyclonucleosides. Some of the benzothiadiazine dioxide acyclonucleosides, in particular 16, proved active against human cytomegalovirus (CMV) at concentrations slightly higher than that found for ganciclovir [50% inhibitory concentration (IC50) = 3. 5-3.7 micrograms/mL, cytotoxicity (CC50) >/= 40 micrograms/mL, MCC = 20 micrograms/mL]. Additionally, compound 16 inhibited the replication of human immunodeficiency virus type 1 (HIV-1) and HIV-2 in CEM cells at concentrations that were 5-fold lower than its cytotoxic concentration.

Abstract Several 2′,3′-dideoxynucleosides have proven to be effective against HIV-1 in cell culture. The 2′,3-unsaturated analogues dideoxycytidinene (D4C) and dideoxythymidinene (D4T) are among the most potent and selective inhibitors of HIV-1 replication in vitro. However, 2′,3′-didehydro-2′,3′-dideoxynucleosides are relatively unstable. A chlorine substituent at the 2′-position increases the stability, and, therefore, some 2′-chloro-2′,3′-didehydro-2′,3′-dideoxynucleosides were synthesized and evaluated for anti-HIV-1 activity.