Inhibition of the in vitro infectivity and cytopathic effect of human T-lymphotrophic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV) by 2',3'-dideoxynucleosides.

Abstract

Human T-lymphotropic virus type III (HTLV-I)/lymphadenopathy-associated virus (LAV) is a newly discovered lymphotropic retrovirus that is cytopathic for helper/inducer T cells in vitro. This virus is the etiologic agent of the acquired immunodeficiency syndrome and related diseases. In the current study, we tested the capacity of purine and pyrimidine nucleoside derivatives to inhibit the infectivity and cytopathic effect of human T-lymphotropic virus type Ill in vitro. With the ribose moiety of the molecule in a 2',3'-dideoxy configuration, every purine (adenosine, guanosine, and inosine) and pyrimidine (cytidine and thymidine) nucleoside tested suppressed the virus, although the thymidine derivative seemed to have substantially less activity in our system than the others. In general, we observed essentially complete suppression of the virus at doses that were lower by a factor of 10 to 20 than those needed to inhibit the proliferation of the target T cells and the immune reactivity of normal T cells in vitro. An analysis of five adenosine congeners, which differed only in the sugar moiety, revealed that reduction (an absence of hydroxyl determinants) at both the 2' and 3' carbons of the ribose was necessary for an anti-viral effect, and an additional reduction at the 5' carbon nullified the anti-viral activity. These observations may be of value in developing a new class of experimental drugs for the therapy of human T-lymphotropic virus type III infections.

Structure-activity relationships of fluorinated nucleoside analogs and their synergistic effect in combination with phosphonoformate against human immunodeficiency virus type 1

“…However, the selectivities of these compounds are all lower than that of the nonfluorinated parent compound, 2',3'-dideoxycytidine, as shown by Kim et al (14). Similarly, our fluorinated adenosine analogs were also less selective than the parent compound 2',3'-dideoxyadenosine (20). The most potent adenosine analog was 5'-amino-3'-fluoro-3'-deoxyadenosine, with a selectivity index of 100.…”

“…The 5'-triphosphates of these compounds act as chain terminators of DNA synthesis since they lack the 3'-hydroxyl group required for further chain polymerization (8,22). The most active of these are 3'-azido-3'-deoxythymidine (AZT) and 2'-3'-dideoxycytidine (20,23). AZT is the only compound licensed for treatment of patients with acquired immunodeficiency syndrome.…”

Phenotypic variation in the response to the human immunodeficiency virus among derivatives of the CEM T and WIL-2 B cell lines.

“…A3 .01, a HAT sensitive derivative of CEM, showed maximal RT activity at 10 d after infection, coincident with cell death (47), which is similar to the time course we observe with our CEM4 clone. The ATH8 T cell line exhibits a cytopathic effect within 4 d of infection by HTLVIIB, but it requires IL-2 for growth and is HTLVI transformed (48). The ease of culturing AA2 cells and its sensitivity to HIV infection make AA2 potentially useful for producing high titer stocks of HIV and for isolation of HIV from clinical samples.…”

Inhibition of Human Immunodeficiency Virus Type 1 Replication by Guanosine Analogues and Lack of Synergistic Antiviral Effect of Acyclovir with 3′-azido-3′-deoxythymidine

“…(919) 966-6781;Fax (919) 966-3015. analogues comprise one class of compounds with activity in vitro against HIV. Included in this group are 3' -azido-3'-deoxythymidine (AZl), the only approved drug for treatment of AIDS, and several others, including 2',3'-dideoxycytidine, 2',3' -dideoxyinosine, 2',3' -dideoxycytidine, and 2' ,3' -didehydro-2' ,3' -dideoxythymidine (Mitsuya and Broder, 1986;Hamamoto et al, 1987;Hartmann et al, 1987;Balzarini et al, 1987).…”