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Suppression of mouse viraemia and retroviral disease by 3'-azido-3'-deoxythymidine
Abstract:
The retroviruses human T-cell lymphotrophic virus-I (HTLV-I) and HTLV-III/LAV (lymphadenopathy-associated virus) are clearly linked to human diseases. Patients with HTLV-I-positive neoplasms may respond transiently to traditional chemotherapy, but are not cured. For patients with acquired immune deficiency syndrome (AIDS) there is no curative therapy. In retroviruses of different species, viral propagation crucially depends on reverse transcriptase, an enzyme not present in normal mammalian cells and different from mammalian DNA polymerases, making it a target for specific inhibition. Reverse transcriptase has been well conserved through evolution: an LAV isolate contained a 250-amino-acid-long domain, presumably the reverse transcriptase core sequence, which has 21% homology to Moloney murine leukaemia virus (MoMLV). Because HTLV-III infects only humans and chimpanzees, we substituted murine retroviruses for in vivo evaluation of candidate anti-AIDS drugs after ascertaining similar inhibition in vitro of HTLV-III and MLVs, which were chosen for their short incubation time. The triphosphate of 3'-azido-3'-deoxythymidine (AZT) is incorporated into complementary DNA by retroviral reverse transcriptase, causing premature chain termination. Here we show that chronic AZT treatment of mice infected with Rauscher murine leukaemia virus complex (RLV) prevents infection of splenocytes and development of splenomegaly, and suppresses viraemia if started soon after inoculation. Starting AZT late in the course of disease still leads to significant prolongation of life; anaemia, however is a significant side-effect. By analogy, AZT may have a role in preventing retroviral disease in humans if started early after infection, and it may lead to significant survival gains even if started later in the course of disease.
Insights
3'-azido-3'-deoxythymidine (AZT) effectively treats retroviral infections in mice by inhibiting reverse transcriptase. Early AZT treatment prevents disease and splenomegaly, while later treatment prolongs life despite side effects.
Area of Science:
- Virology
- Immunology
- Pharmacology
Background:
- Retroviruses like HTLV-I and HTLV-III/LAV cause human diseases, including neoplasms and acquired immune deficiency syndrome (AIDS).
- Current therapies for HTLV-I neoplasms are not curative, and no curative therapy exists for AIDS.
- Retroviral reverse transcriptase, essential for viral propagation and absent in mammalian cells, is a viable target for antiviral drug development.
Purpose of the Study:
- To evaluate 3 -azido-3 -deoxythymidine (AZT) as a potential anti-AIDS drug by testing its efficacy in murine retrovirus models.
- To determine the impact of early versus late administration of AZT on disease progression and survival in infected mice.
Main Methods:
- In vitro inhibition of HTLV-III and Moloney murine leukemia virus (MLV) reverse transcriptases by AZT was assessed.
- Mice infected with Rauscher murine leukemia virus complex (RLV) were treated with AZT either soon after inoculation or later in the disease course.
- Viral propagation, splenocyte infection, splenomegaly, viremia, and survival rates were monitored in treated and control mice.
Main Results:
- AZT triphosphate acts as a chain terminator by incorporating into complementary DNA synthesized by reverse transcriptase.
- Chronic AZT treatment of RLV-infected mice prevented splenocyte infection and splenomegaly, and suppressed viremia when initiated early.
- Late-stage AZT treatment significantly prolonged survival but was associated with anemia as a notable side effect.
Conclusions:
- AZT demonstrates significant potential for preventing and treating retroviral infections, analogous to its potential role in human diseases like AIDS.
- Early intervention with AZT may be crucial for preventing retroviral disease progression.
- AZT can offer survival benefits even when administered later in the course of infection, though potential side effects require consideration.