Back to Search
Start Over
Response of simian immunodeficiency virus to the novel nucleoside reverse transcriptase inhibitor 4'-ethynyl-2-fluoro-2'-deoxyadenosine in vitro and in vivo.
- Source :
-
Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2012 Sep; Vol. 56 (9), pp. 4707-12. Date of Electronic Publication: 2012 Jun 19. - Publication Year :
- 2012
-
Abstract
- Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) are essential components in first-line therapy for human immunodeficiency virus (HIV) infection. However, long-term treatment with existing NRTIs can be associated with significant toxic side effects and the emergence of drug-resistant strains. The identification of new NRTIs for the continued management of HIV-infected people therefore is paramount. In this report, we describe the response of a primary isolate of simian immunodeficiency virus (SIV) to 4'-ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) both in vitro and in vivo. EFdA was 3 orders of magnitude better than tenofovir (TFV), zidovudine (AZT), and emtricitabine (FTC) in blocking replication of SIV in monkey peripheral blood mononuclear cells (PBMCs) in vitro, and in a preliminary study using two SIV-infected macaques with advanced AIDS, it was highly effective at treating SIV infection and AIDS symptoms in vivo. Both animals had 3- to 4-log decreases in plasma virus burden within 1 week of EFdA therapy (0.4 mg/kg of body weight, delivered subcutaneously twice a day) that eventually became undetectable. Clinical signs of disease (diarrhea, weight loss, and poor activity) also resolved within the first month of treatment. No detectable clinical or pathological signs of drug toxicity were observed within 6 months of continuous therapy. Virus suppression was sustained until drug treatment was discontinued, at which time virus levels rebounded. Although the rebound virus contained the M184V/I mutation in the viral reverse transcriptase, EFdA was fully effective in maintaining suppression of mutant virus throughout the drug treatment period. These results suggest that expanded studies with EFdA are warranted.
- Subjects :
- Adenine analogs & derivatives
Adenine pharmacology
Animals
Antiviral Agents therapeutic use
Cells, Cultured
Deoxyadenosines therapeutic use
Deoxycytidine analogs & derivatives
Deoxycytidine pharmacology
Emtricitabine
Leukocytes, Mononuclear drug effects
Leukocytes, Mononuclear virology
Macaca mulatta
Male
Mutation
Organophosphonates pharmacology
RNA-Directed DNA Polymerase metabolism
Recurrence
Reverse Transcriptase Inhibitors therapeutic use
Simian Acquired Immunodeficiency Syndrome virology
Simian Immunodeficiency Virus genetics
Simian Immunodeficiency Virus growth & development
Tenofovir
Viral Load drug effects
Zidovudine pharmacology
Antiviral Agents pharmacology
Deoxyadenosines pharmacology
Reverse Transcriptase Inhibitors pharmacology
Simian Acquired Immunodeficiency Syndrome drug therapy
Simian Immunodeficiency Virus drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1098-6596
- Volume :
- 56
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- Antimicrobial agents and chemotherapy
- Publication Type :
- Academic Journal
- Accession number :
- 22713337
- Full Text :
- https://doi.org/10.1128/AAC.00723-12