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Prolonged tenofovir treatment of macaques infected with K65R reverse transcriptase mutants of SIV results in the development of antiviral immune responses that control virus replication after drug withdrawal

Koen K A Van Rompay1*, Kristin A Trott1, Kartika Jayashankar1, Yongzhi Geng1, Celia C LaBranche2, Jeffrey A Johnson3, Gary Landucci4, Jonathan Lipscomb3, Ross P Tarara1, Don R Canfield1, Walid Heneine3, Donald N Forthal4, David Montefiori2 and Kristina Abel5

Author Affiliations

1 California National Primate Research Center, University of California, Davis, CA, 95616, USA

2 Department of Surgery, Duke University, Durham, NC, 27710, USA

3 Division of HIV/AIDS Prevention, National Center for HIV, STD and Tuberculosis Prevention, Centers for Disease control and Prevention, Atlanta, GE, 30333, USA

4 Division of Infectious Diseases, Department of Medicine, University of California, Irvine School of Medicine, Irvine, CA, 92697, USA

5 Department of Microbiology and Immunology, School of Medicine, University of North Carolina, Chapel Hill, NC, 27599, USA

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Retrovirology 2012, 9:57  doi:10.1186/1742-4690-9-57

Published: 17 July 2012

Abstract

Background

We reported previously that while prolonged tenofovir monotherapy of macaques infected with virulent simian immunodeficiency virus (SIV) resulted invariably in the emergence of viral mutants with reduced in vitro drug susceptibility and a K65R mutation in reverse transcriptase, some animals controlled virus replication for years. Transient CD8+ cell depletion or short-term tenofovir interruption within 1 to 5 years of treatment demonstrated that a combination of CD8+ cell-mediated immune responses and continued tenofovir therapy was required for sustained suppression of viremia. We report here follow-up data on 5 such animals that received tenofovir for 8 to 14 years.

Results

Although one animal had a gradual increase in viremia from 3 years onwards, the other 4 tenofovir-treated animals maintained undetectable viremia with occasional viral blips (≤ 300 RNA copies/ml plasma). When tenofovir was withdrawn after 8 to 10 years from three animals with undetectable viremia, the pattern of occasional episodes of low viremia (≤ 3600 RNA/ml plasma) continued throughout the 10-month follow-up period. These animals had low virus levels in lymphoid tissues, and evidence of multiple SIV-specific immune responses.

Conclusion

Under certain conditions (i.e., prolonged antiviral therapy initiated early after infection; viral mutants with reduced drug susceptibility) a virus-host balance characterized by strong immunologic control of virus replication can be achieved. Although further research is needed to translate these findings into clinical applications, these observations provide hope for a functional cure of HIV infection via immunotherapeutic strategies that boost antiviral immunity and reduce the need for continuous antiretroviral therapy.

Keywords:
Tenofovir; PMPA; SIV; Functional cure; Antiretroviral; HIV