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.
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 When tenofovir was withdrawn after 8 to 10 years from three animals with undetectable viremia, the pattern of occasional episodes of low viremia (≤ 3600 RNA/ml plasma) continued throughout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.


CONCLUSIONS
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.
California National Primate Research Center, University of California, Davis, CA 95616, USA. kkvanrompay@ucdavis.edu
Koen K A
KK
Van Rompay
Kristin A
KA
Trott
Kartika
K
Jayashankar
Yongzhi
Y
Geng
Celia C
CC
LaBranche
Jeffrey A
JA
Johnson
Gary
G
Landucci
Jonathan
J
Lipscomb
Ross P
RP
Tarara
Don R
DR
Canfield
Walid
W
Heneine
Donald N
DN
Forthal
David
D
Montefiori
Kristina
K
Abel
D000225:Adenine / Q000031:analogs & derivatives* / Q000276:immunology / Q000494:pharmacology; D000483:Alleles; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood / Q000276:immunology; D000917:Antibody Formation; D000998:Antiviral Agents / Q000276:immunology / Q000494:pharmacology; D018791:CD4 Lymphocyte Count; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D004195:Disease Models, Animal; D005805:Genes, MHC Class I; D060005:Genotyping Techniques; D007111:Immunity, Cellular; D008213:Lymphocyte Activation; D008253:Macaca mulatta; D009500:Neutralization Tests; D063065:Organophosphonates / Q000276:immunology / Q000494:pharmacology*; D012367:RNA, Viral / Q000097:blood; D012194:RNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000276:immunology / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000201:enzymology / Q000276:immunology / Q000472:pathogenicity* / Q000502:physiology; D000068698:Tenofovir; D013997:Time Factors; D016896:Treatment Outcome; D014766:Viremia / Q000473:pathology / Q000821:virology; D014779:Virus Replication
D000914:Antibodies, Viral; D000998:Antiviral Agents; D063065:Organophosphonates; D012367:RNA, Viral; D000068698:Tenofovir; D012194:RNA-Directed DNA Polymerase; D000225:Adenine