Tenofovir treatment augments anti-viral immunity against drug-resistant SIV challenge in chronically infected rhesus macaques.
BACKGROUND
Emergence of drug-resistant strains of human immunodeficiency virus type 1 (HIV-1) is a major obstacle to successful antiretroviral therapy (ART) in HIV-infected patients. Whether antiviral immunity can augment ART by suppressing replication of drug-resistant HIV-1 in humans is not well understood, but can be explored in non-human primates infected with simian immunodeficiency virus (SIV). Rhesus macaques infected with live, attenuated SIV develop robust SIV-specific immune responses but remain viremic, often at low levels, for periods of months to years, thus providing a model in which to evaluate the contribution of antiviral immunity to drug efficacy. To investigate the extent to which SIV-specific immune responses augment suppression of drug-resistant SIV, rhesus macaques infected with live, attenuated SIVmac239Deltanef were treated with the reverse transcriptase (RT) inhibitor tenofovir, and then challenged with pathogenic SIVmac055, which has a five-fold reduced sensitivity to tenofovir.


RESULTS
Replication of SIVmac055 was detected in untreated macaques infected with SIVmac239Deltanef, and in tenofovir-treated, naïve control macaques. The majority of macaques infected with SIVmac055 experienced high levels of plasma viremia, rapid CD4+ T cell loss and clinical disease progression. By comparison, macaques infected with SIVmac239Deltanef and treated with tenofovir showed no evidence of replicating SIVmac055 in plasma using allele-specific real-time PCR assays with a limit of sensitivity of 50 SIV RNA copies/ml plasma. These animals remained clinically healthy with stable CD4+ T cell counts during three years of follow-up. Both the tenofovir-treated and untreated macaques infected with SIVmac239Deltanef had antibody responses to SIV gp130 and p27 antigens and SIV-specific CD8+ T cell responses prior to SIVmac055 challenge, but only those animals receiving concurrent treatment with tenofovir resisted infection with SIVmac055.


CONCLUSIONS
These results support the concept that anti-viral immunity acts synergistically with ART to augment drug efficacy by suppressing replication of viral variants with reduced drug sensitivity. Treatment strategies that seek to combine immunotherapeutic intervention as an adjunct to antiretroviral drugs may therefore confer added benefit by controlling replication of HIV-1, and reducing the likelihood of treatment failure due to the emergence of drug-resistant virus, thereby preserving treatment options.
Metzner
Karin J
KJ
Aaron Diamond AIDS Research Center and The Rockefeller University, New York, NY 10016, USA. Karin.Metzner@viro.med.uni-erlangen.de
Binley
James M
JM
Gettie
Agegnehu
A
Marx
Preston
P
Nixon
Douglas F
DF
Connor
Ruth I
RI
D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000914:Antibodies, Viral / Q000097:blood; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002908:Chronic Disease; D024882:Drug Resistance, Viral; D008253:Macaca mulatta; D063065:Organophosphonates / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000187:drug effects* / Q000472:pathogenicity*; D000068698:Tenofovir; D016896:Treatment Outcome; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D000914:Antibodies, Viral; D063065:Organophosphonates; D018894:Reverse Transcriptase Inhibitors; D000068698:Tenofovir; D000225:Adenine