Editorial expression of concern

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Science  06 Sep 2019:
Vol. 365, Issue 6457, pp. 991
DOI: 10.1126/science.aaz2722

On 14 October 2016, Science published the Research Article “Sustained virologic control in SIV+ macaques after antiretroviral and α4β7 antibody therapy” by S. N. Byrareddy et al. (1). The virus used in this study had a stop codon in the SIV nef gene. The presence of the stop codon was known by Dr. Villinger, who provided the virus, and he selected this strain intentionally as he believes it provides a better model for chronic HIV infection. However, this information was not communicated to other authors of the Byrareddy paper nor explicitly stated in the manuscript. In macaques, viral variants that can replicate more effectively because they have this stop codon corrected are selected over a period of weeks. Variability in correcting the stop codon introduces variation in the level of viral pathogenicity between different animal subjects, which may have affected the conclusions and should have been discussed in the Research Article. Byrareddy et al. (1) has been corrected to indicate that the virus used was not wild-type SIVmac239, but SIVmac239-nef-stop.

On 21 March 2019, Science published an Editorial Expression of Concern alerting readers to this error. Three studies published in this issue of Science have attempted to replicate this work, two using the same SIVmac239-nef-stop virus used in Byrareddy and one using a different SIV strain (24). In no case did treating with antibody against integrin α4β7 result in robust, long-term decreases in SIV load after stopping antiretroviral therapy. In addition, a phase-1 clinical trial in humans published in Science Translational Medicine failed to show any significant benefit of including a similar FDA-approved antibody in an HIV treatment protocol (5).

We are maintaining an Editorial Expression of Concern on Byrareddy et al. (1) to alert readers that current evidence suggests that the reported result is not robust and therefore does not provide a good basis for guiding work on therapies for HIV. Science is not moving beyond an Editorial Expression of Concern because neither the Byrareddy authors, the authors of the attempted replication studies, nor the editors can account for the differences in results. Moreover, there is a substantial scientific basis supporting the idea that targeting the integrin α4β7 may have a positive impact on the course of infection.

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