Following three failed replications of 2016 study, Science maintains ‘EEoC’

After having issued an Editorial Expression of Concern on a 2016

Science

study by Siddappa N. Byrareddy

et al.

in March of this year, to flag that the journal had learned the study had used a virus variant that could have affected results,

Science

is now issuing an official Correction to this study – to denote the virus used was not the wild-type. The study by Byrareddy and colleagues had reported that coupling an antibody targeting the integrin protein α4β7 with standard-of-care antiretroviral treatment (ART) kept SIV virus levels very low in nonhuman primates–including for more than nine months after all anti-viral agents were stopped. This result, significant for public health, motivated a clinical trial in humans using a similar, FDA-approved antibody (vedolizumab), as well as three replication studies–efforts initiated to confirm the study and to potentially give mechanistic insight into the antibody effects.

The March 2019 Editorial Expression of Concern (EEoC) on Byrareddy

et al.

was published after

Science

learned that the virus used in the study featured a stop codon in the SIV

nef

gene, the presence of which was known by author Francois Villinger, who chose this strain intentionally; he believes it provides a better model for chronic HIV infection. However, use of this strain was not communicated to co-authors nor explicitly stated in the manuscript. Following the EEoC to flag this issue in March,

Science

is now correcting Byrareddy

et al.

to indicate the virus used was not wild-type SIVmac239, but SIVmac239-

nef

-stop (use of which introduces variation in the level of viral pathogenicity among animals).

Separately, all three attempts to replicate all or some aspects of Byrareddy

et al.

failed, three reports in this issue of

Science

will show. As such,

Science

is maintaining an Editorial Expression of Concern on this study to alert readers that current evidence suggests that the reported 2016 result “is not robust and therefore does not provide a good basis for guiding work on therapies for HIV.”Two of the replication attempts (Di Mascio

et al.

and Iwamoto

et al.

) used the same SIVmac239-

nef

-stop virus as in Byrareddy

et al.

but did not replicate the sustained low viral load, a result suggesting the nef-STOP virus was not the reason for the positive effect of antibody treatment reported in the 2016 paper

.

The third study (Abbink

et al

.) used a different SIV strain but a similar antibody approach but did not replicate the findings either.

Science

is not moving beyond Editorial Expression of Concern because neither the Byrareddy authors, the authors of the attempted replication studies, nor the editors can account for the differences between the 2016 study and the three failed replications. Moreover, there is a scientific basis supporting the idea that targeting α4 β7 may have a positive impact on the course of infection.

Providing results from a phase 1 clinical trial using vedolizumab (an antibody currently approved as a therapy for ulcerative colitis and Crohn’s disease),

a report

in

Science Translational Medicine

reveals that the antibody did not show sustained antiviral effects in 19 HIV-positive individuals who stopped receiving ART after the seventh antibody infusion (at week 22). Although the antibody treatment was well-tolerated and showed no serious side effects, the results indicate that blocking α4β7 may not be an effective treatment for controlling the virus in HIV-positive patients. Thus, the results support the findings of the 3 replication studies described above. In their study, Michael Sneller and colleagues administered several infusions of vedolizumab antibody to 19 HIV-infected individuals over the course of 30 weeks and measured CD4+ T cell counts and viral loads in plasma every two weeks after ART was stopped at week 22. Halting ART was done in order to determine if the antibody alone could suppress viral load. With the exception of one subject, the treatment did not lead to a significant decline in CD4+ T cells carrying HIV DNA and RNA, the authors report.

In a related Editorial,

Science

Editor-in-Chief Jeremy Berg highlights the importance of replicating experiments and comparing results “as a cornerstone of science.” He further elaborates on the events that followed publication of the study by Byrareddy

et al

. He also addresses the challenge it is for the scientific and publishing communities alike, to facilitate and communicate replications of important results.

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