Three separate and independent teams of researchers in the United States attempted to replicate the results of a team that, back in 2016, claimed to have cured monkeys of an HIV-like infection, writes Bob Yirka of Medical Xpress. All three studies failed to replicate the results, and have published their work and findings in the journal Science.
Notably, the original paper was published in the same journal. After questions arose regarding the work done by the 2016 team, the editors at Science published an “editorial expression of concern”.
The work by the team in 2016 involved giving monkeys infected with SIV (the monkey equivalent of HIV) the standard antiviral treatment for HIV—they also administered an antibody to target a protein called a4b7, which prior research had suggested the virus exploits to hide from antibodies.
The team reported that nine months after discontinuing treatment, the monkeys showed no signs of resurgence of the virus. It appeared they had found a cure.
News of the possible cure spread quickly through the bioscience community, leading others to attempt to replicate these efforts, but none could.
Then, reports emerged that one of the 2016 team members had substituted a different type of SIV virus during the study without telling anyone. Once outed, he explained that he had changed the virus because he thought it was more like the HIV virus in humans. That was enough for Science to publish its editorial of concern.
Once this news emerged, two teams of researchers attempted to replicate the results of the 2016 team using the same SIV variant. Both are now reporting that they were unsuccessful in their attempts to replicate the results, and both have published papers describing their efforts in Science.
Meanwhile, another team tried to replicate the results, as well, using a third variant of SIV. They report in their article, also published in Science, that they were unable to replicate the results.
In light of the failure of all three teams to replicate the results of the 2016 team, Science Editor-In-Chief Jeremy Berg has published a letter in the journal describing his reasons for maintaining an editorial expression of concern rather than a retraction.
Editorial expression of concern
Jeremy Berg, Editor-in-Chief.
Science, 6 September 2019.
On 14 October 2016, Science published the Research Article “Sustained virologic control in SIV+macaques after antiretroviral and α4β7 antibody therapy” by SN Byrareddy et al.
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 alhas 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 Sciencehave attempted to replicate this work, two using the same SIVmac239-nef-stop virus used in Byrareddy and one using a different SIV strain.
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.
We are maintaining an Editorial Expression of Concern on Byrareddy et alto 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.
An antibody is not the antidote
The reports of the three independent research teams, published in Science on 6 September 2019, were preceded by the following:
An HIV therapeutic that would give long-term remission without sustained antiretroviral therapy (ART) is a long-term goal. Byrareddy et al [Science354, 197 (2016)] reported that treating simian immunodeficiency virus (SIV)-positive macaques with an antibody against integrin α4β7 during and after ART results in sustained virologic control after stopping all treatment.
Three studies in this issue question the reproducibility of that result. Di Mascio et al sequenced the virus used in the 2016 study and found that it was a variant with a stop codon in the nef gene rather than a wild-type virus. Abbink et al used the same antibody for α4β7 as before but tested control of a more commonly used pathogenic virus. Iwamato et al used the same nef-stop virus as in the earlier paper but combined the antibody against the integrin with an antibody against the SIV envelope glycoprotein, which also blocks viral binding of the integrin.
None of these three new studies found that treating with the antibody had any effect on virologic control after stopping ART treatment.
Evaluation of an antibody to α4β7 in the control of SIVmac239-nef-stop infection
Science 06 Sep 2019.
Treatment of SIV-infected rhesus macaques with short-term antiretroviral therapy (ART) and partially overlapping infusions of antibody to integrin α4β7 was reported to induce durable posttreatment viral suppression. In an attempt to replicate those observations, we treated macaques infected with the same virus and with the same ART and monoclonal antibody (mAb) regimens (anti-α4β7 versus control mAb). Sequencing demonstrated that the virus used was actually SIVmac239-nef-stop, not wild-type SIVmac239.
A positive correlation was found at 2 weeks after infection between the frequency of repair of attenuated Nef-STOP virus to pathogenic Nef-OPEN and plasma SIV RNA levels. Levels of plasma viremia before the first antibody infusion and preinfection levels of α4β7hi CD4+ T cells, but not treatment with antibody to α4β7, correlated with levels of viral replication upon discontinuation of all treatments.
Follow-up plasma viremia, peripheral blood CD4+ T cell counts, and lymph node and rectal tissue viral load were not significantly different between anti-α4β7 and control mAb groups.
M De Mascio, JD Lifson, S Srinivasula, I Kim, P DeGrange, BF Keele, AJ Belli, KA Reimann, Y Wang, M Proschan, HC Lane and AS Fauci.
The authors are primarily from the National Institute of Allergy and Infectious Diseases (NIAID) in Bethesda, United States; Frederick National Laboratory; and the University of Massachusetts Medical School.
Lack of therapeutic efficacy of an antibody to α4β7 in SIVmac251-infected rhesus macaques
Science 06 Sep 2019.
Sustained virologic control of human immunodeficiency virus type 1 (HIV-1) infection after discontinuation of antiretroviral therapy (ART) is a major goal of the HIV-1 cure field. A recent study reported that administration of an antibody against α4β7 induced durable virologic control after ART discontinuation in 100% of rhesus macaques infected with an attenuated strain of simian immunodeficiency virus (SIV) containing a stop codon in nef.
We performed similar studies in 50 rhesus macaques infected with wild-type, pathogenic SIVmac251. In animals that initiated ART during either acute or chronic infection, anti-α4β7 antibody infusion had no detectable effect on the viral reservoir or viral rebound after ART discontinuation.
These data demonstrate that anti-α4β7antibody administration did not provide therapeutic efficacy in the model of pathogenic SIVmac251 infection of rhesus macaques.
Peter Abbink, Noe B Mercado, Joseph P Nkolola, Rebecca L Peterson, Hubert Tuyishime, Katherine McMahan, Edward T Moseley, Erica N Borducchi, Abishek Chandrashekar, Esther A Bondzie, Arshi Agarwal, Aaron J Belli, Keith A Reimann, Brandon F Keele, Romas Gelezuinas, Mark G Lewis and Dan H Barouch.
The authors are mainly from Harvard Medical School, the University of Massachusetts Medical School, Frederick National Laboratory, Bilead Sciences, Bioqal and the Massachusetts Institute of Technology.
Blocking α4β7 integrin binding to SIV does not improve virologic control
Science 06 Sep 2019.
A study in nonhuman primates reported that infusions of an antibody against α4β7 integrin, in combination with antiretroviral therapy, showed consistent, durable control of simian immunodeficiency virus (SIV) in rhesus macaques.
The antibody used has pleiotropic effects, so we set out to gain insight into the underlying mechanism by comparing this treatment to treatment with non-neutralizing monoclonal antibodies against the SIV envelope glycoprotein that only block α4β7 binding to SIV Env but have no other host-directed effects.
Similar to the initial study, we used an attenuated strain of SIV containing a stop codon in nef. The study used 30 macaques that all began antiretroviral therapy and then were divided into five groups to receive different antibody treatments.
Unlike the published report, we found no sustained virologic control by these treatments in vivo.
Nami Iwamoto, Rosemarie D Mason, Kaimei Song, Jason Gorman, Hugh C Welles, James Arthos, Claudia Cicala, Susie Min, Hannah AD King, Aaron J Belli, Keith A Reimann, Kathryn E Foulds, Peter D Kwong, Jeffrey D Lifson, Brandon F Keels and Mario Roederer.
The authors are primarily with the National Institute of Allergy and Infectious Diseases (NIAID), Frederick National Laboratory and the University of Massachusetts Medical School.
This is the original 2016 article by Siddappa N Byrareddy et al.