A new open access paper from the laboratory of Warner Greene at the Gladstone Institutes was published online yesterday in the journal Cell Reports, accompanied by a poorly conceived press release that prompted some of the most egregiously inaccurate media headlines about HIV research in recent history.
The study, led by Nicole Galloway and Gilad Doitsh, is a continuation of the lab’s work on pyroptosis, an inflammatory form of cell death that can be triggered by abortive infection of CD4 T cells by HIV (the virus gains entry but does not complete further steps in the viral life cycle). The crux of the new findings is that cell-free HIV particles cannot cause pyroptosis; rather, cell-to-cell transmission of virions is required to initiate the cascade of events that ends in pyroptotic CD4 T cell death. Regrettably, whoever at Gladstone Institutes was responsible for the press release decided the best way to try and hook the media into covering the paper was to use the headline “HIV particles do not cause AIDS, our own immune cells do.” Not only is this ripe for misunderstanding, it is not even an accurate representation of what the study shows – the immune cells don’t do anything to cause AIDS unless HIV is spreading between them. Yet worse, the notion that this research entirely explains how HIV causes AIDS—which is treated as fact in both press release and paper—is still unproven.
The resulting media coverage has thus been misleading in two ways. First there was a jaw-droppingly inaccurate version of the press release headline offered by United Press International: “Study: HIV does not cause AIDS, human immune cells do.” To their credit, UPI have since made corrections (the original headline can still be seen in the URL) but the original circulated far and wide on the internet and several other outlets have offered variants (e.g. “AIDS: HIV Not Culprit”). Inevitably, these headlines will be picked up and used as propaganda by AIDS denialists, who are always on the lookout for material that can be quote-mined and will have no interest in the actual content of the news articles or the paper.
Secondly, news stories are credulously repeating the claims in the Gladstone Institutes press release that pyroptosis underlies progression to AIDS. But there are uncertainties about this because the data almost entirely derives from studies involving X4-tropic HIV isolates (see prior blog post on the 2013 papers). Specifically, the claim in the press release that “95% of cell death from HIV is caused by immune cells committing suicide in self-defense after an unsuccessful infection” derives from findings in the ex vivo human lymphoid aggregate culture (HLAC) system showing that X4-tropic and dual R5/X4 HIV isolates cause massive depletion of bystander CD4 T cells that are not productively infected. But the original studies that reported this finding also showed that R5-tropic HIV isolates cause very little depletion of bystander CD4 T cells (see figure 2 of this 2003 Journal of Virology paper). Like the press release, the Cell Reports paper also glosses over this distinction, simply stating: “infection of HLACs with HIV-1 produces extensive loss of CD4 T cells––less than 5% of the cells die as a result of productive viral infection, while >95% of them die as a consequence of abortive infection.” The experiments reported in the new paper only involve an X4-tropic laboratory HIV isolate.
This is not to argue that pyroptosis plays no role in disease progression (there is a strong case to be made that it explains the consistent association between X4 tropism and rapid CD4 T cell loss), but rather that it is not yet clear how it contributes in R5-tropic HIV infection. For example, many individuals progress to AIDS without showing evidence of the emergence of X4-tropic variants, and R5-tropic SHIVs cause simian AIDS in macaques. As far as is known at this juncture, progression in these settings occurs without 95% of the CD4 T cell death resulting from pyroptosis. There has been a preliminary report that pyroptosis is involved in the death of CCR5-expressing CD4 T cells in the gut, but more research is needed.
It is understandable that scientists and their institutions might want to raise the profile of their work, particularly in a time of shrinking research funding, but in this case I think the significance of largely in vitro research findings has been hugely oversold and it has resulted in some horribly misleading news stories. For community-based advocates like TAG who try to promote public understanding of—and support for—scientific research, this type of debacle is extremely unwelcome, because no responses, caveats, or explanations we offer will ever reach the vast numbers of people who will read the misleading media reports.
Cell Reports 12, 1–9, September 8, 2015
Nicole L.K. Galloway5, Gilad Doitsh5, Kathryn M. Monroe, Zhiyuan Yang, Isa Muñoz-Arias, David N. Levy, Warner C. Greene
Publication stage: In Press Corrected Proof
The progressive depletion of CD4 T cells underlies clinical progression to AIDS in untreated HIV-infected subjects. Most dying CD4 T cells correspond to resting nonpermissive cells residing in lymphoid tissues. Death is due to an innate immune response against the incomplete cytosolic viral DNA intermediates accumulating in these cells. The viral DNA is detected by the IFI16 sensor, leading to inflammasome assembly, caspase-1 activation, and the induction of pyroptosis, a highly inflammatory form of programmed cell death. We now show that cell-to-cell transmission of HIV is obligatorily required for activation of this death pathway. Cell-free HIV-1 virions, even when added in large quantities, fail to activate pyroptosis. These findings underscore the infected CD4 T cells as the major killing units promoting progression to AIDS and highlight a previously unappreciated role for the virological synapse in HIV pathogenesis.