Up close and 3-dimensional: HIV caught in the act inside the gut

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HIV infection has many unhealthy consequences on the body, but in particular it messes up the gut. The human intestine has the highest concentration of HIV target cells, the majority of which are destroyed within days of infection, and before CD4 T cell counts drop measurably in the blood. A study published on January 30th in PLOS Pathogens reports the first three-dimensional ultra-structural study of HIV infection in vivo. Not only does it reveal details on how the virus quickly infects immune cells in the gut, using them as virus-producing factories, but it also highlights where the virus "hides out" deep within the intestinal tissue.

Pamela Bjorkman, from the Howard Hughes Medical Institute and the California Institute of Technology, USA, and colleagues used electron tomography for a high-resolution study of HIV virus in the guts of "humanized" mice, whose immune system is made up to a large degree of human cells. They infected these "BLT mice" (so-called because they have human bone marrow, thymus, and liver cells) with HIV virus and developed methods that allowed them to safely examine and visualize the three-dimensional architecture of infected parts of the gut.

They saw HIV-infected human immune cells, caught virus particles in the act of budding from such cells, and also found groups of free immature and mature viruses. For one infected host cell (turned HIV factory) the researchers counted 63 virus particles it had likely released. The actual number is almost certainly much higher, because the method can only visualize virus particles surrounding the host cell within a relatively small part of the tissue. Nevertheless, they discovered that groups of viruses that were farther from the host cell were more mature than those closer to it, which suggested that the host cell releases new virus in a series of "semi-synchronized" waves.

Among the samples, the researchers found some where viruses released from one infected cell seemed directly to attach to a neighboring host cell, presumably infecting it. In addition to such "virological synapses," they also observed free virus particles that appear to have covered some distance between their "mother" cell and the cell that would become their target to infect.

These images provide the first 3D ultrastructural details on HIV infection and virus production in a setting that closely resembles the gut of human patients. Some results confirm earlier findings from in vitro experiments-cells grown and infected in a petri dish-but others are seen for the first time and advance the understanding of how HIV infection spreads in real life.

"To me, an important finding is that the majority of the viral transmission events within tissue involved free virus rather than virological synapses", says Bjorkman. "The spread of viruses through synapses had been speculated to be a major route of transmission in tissue, but our results reveal large pools of free virions. This discovery provides hope that possible therapeutics, such as antibodies, would be able to access infecting viruses that are not hidden within a virological synapse."

P.S. A picture is worth 1000 words, and the movies in this article have thousands of pictures. To appreciate the fascinating data generated in this study, see for yourself at the following video clip: https://www.plos.org/wp-content/uploads/2013/05/PLOS_Pathogens_Bjorkman_Jan30_Video.mp4 (Video Credit: Ladinsky et al).

Funding: This work was supported by the National Institutes of Health (2 P50 GM082545-06; WI Sundquist, PI), a Ragon Institute post-doctoral fellowship (CK), and gifts from the Gordon and Betty Moore Foundation and the Agouron Institute to support electron microscopy at Caltech. DSK is supported by an NIH K08 Award (K08 AI084546-04) and a fellowship from the Burroughs Wellcome Fund. The MGH Humanized Mouse Program is supported by the Harvard University Center for AIDS Research (P30 AI060354). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests: The authors have declared that no competing interests exist.

Citation: Ladinsky MS, Kieffer C, Olson G, Deruaz M, Vrbanac V, et al. (2014) Electron Tomography of HIV-1 Infection in Gut-Associated Lymphoid Tissue. PLoS Pathog 10(1): e1003899. doi:10.1371/journal.ppat.1003899