First evidence of HIV reservoirs in macrophages

Basic scientists in France have recently discovered that macrophages located in urethral tissue can contribute to cellular HIV reservoirs, and that the quantity of these specific immune cells is surprisingly high. Results were published in Nature Microbiology last week.

The well-documented existence of cellular reservoirs that contain ’latent’ HIV is a major barrier to HIV eradication or cure. These reservoirs are HIV-1 infected cells of the immune system that, under the pressure of antiretrovirals, do not actively produce new virus. However, as soon as antiretroviral therapy is discontinued, the virus starts to replicate again.

Most research in this field has focused essentially on T lymphocytes, known to be among the first immune cells to be targeted by HIV. Research has attempted, among several strategies, to eliminate latent HIV from reservoir cells by reactivating them through a “shock and kill” approach. This approach consists of two steps:

  • reactivating the latently infected cells with specific products such as “latency reversing agents”
  • having them destroyed by the patient’s immune system, helped by novel medicines.

Glossary

macrophage

A white blood cell that roams the body tissues engulfing foreign organisms. Macrophages can hide large quantities of HIV without being killed, acting as reservoirs of the virus.

reservoir

The ‘HIV reservoir’ is a group of cells that are infected with HIV but have not produced new HIV (latent stage of infection) for many months or years. Latent HIV reservoirs are established during the earliest stage of HIV infection. Although antiretroviral therapy can reduce the level of HIV in the blood to an undetectable level, latent reservoirs of HIV continue to survive (a phenomenon called residual inflammation). Latently infected cells may be reawakened to begin actively reproducing HIV virions if antiretroviral therapy is stopped. 

cure

To eliminate a disease or a condition in an individual, or to fully restore health. A cure for HIV infection is one of the ultimate long-term goals of research today. It refers to a strategy or strategies that would eliminate HIV from a person’s body, or permanently control the virus and render it unable to cause disease. A ‘sterilising’ cure would completely eliminate the virus. A ‘functional’ cure would suppress HIV viral load, keeping it below the level of detection without the use of ART. The virus would not be eliminated from the body but would be effectively controlled and prevented from causing any illness. 

latency reversing agents

Small pharmacological molecules that could help uncover where HIV is hiding in the cells of HIV-positive persons whose viral load had been suppressed below the level of detection (or reverse HIV latency). Researchers are investigating these molecules hoping they may be part of a combination approach to eradicating HIV (‘kick HIV out’ of latently infected cells to suppress it with ARVs).

treatment interruption

Taking a planned break from HIV treatment, sometimes known as a ‘drugs holiday’. As this has been shown to lead to worse outcomes, treatment interruptions are not recommended. 

So far, these leads have not proven successful, although it may take years to do so. What is reassuring, however, is that scientists are pursuing them.

Morgane Bomsel, Yonatan Ganor and colleagues at the Institut Cochin in Paris examined urethral tissue from 20 men with HIV who were on antiretroviral therapy and had a suppressed plasma viral load. Scientists rarely have access to urethral tissue samples: these were obtained from individuals undergoing gender reassignment surgery. The researchers aimed to identify and characterise HIV reservoirs present in the tissue.

One of the motivations behind this work was that previous studies had shown that HIV genetic material, as well as a proportion of reappearing viruses (in the viral rebound that follows treatment interruption), came from a different, unidentified, cellular reservoir, other than T-cells. Moreover, macrophages were strongly suspected as they are among the first immune cells – like T lymphocytes – to be targeted by HIV during sexual transmission.

The researchers found HIV genome in macrophages but, contrary to what could have been expected, not in T lymphocytes. Additionally, while infectious virus was produced from all cells after macrophage reactivation, it was not observed following the stimulation of T lymphocytes. Finally, the investigators were able to characterise macrophages containing infectious reservoirs as a new subtype of these immune cells and observe that they were considerably increased in their study participants’ samples.

By contrast to current theories, whereby HIV reservoirs were thought to only be present in T lymphocytes, this study is the first to reveal the existence of major reactivable HIV reservoirs in human tissue macrophages. While the authors call for more systematic attempts to identify such HIV reservoirs in macrophages from mucosal or lymphoid tissues, their study also implies that researchers will probably be compelled to rethink their strategies – new approaches, new agents – towards an HIV cure.

References

Ganor Y et al. HIV-1 reservoirs in urethral macrophages of patients under suppressive antiretroviral therapy. Nature Microbiology, online ahead of print, 2019. (Abstract).