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