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.