The extent to which HIV may infect CD34+ hematopoietic
progenitor cells (stem cells) in the bone marrow has been the subject of
controversy for more than two decades. Early studies documented the presence of HIV in CD34+ cells in a subset of
people with advanced disease, but a subsequent report offered little evidence of infection in asymptomatic individuals. In the new
issue of Nature Medicine, a group of researchers from the University of
Michigan revisit the issue in a paper that garnered substantial press coverage when
it was released online a few weeks ago. The paper contains data indicating that
CD34+ stem cells can be infected in vitro and also reports that HIV DNA could
be detected in CD34+ cells sampled from the bone marrow of people with HIV
infection, including four out of nine individuals on antiretroviral therapy (ART) with undetectable viral loads in peripheral blood. The researchers conclude
that stem cells may be an important reservoir of latent HIV in people on ART.
There are some caveats, however, and it will be important
for the findings to be confirmed (the researchers themselves acknowledge as
much, stating: “further studies are needed to show that CD34+ stem cells are
infected”). The in vitro work is primarily based on HIV isolates that are
dual-tropic or target the X4 co-receptor, and the efficiency of infection by
CCR5-using HIV appears lower (see the supplemental information panel “a” and compare the percentage of infected cells
with the X4 and dual tropic viruses NL4-3 and 89.6 to the R5 viruses 94UG, MJ4
and YU2). The numbers of individuals sampled for the in vivo results is also
very small and analyses of larger cohorts are needed.
Nat Med. 2010 Mar 7. [Epub ahead of print]
Carter CC, Onafuwa-Nuga A, McNamara LA, Riddell J 4th, Bixby
D, Savona MR, Collins KL.
[1] Graduate
Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor,
Michigan, USA. [2] Medical Scientist Training Program, University of Michigan,
Ann Arbor, Michigan, USA. [3] These authors contributed equally to this work.
HIV causes a chronic infection characterized by depletion of
CD4(+) T lymphocytes and the development of opportunistic infections. Despite
drugs that inhibit viral spread, HIV infection has been difficult to cure
because of uncharacterized reservoirs of infected cells that are resistant to
highly active antiretroviral therapy (HAART) and the immune response. Here we
used CD34(+) cells from infected people as well as in vitro studies of
wild-type HIV to show infection and killing of CD34(+) multipotent
hematopoietic progenitor cells (HPCs). In some HPCs, we detected latent
infection that stably persisted in cell culture until viral gene expression was
activated by differentiation factors. A unique reporter HIV that directly
detects latently infected cells in vitro confirmed the presence of distinct populations
of active and latently infected HPCs. These findings have major implications
for understanding HIV bone marrow pathology and the mechanisms by which HIV
causes persistent infection.
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