HIV Reservoir Found in Blood Progenitor Cells in Bone Marrow

		SUMMARY: HIV can hide in the bone marrow inside hematopoietic progenitor stem cells, even in people with long-term undetectable plasma viral load, according to study results reported in the March 7, 2010 online edition of Nature Medicine. When the cells are forced to differentiate into different types of blood cells, the viral genome becomes active and begins producing new viral particles. The ramifications of this finding are not yet clear, but will certainly have implications for the growing effort to accomplish HIV eradication.

By Liz Highleyman

It is well known that HIV can lie dormant in latent immune cell for years or decades, where the viral genome (or "provirus") is protected from current antiretroviral drugs and invisible to the immune system. Over time, this virus can "wake up" and begin replicating if the latent cells become activated, which is why antiretroviral therapy (ART) must be life-long.

In a plenary lecture at last year's Conference on Retroviruses and Opportunistic Infections (CROI 2009), Robert Siliciano from Howard Hughes Medical Institute said that recent unsuccessful treatment intensification studies support the hypothesis that the residual HIV remaining in the body despite ART is not due to ongoing low-level viral replication, but rather emerges from stable reservoir sites. Latent CD4+ T-cells and macrophages account for some of this hidden virus, he said, but gene sequencing studies indicate that a majority of residual virus arises from an additional "not-yet-identified source."

 

This week, Christoph Carter, Kathleen Collins, and colleagues from the University of Michigan at Ann Arbor shed light on a potential candidate for this mystery source of virus.

The researchers looked at CD34+ cells found in bone marrow samples from 15 HIV positive individuals. These CD34+ cells are multipotent hematopoietic progenitor cells, a type of stem cell residing in the bone marrow (as well as umbilical cords of infants) that gives rise to multiple types of blood cells.

The study authors found HIV genetic material not only in hematopoietic progenitor cells from all 6 participants with high blood viral loads, but also in cells from 4 of the 9 patients on ART who had undetectable virus for at least 6 months. Collins suggested this might also have been true for the other 5, but the samples may have been too small or the test not sensitive enough.

The investigators also conducted laboratory studies using wild-type, or non-mutated, HIV. They showed that HIV is able to infect and kill hematopoietic progenitor cells taken from HIV negative donors. But in some of these cells, the viral genome went latent and persisted indefinitely in laboratory cultures.

This virus remained dormant until the researchers used differentiation factors (such as granulocyte-macrophage colony-stimulating factor, or GM-CFS) to activate the cells and make them start developing into different types of blood cells, thereby triggering viral gene expression.

The activated virus kills the host progenitor cells, but not before it produces progeny virus particles that can go on to infect additional cells. Because this processes is fatal to the original progenitor cell, the authors explained, HIV does not end up in differentiated daughter blood cells of types that do not normally harbor the virus.

Other researchers have suspected that hematopoietic progenitor cells might be a possible HIV reservoir, but these cells are difficult to maintain in the laboratory culture, and no one until now has been establish that these cells can be infected with the virus.

Based on these results, the investigators concluded, "These findings have major implications for understanding HIV bone marrow pathology and the mechanisms by which HIV causes persistent infection."

"This finding is important because it helps explain why it's hard to cure the disease," Collins said in a press release issued by the University of Michigan. "Currently people have to take antiviral drugs for their entire life to control the infection...It would be easier to treat this disease in countries that don't have the same resources as we do with a course of therapy for a few months, or even years."

"Ultimately to cure this disease, we're going to have to develop specific strategies aimed at targeting these latently infected cells," she concluded.

Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI; Medical Scientist Training Program, University of Michigan, Ann Arbor, Michigan, MI.

3/12/10

Reference
CC Carter, A Onafuwa-Nuga, LA McNamara, and others. HIV-1 infects multipotent progenitor cells causing cell death and establishing latent cellular reservoirs. Nature Medicine (Abstract). March 7, 2010 (Epub ahead of print).

Other source
University of Michigan Health System. U-M scientists identify reservoirs where HIV-infected cells can lie in wait. Press release. March 7, 2010.