Researchers Reverse HIV-Related B-Cell Exhaustion

SUMMARY Chronic HIV infection reduces B-cell activity and production of antibodies against the virus, but gene therapy may restore memory B-cell proliferation and responsiveness.

Chronic HIV infection is associated with persistent immune activation, even among people with undetectable viral load. Most attention in the field has focused on CD4 T-cells -- the primary target of HIV -- and CD8 T-cells that play a role in cell-mediated immune response.

But B-cells, which produce antibodies, have also been found to show exhaustion in HIV positive people not treated with antiretroviral therapy, as indicated by changes in cell surface markers.

Anthony Fauci

In the June 1, 2011, Journal of Clinical Investigation Anthony Fauci from the National Institute of Allergy and Infectious Diseases (NIAID) and colleagues reported that increased expression of B-cell inhibitory receptors leads to inefficient HIV-specific antibody responses. Conversely, they found, using small interfering RNA pieces (siRNAs) to down-regulate several of these receptors led to increased tissue-like memory B-cell proliferation, cytokine production, and responsiveness against HIV.

"These findings on HIV-associated B cell exhaustion define potential targets for reversing the deleterious effect of inhibitory receptors on immune responses against persistent viral infections," the study authors wrote.

Below is an edited excerpt from a NIAID press release describing the reseach and its findings.

NIH Scientists Reactivate Immune Cells
Exhausted by Chronic HIV

June 3, 2011 -- Scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, have demonstrated why certain immune cells chronically exposed to HIV shut down, and how they can be reactivated.

Healthy B cells have a balanced mix of surface proteins that the immune system can use, like the gas pedal and brake of a car, either to activate the cell or to damp down its activity. However, in people with long-term HIV infection who have not begun antiretroviral therapy, their B cells -- responsible for producing anti-HIV antibodies -- display a surplus of inhibitory receptors, the surface proteins used to apply the brakes on a B cell. Scientists from the NIAID Laboratory of Immunoregulation led by Lela Kardava, PhD, Susan Moir, PhD, and Anthony S. Fauci, MD, NIAID Director and Chief of the laboratory, wanted to know if this phenomenon can help explain why B cells become "exhausted" and essentially shut down in people who are HIV-infected but treatment-naive.

To test their hypothesis, the scientists used molecules called small interfering RNAs (siRNAs), which acted at the genetic level to prevent exhausted B cells from replenishing inhibitory receptors. After treatment with siRNAs, the exhausted cells responded more normally to conditions that typically would spur a B cell into action, such as the presence of a virus, demonstrating that the excess of inhibitory receptors may explain why exhausted B cells are so unresponsive.

Because B cells generally are difficult to manipulate, the new siRNA-based approach may hold promise for scientists seeking to develop therapies to improve the human antibody response against HIV and other pathogens by altering the expression of specific B-cell genes.

Investigator affiliations: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, MD; Howard Hughes Medical Institute-NIH Research Scholars Program, Chevy Chase, MD; Laboratory of Immunogenetics, NIAID, NIH, Bethesda, MD.