Researchers uncover how HIV causes abnormalities in antibody-producing cells

HIV wreaks much of its damage by targeting the “orchestra conductor” of the immune system, a key class of T cells—CD4+ T cells—whose destructive relationship with HIV has been well-studied by AIDS researchers.

More poorly understood has been the effect of HIV on another key class of immune cells, antibody-producing B cells. The malfunction of B cells in HIV-infected patients was first described more than 20 years ago by H. Clifford Lane, M.D., Anthony S. Fauci, M.D., and colleagues at the National Institute of Allergy and Infectious Diseases (NIAID). Now, writing in the Sept. 7 online edition of The Journal of Experimental Medicine, Dr. Fauci, Susan Moir, Ph.D., Angela Malaspina, Ph.D., and their colleagues identify a number of pathways that HIV activates to damage or destroy B cells.

“Our findings further illuminate the insidious nature of HIV,” notes Dr. Moir, head of the B Cell HIV Unit in the Immunopathogenesis Section of the NIAID Laboratory of Immunoregulation (LIR). “The virus has numerous ways of paralyzing or destroying the very cells of the immune system that are supposed to eliminate it.”

One of the most paradoxical properties of HIV is the fact that it activates the immune system, which is necessary for an appropriate immune response, at the same time that the activation itself leads to deleterious effects. “During the course of HIV infection, the B cells of people whose virus is not kept under control with antiretroviral drugs become progressively dysfunctional through virus-driven, aberrant activation,” explains Dr. Fauci, who is NIAID director and LIR chief.

These abnormal B cells exhibit visible changes in their structure and surface. They also overproduce nonessential antibodies, fail to respond properly to normal immune system signals, and have an increased chance of dying through apoptosis, a process also called “programmed cell death.”

In their experiments, Drs. Fauci and Moir and their LIR colleagues, in collaboration with scientists from Human Genome Sciences (Rockville, MD), set out to uncover what drives B-cell abnormalities in HIV infection. Using gene chip technology developed by Human Genome Sciences, they probed thousands of genes taken from B cells of HIV-infected patients. The researchers compared which genes were “turned on,” or expressed, in the patients whose viral burden was high with profiles of gene expression in patients whose virus was controlled by antiretroviral therapy. The research team also examined gene expression in healthy HIV-negative individuals.

“We found more than 40 genes that were ‘over-expressed’ in the group with high HIV levels compared with the two other groups,” says Dr. Moir. Most of these genes, she notes, belong to either one of two major physiologic pathways. Of note, in patients with HIV levels, certain elements from both pathways helped prime B cells for apoptosis.

The researchers not only discovered new pathways that are perturbed during the course of HIV infection, but also illuminated how HIV affects a key B-cell survival system. The principal player in this survival system, B Lymphocyte Stimulator (BLyS), was discovered by Human Genome Sciences. The discovery was first reported in a scientific journal in 1999. BLyS (also known as BAFF) and BAFF-R—one of three known docking molecules for BLyS on B cells—are essential for B-cell development and survival. Dr. Moir and her team discovered that B cells of patients with high levels of HIV have reduced levels of BAFF-R on their surfaces, making these B cells more susceptible to cell death.

The LIR researchers plan to examine whether similar pathways are triggered in other cells of the immune system that are over-activated by HIV, including CD8+ T cells, CD4+ T cells and natural killer (NK) cells.

“Whether common or distinct pathways are involved, these new findings help explain one of the driving forces of HIV immunopathogenesis and may lead to therapeutic strategies aimed at quelling the aberrant levels of immune cell activation,” notes Dr. Fauci.