Pathogenic mechanisms of B-lymphocyte dysfunction in HIV disease

Abstract

HIV disease is associated with abnormalities in all major lymphocyte populations, including B cells. Aberrancies in the B-cell compartment can be divided into 3 broad categories: changes that arise as a result of HIV-induced immune activation, changes that arise as a result of HIV-induced lymphopenia, and changes that arise independently of these 2 parameters. We review recent developments in all 3 categories of abnormalities and highlight how observations made in the early years of the HIV epidemic are better understood today in large part because of the advent of effective antiretroviral therapy. Insight into the mechanisms of B-cell dysfunction in HIV disease has also been achieved as a result of increased knowledge of the B-cell subpopulations as they exist in healthy individuals, compared with their abnormalities in HIV-infected individuals. A better understanding of the pathogenic mechanisms of B-cell abnormalities in HIV disease can potentially lead to new strategies for improving antibody responses against opportunistic pathogens that afflict HIV-infected individuals and against HIV itself, in the context of both HIV infection and an antibody-based HIV vaccine.

FIG 1

Phenotypic and genotypic aberrancies associated with HIV viremia. A, Phenotypic profile of peripheral blood–derived B cells isolated from representative HIV-negative and HIV-viremic individuals illustrating decreased CD21 expression on B cells of the HIV-viremic individual. B, Electron micrograph illustrating presence of cells with plasmacytoid features in the CD21^lo B-cell fraction of a representative HIV-viremic individual. Micrograph originally appeared in Moir S, Malaspina A, Ogwaro KM, Donoghue ET, Hallahan CW, Ehler LA, et al. HIV-1 induces phenotypic and functional perturbations of B cells in chronically infected individuals. Proc Natl Acad Sci U S A 2001;98:10362–7. C, Main findings from DNA microarray analyses performed on blood-derived B cells isolated from HIV-viremic individuals and compared with B cells isolated from HIV-aviremic and HIV-negative individuals. BCMA, B-cell maturation protein; IFI, IFN-induced family of genes; ISG, IFN-stimulated gene.

FIG 2

HIV disease is associated with increased B-cell turnover and increased B-cell death by intrinsic and extrinsic apoptosis. A, Identification of B-cell subpopulations in the peripheral blood of a representative HIV-infected individual with active disease. B, Increased expression of CD95 on CD10⁻/CD21^lo mature/activated B cells correlates with increased susceptibility to CD95-mediated extrinsic apoptosis. C, CD10⁻/CD21^lo mature/activated B cells also express increased levels of the cell-cycling marker Ki-67. Decreased expression of (D) Bcl-2 and (E) Bcl-xL in CD10⁺ immature/transitional B cells is associated with increased susceptibility to intrinsic apoptosis. These profiles originally appeared in Ho J, Moir S, Malaspina A, Howell ML, Wang W, DiPoto AC, et al. Two overrepresented B cell populations in HIV-infected individuals undergo apoptosis by different mechanisms. Proc Natl Acad Sci U S A 2006;103:19436–41. Max, Maximum.