Over the course of the past year, we have revealed several novel facets of HIV-1 immunopathogenesis. We have demonstrated that in vivo, replication-competent HIV-1 binds directly to B cells through interactions involving complement fragments on virions (mainly the C3 fragment C3dg) and CD21 on B cells. B cells isolated from peripheral blood mononuclear cells (PBMC) of 23 chronically infected/ recently viremic or chronically viremic patients were found to carry HIV on their surface, and in the case of the latter group, virions were also discovered on B cells isolated from lymph node biopsies. The B cells of these patients demonstrated similar capacities to pass virus to activated HIV-negative PBMC when compared to CD4-positive T cells isolated from the same individual. However, in contrast to the T cell-associated virus, the B cell-associated virus was found to be sensitive to pronase treatment, strongly suggesting that B cell- but not T cell-associated HIV is surface-bound. This observation was confirmed by using an in situ HIV RNA amplification technique (NASBA) on single cells to show that the signal for HIV RNA was restricted to the surface of B cells whereas viral RNA was dispersed throughout the cytoplasm of T cells. Further experiments designed to establish the mechanism of interaction between HIV virions and B cells involved assaying for the presence of replication-competent virus by sorting cells on the basis of B cell surface markers that have been shown to potentially bind HIV, including CD32, CD21, and surface Ig. Using this approach, we found that replication-competent HIV segregated with CD21-positively sorted B cells, suggesting that HIV virions were shrouded with C3dg, a high-affinity ligand for CD21. To confirm this specific and unique association between CD21 on B cells and C3 fragments on HIV virions, we used the C3-displacing anti-CD21 monoclonal antibody FE8 to show that replication-competent virus was depleted from B cells upon incubation with FE8. Furthermore, the association between HIV virions and C3 fragments was confirmed by capturing FE8-displaced virus with an anti-C3 antibody. Finally, we have shown that surface levels of CD21 are reduced on B cells of HIV-infected individuals and that this reduction correlates directly with viral load. A detailed investigation of the causes and consequences of reduced CD21 expression on B cells of HIV-infected individuals is currently being conducted.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI000825-03
Application #
6431699
Study Section
(LIR)
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2000
Total Cost
Indirect Cost
Name
Niaid Extramural Activities
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Moir, Susan; Fauci, Anthony S (2008) Pathogenic mechanisms of B-lymphocyte dysfunction in HIV disease. J Allergy Clin Immunol 122:12-9;quiz 20-1
Chun, Tae-Wook; Nickle, David C; Justement, Jesse S et al. (2008) Persistence of HIV in gut-associated lymphoid tissue despite long-term antiretroviral therapy. J Infect Dis 197:714-20
Moir, Susan; Ho, Jason; Malaspina, Angela et al. (2008) Evidence for HIV-associated B cell exhaustion in a dysfunctional memory B cell compartment in HIV-infected viremic individuals. J Exp Med 205:1797-805
Moir, Susan; Malaspina, Angela; Ho, Jason et al. (2008) Normalization of B cell counts and subpopulations after antiretroviral therapy in chronic HIV disease. J Infect Dis 197:572-9
Malaspina, Angela; Moir, Susan; DiPoto, Angela C et al. (2008) CpG oligonucleotides enhance proliferative and effector responses of B Cells in HIV-infected individuals. J Immunol 181:1199-206
Meyers, Jennifer Hartt; Justement, J Shawn; Hallahan, Claire W et al. (2007) Impact of HIV on cell survival and antiviral activity of plasmacytoid dendritic cells. PLoS ONE 2:e458
Malaspina, Angela; Moir, Susan; Chaitt, Doreen G et al. (2007) Idiopathic CD4+ T lymphocytopenia is associated with increases in immature/transitional B cells and serum levels of IL-7. Blood 109:2086-8
Ho, Jason; Moir, Susan; Kulik, Liudmila et al. (2007) Role for CD21 in the establishment of an extracellular HIV reservoir in lymphoid tissues. J Immunol 178:6968-74
Chun, Tae-Wook; Justement, J Shawn; Moir, Susan et al. (2007) Decay of the HIV reservoir in patients receiving antiretroviral therapy for extended periods: implications for eradication of virus. J Infect Dis 195:1762-4
Malaspina, Angela; Moir, Susan; Ho, Jason et al. (2006) Appearance of immature/transitional B cells in HIV-infected individuals with advanced disease: correlation with increased IL-7. Proc Natl Acad Sci U S A 103:2262-7

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