I have worked on a variety of human immunodeficiency virus (HIV) projects, but only recently became aware of not-so-new research suggesting the HIV envelope glycoprotein, gp 120, is an Ig superantigen for a subpopulation of B cells. A superantigen has been defined as an antigen binding 5-25% of the T or B cell population, dramatically more than the <0.01% of a conventional antigen (Goodglick, 1995).
It is well known that infection with HIV depletes CD4+ T cells. B cell repertoires, which lack CD4, are also impacted by the virus (Berberian, 1993). Antibody specificity is determined by the variable regions of their heavy (VH) and light chains. The VH genes are divided into 7 families (VH1-7) that are distinguished by at least 80% nucleotide homology in certain VH framework regions. In adult peripheral B cells, VH3 comprises about half of the expressed VH repertoire (Scamurra, 2000). HIV gp120 stimulates endogenous B cells from the VH3 family by binding to membrane Ig, outside the conventional, (hypervariable) Ag-binding site. HIV-1 gp120 has thus been labeled a superantigen, binding an estimated 4-6% of the B cell population (Goodglick, 1995). This binding results in an increase in VH3 B cells in early disease. This overactive humoral state is followed by a decline in B cell response which is prior to the significant depletion of CD4+ T cells (Karray, 1997). The resulting B cell loss and/or shift in distribution may result in impaired humoral responses to infections and vaccines (Scamura, 2000).
After writing the above, I received some pre-blog feedback from Elisabeth Bowers, a pre-doctoral fellow in the Microbiology department working in this area. She noted that a direct association between the increase in VH3 B cells in early disease and the B cell dysfunction seen during infection has not been shown. (B cell dysfunction includes hypergammaglobulinemia –a high amount of antibody in the blood, lymphadenopathy, and increased risk of B cell lymphomas.) The B cell dysfunction may be, in part, a result of increased VH3 B cells, but much of the response is directed against HIV. “So the current hypothesis for some (but not all) of the B cell dysfunction is humoral immune reaction to the virus itself, leading to B cells producing virus-specific antibodies, and ‘bystander’ B cell responses – B cells that are not specific to virus, but still become activated anyway (these may not all be VH3 B cells) (Shirai, 1992; Amadori, 1990; Schnittman, 1986). B cell abnormalities have been directly associated with high viral loads (Viau, 2007).”
Berberian, et al., “Immunolglobulin VH3 gene products: natural ligands for HIV gp120”. Science. 1993. 261: 1588-91.
Goodglick, et al,. “Mapping the Ig superantigen-binding sit of HIV gp120”. The Journal of Immunology. 1995. 155: 5151-59.
Karray, et. al., “Identification of the B cell superantigen-binding site of HIV-1 gp120”. PNAS. 94: 1356-60.
Scamurra et al., “Impact of HIV-1 infection of Vh3 gene repertoire of naïve human B cells”. The Journal of Immunology. 2000. 164: 5482-91.
Shirai et al., “Human Immunodeficiency Virus Infection Induces Both Polyclonal and Virus-specific B Cell Activation”. The Journal of Clinical Investigation. 1992. 89: 561-566.
Amadori et al., “B-cell activation and HIV-1 infection: deeds and misdeeds”. Immunology Today. 1990. 11(10): 374-379.
Schnittman et al., “Direct Polyclonal Activation of Human B Lymphocytes by the Acquired Immune Deficiency Syndrome Virus”. Science. 1986. 233: 1084-1086.
Viau et al., “Direct impact of inactivated HIV-1 virions on B lymphocyte subsets”. Molecular Immunology. 2007. 44: 2124-2134.
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B cells are activated in a T cell independent manner but they are not responding specifically to HIV. The B cell are activated non-specifically by the superantigen gp 120- so they may not be dysfunctional. Can these B cells class switch? Do they do this independently of T cells? If they need T cell help- does this activation of the CD4+ T cells make them more susceptible to HIV viral invasion? For instance, do activated Th cells increase their expression of CD4+ cells making them more susceptible to HIV invasion?
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