AIDSWEEKLY Plus; Monday, October 5, 1998
Daniel J. DeNoon, Senior Editor
New studies suggest that HIV induced perturbations in B-cell immune responses - caused, perhaps, by viral superantigens - increase a person's lymphoma risk.
"The results of our study are consistent with the notion that B cells of persons infected with HIV are undergoing rapid turnover, with successive waves of stimulation, expansion, and/or deletion," wrote Alberto Bessudo and colleagues of the University of California, San Diego. "Such turnover may allow for chance acquisition of somatic changes that can lead to the malignant transformation of a responding B-cell clone."
Bessudo et al. reported their findings in the journal Blood ("Aberrant and Unstable Expression of Immunoglobulin Genes in Persons Infected with Human Immunodeficiency Virus," Blood, 1998;92(4):1317- 23).
The same mutations in B-cell immunoglobulin heavy-chain variable- region genes (V[H] genes) most often seen in AAL are those expressed by B cells actively performing their jobs during secondary immune responses to antigen.
"This is striking, considering the profound immune deficiency of the patients who develop such lymphomas," Bessudo et al. noted. "The B cells that subsequently develop into B-cell lymphoma may have originated at stages of the HIV infection that are earlier than that of end-stage AIDS when most lymphomas become clinically apparent."
To test this hypothesis, the researchers obtained serial blood samples from several groups of volunteers: nine people with HIV but not AIDS and with CD4 counts of >500 cells/(micro)L (Group I); five AIDS patients with CD4 counts of <200 cells/(micro)L who did not develop AAL (Group II); and nine similar patients who eventually developed AAL (Group III); 14 AIDS patients sampled at the time of AAL diagnosis (Group IV); and six healthy, HIV negative controls.
Compared to the controls, who had similar and stable V[H] gene repertoires, subjects with HIV had very heterogeneous and unstable V[H] repertoires.
Like earlier studies, Bessudo et al. found that the V[H]3 subset - the largest of the seven human immunoglobulin (Ig) V[H] subsets - was skewed in their HIV infected population. But they also found that other V[H] subsets were skewed.
Interestingly, most of the V[H]3 skewing appeared during early infection and was not seen in the later stages of disease (although skewing of other V[H] subsets remained frequent).
"Conceivably, B-cell superantigens may account for the abnormal levels of Ig V[H] gene subgroups observed in patients infected with HIV," Bessudo et al. wrote. "B-cell superantigens are substances that bind the immunoglobulin encoded by most Ig V[H] genes of a given subgroup. ... Such antigens can induce expansion or depletion of all B cells that express surface Ig encoded by a specific Ig V[H] gene subgroup. This is in contrast to conventional antigens that generally induce specific antibodies encoded by any one of several different Ig V[H] subgroups."
The authors noted that this hypothesis does not rule out a V[H] perturbation effect from ongoing immune responses to HIV or from interactions between HIV surface glycoproteins and Ig on the surface of B cells. They further suggest that B-cell chemokine receptors may provide an interface for direct actions of the virus on B cells.
"Further study on the mechanism(s) underlying the dynamics within the B-cell compartment of persons infected with HIV may show the factor(s) accounting for the high rate of lymphomas that occur in patients with AIDS," Bessudo et al. wrote.
This project was funded by NIH grants RO1 CA 65408-03, AI27670, and AI36214 and the Research Center for AIDS and HIV Infection of the San Diego Veterans Affairs Medical Center.
The corresponding author for this study is Thomas J. Kipps, Divisions of Hematology/Oncology and Infectious Diseases, Department of Medicine, University of California, San Diego, California 92093- 0663.
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