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In-Depth Information
consist of uniformly monoclonal B cells, expressing EBV but not rearranged
c-myc genes (Ng and McGrath, 1998). Patients with large-cell lymphoma sur-
vive longer and the length of survival correlates with CD4 T-cell count, whereas
patients with monoclonal EBV
lymphomas have a very poor prognosis. The
interactions between HIV, EBV, and c-myc that lead to malignant transforma-
tion of B cells in vitro are known, but the presence of HIV within tumor cells in
vivo is poorly documented and remains controversial. Indeed, to our knowl-
edge, only two articles have suggested that HIV-1 is present in lymphomatous B
cells or in B cells from hyperplastic lymph nodes (Astrin et al., 1992; PrÂvot et
al., 1993). Most AIDS-related lymphomas are HIV
ÿ
, suggesting that lympho-
magenesis does not require B-cell infection by HIV-1, although viral proteins
probably increase the selection pressure on B cells.
Data on AIDS-related lymphoma Igs, VH use, and somatic mutations pro-
vide evidence that these cells may be outgrowths of polyreactive B cells that
escape normal B-cell selection ( Bessudo et al., 1996; Ng et al., 1994, 1997;
Przybylski et al., 1996). These B cells, destined to become malignant in HIV-
infected patients, are probably present early in the disease, during the hyper-
plastic stage. The loss of B-cell di¨erentiation control facilitates their survival
and expansion in the host. Chronic stimulation is likely to result in polyclonal
lymphomas that may then evolve into monoclonal processes. The studies on
AIDS-related lymphoma and the progressive loss of speci®c B-cell memory
observed in HIV
patients suggest that most promalignant B-cell clones arise
from the normal hypermutation process but that the impairment of positive or
negative selection allows them to survive. Tat may favor the survival of these
cells by increasing the expression of Bcl-
xL
or of other antiapoptotic molecules,
whereas the loss of GC organization may decrease the frequency of CD95/
CD95L interactions. It should be noted that tat-transgenic mice develop cen-
trofollicular lymphomas ( Kundu et al., 1998) even in this absence of HIV-1
infection.
CONCLUSION
Although the in vivo infection of B cells by HIV-1 remains to be demonstrated,
it is clear that B cells are direct targets of viral HIV-1 proteins. Thus, in addi-
tion to promoting the T-cell response and CD4
T survival in HIV patients, it
seems to be important in protecting the integrity of the humoral response and
B-cell functions. Monkeys are useful for studying the B-cell compartment in
blood and within the lymphoid organs during HIV infection, in the presence or
absence of Ag stimulation. Alternatively, therapeutic trials in experimentally
infected monkeys could evaluate B-cell functions in general, and the a½nity of
Ab raised against viral proteins in particular.
Acknowledgments. This work was supported by grants from the Agence
Nationale de Recherche sur le SIDA (ANRS), Ensemble contre le SIDA, the
