Impact of HIV-1 infection on V(H)3 gene repertoire of naive human B cells

B cells of the largest Ig variable heavy chain gene (V(H)) family, V(H)3, are reportedly decreased in patients with late stage HIV-1 disease. This deficit may contribute to their impaired responses to infections and vaccines. We confirmed that the V(H)3 family was underrepresented in serum IgM proteins, with a 45% decrease in patients with advanced HIV-1 disease. However, the proportion of V(H)3 within V(H)(1-6) IgM mRNA from peripheral B cells did not differ from that of control subjects (mean ± SD, 57.1 ± 9.7 vs 61.1 ± 8.7%). Similarly, within V(H)(1-6) IgD mRNA, which even more closely represents the unstimulated naive repertoire, the relative expression of V(H)3 mRNA was comparable in the two groups. Moreover, the frequency of individual genes within the V(H)3 family for IgD, particularly genes which encode putative HIV-1 gp120 binding sites, also was normal in HIV-1-infected patients. However, V(H)3 family expression for IgG mRNA was significantly decreased (17%) and V(H)4 IgG was increased (33%) relative to other V(H) families in advanced HIV-1-infected patients. Thus, the changes in V(H) family expression were more readily apparent in previously activated IgG 'memory' B cell populations and, likely, in cells actively producing IgM rather than in resting naive cells. The presence of a relatively normal naive V(H)3 IgM and IgD mRNA repertoire in resting cells supports the prospect that with proper stimulation, particularly in conjunction with effective antiviral therapy, vigorous humoral immune responses to infections and vaccines may be elicited in this high-risk population.