Impact of HIV-1 Infection on VH3 Gene Repertoire of Naive Human B Cells

Abstract

B cells of the largest Ig variable heavy chain gene (VH) family, VH3, 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 VH3 family was underrepresented in serum IgM proteins, with a 45% decrease in patients with advanced HIV-1 disease. However, the proportion of VH3 within VH(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 VH(1–6) IgD mRNA, which even more closely represents the unstimulated naive repertoire, the relative expression of VH3 mRNA was comparable in the two groups. Moreover, the frequency of individual genes within the VH3 family for IgD, particularly genes which encode putative HIV-1 gp120 binding sites, also was normal in HIV-1-infected patients. However, VH3 family expression for IgG mRNA was significantly decreased (17%) and VH4 IgG was increased (33%) relative to other VH families in advanced HIV-1-infected patients. Thus, the changes in VH 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 VH3 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.

HIV Type 1 Glycoprotein 120 Inhibits Human B Cell Chemotaxis to CXC Chemokine Ligand (CXCL) 12, CC Chemokine Ligand (CCL)20, and CCL21

“…It may therefore play a role in the gp120-mediated increase in CD95 expression and CD95-mediated apoptosis in B cells. An increase in susceptibility to CD95 apoptosis may be involved in the depletion of peripheral B cells reported by several groups in HIV-infected patients (3,9,10,57). The gp120-induced decrease in membrane CD62L expression was dependent on CD4, CXCR4 triggering, and on the activation of G␣ i , p38 MAPK, and its cleavage by MMP.…”

“…As V H 3 genes are the key determinants of Abs specific for bacterial polysaccharide Ags, the depletion of V H 3-expressing B cells may contribute to the observed increase in the incidence of secondary infections in HIV-infected patients (19). Scamurra et al (10) recently showed in vivo that the depletion of peripheral V H 3-expressing memory B cells, but not of naive B cells, in HIV-infected patients involves gp120 binding.…”

“…The B cells of HIV-infected patients spontaneously secrete Ig but are unable to mount a T cell-dependent B cell response (1,9,10). Antiretroviral therapy decreases HIV-1-driven B cell hyperactivity, polyclonal B cell activation, and Ig production in patients (11).…”

High-throughput antibody sequencing reveals genetic evidence of global regulation of the naïve and memory repertoires that extends across individuals

“…9,11 Further, alteration of this gene family homeostasis in the circulating B-cell repertoire is associated with disease states. [19][20][21][22] In recent work, long-lived plasma cells were shown to contain significantly fewer autoreactive B cells than the circulating IgG memory subset, and this difference was attributed to differential repertoire regulation within the two subsets. 23 Thus, although no mechanism for regulation of circulating human antibody repertoires has been identified, mounting indirect evidence, including the data presented in this report, suggests the presence of such regulation.…”

Longitudinal analysis of B cell repertoire and antibody gene rearrangements during early HIV infection

“…A role for humoral immunity in this process is supported by the common development of hypergammaglobulinemia in chronically infected individuals, associated with B cell hyperactivation, clonal expansions and deletions, and deficient costimulatory function. [1][2][3][4][5][6] It is unclear, however, if these abnormalities are the result of viremia and a direct effect of virus on B lymphocytes or, alternatively, mediated by long-term infectioninduced changes in T-cell subsets and cytokine production. To assess the early effect of HIV infection on the integrity of the peripheral B cell repertoires, we analyzed the B cellreceptor diversity in a longitudinal cohort of 10 affected individuals who had been treated with HAART immediately after diagnosis and 10 infected individuals who chose not to be treated.…”