B cells in early and chronic HIV infection: evidence for preservation of immune function associated with early initiation of antiretroviral therapy

Abstract

IntroductionNumerous perturbations of B-cell phenotype and function have been described in HIV-infected individuals (reviewed in Cagigi et al 1 and Moir and Fauci 2 ). Phenotypic perturbations of B cells circulating in the peripheral blood include over-representation of activated, exhausted, and terminally differentiated B cells associated with HIV viremia 3-5 ; over-representation of immature/ transitional B cells associated with HIV-induced CD4 ϩ T-cell lymphopenia 6,7 ; and reduced representation of CD27 ϩ memory B cells associated with most stages of HIV infection. [8][9][10][11][12][13] Most of these studies, whether longitudinal or cross-sectional, have been conducted on chronically HIV-infected individuals, whereas only a few studies, generally with small sample sizes, have addressed the effect of duration of infection and initiation of antiretroviral therapy (ART) on perturbations of B-cell subpopulations in HIVinfected individuals. 9,14,15 Functional perturbations of B cells in HIV-infected individuals include hypergammaglobulinemia associated with polyclonal and HIV-specific activation of B cells induced by ongoing HIV replication, 15,16 as well as decreased B-cell responses to specific immunogens and non-HIV pathogens. 11,17,18 The latter is likely a reflection of both CD4 ϩ T-cell dependent and independent defects in B cells that arise in HIV-infected individuals, and especially in individuals with ongoing viral replication. Many of the functional B-cell defects described in HIV-viremic individuals can be improved with ART, although there is 1 important exception that has received relatively little attention. While B-cell responses against non-HIV antigens are either stabilized or increased after initiation of ART, 19-22 the reverse is often observed for B-cell responses against HIV antigens,15,23,24 suggesting that the humoral response against HIV is dependent on continuous HIV replication. In the most comprehensive study on B-cell responses after ART, Morris and colleagues described a rapid loss of HIV-specific B cells (actively secreting plasmablasts) during therapy, followed by a more gradual decrease in antibody titers against HIV in chronically infected individuals; the loss was even more rapid in early-treated individuals. 15 In a previous study of chronically HIV-infected individuals, we reported a reduction in B-cell numbers and the presence of perturbed B-cell subpopulations before initiation of ART followed by partial normalization 1 year after successful reduction in viremia by ART. 25 In a more recent study, 5 we identified a subpopulation of CD27 Ϫ tissue-like memory B cells within an abnormal CD21 lo B-cell compartment of the peripheral blood of chronically HIVviremic individuals; this subpopulation had been included within the activated B-cell compartment that we had previously described. 25 These CD27 Ϫ tissue-like memory B cells bore many features of exhausted cells, arising in the context of chronic immune activation, and with features that include expression of multiple inhibitory...

Humans with chronic granulomatous disease maintain humoral immunologic memory despite low frequencies of circulating memory B cells

“…12 The following fluorochromeconjugated monoclonal antibodies were used to stain and sort B cells: allophycocyanin (APC) anti-CD10, APC-H7 anti-CD20, PE-Cy5 anti-CD80, and PE anti-IgG (BD Biosciences); peridinin chlorophyll proteinCy5.5 anti-CD19 and PE-Cy7 anti-CD27 (eBioscience); FITC anti-CD21 (Beckman Coulter); FITC anti-IgA (Dako North America); and FITC anti-CD95, APC-IgM, V421 anti-CD27, PE-Cy7 anti-IgD, and PE anti-TACI (BioLegend). Cell sorting and immunophenotyping were performed on BD FACSAria II and BD FACSCanto II (BD Biosciences) flow cytometers, respectively.…”

“…18 Based on a five-subset definition of mature (CD10 Ϫ ) B-cell subsets, 12 increased resting (CD21 hi / CD27 ϩ ), activated (CD21 lo /CD27 ϩ ), tissue-like (CD21 lo /CD27 Ϫ ) memory, and plasmablast (CD20 Ϫ /CD21 lo /CD27 ϩϩ ) but not naive (CD21 hi /CD27 Ϫ ) B-cell counts were observed in HDs compared with CGD patients ( Figure 1B). These data further demonstrate the paucity of memory and terminally differentiated B cells in CGD patients; however, there was no increase in CD21 lo subsets that have been reported in other B-cell immunodeficiencies.…”

“…In vitro differentiation with polyclonal B-cell stimuli and ELISPOT were performed as previously described. 12 For functional analyses of B-cell subsets, B cells were isolated by negative selection and fractionated by CD27 as previously described. 12 …”

Immune responses during spontaneous control of HIV and AIDS: what is the hope for a cure?

“…Early treatment limits the establishment of viral reservoirs [206] and severely restricts viral diversity [207]. In addition, treatment initiation during primary infection has been shown to preserve CD4þ T cell homeostasis and the function of NK cells, B cells and HIV-specific T cells [55,145,208]. Therefore, early treatment may allow an optimal maturation of the anti-HIV response by reducing viraemia and inflammation, which may favour the control of infection after treatment interruption in some individuals with low levels of infected cells.…”

High HIV Prevalence Among Low-Income, Black Women in New York City with Self-Reported HIV Negative and Unknown Status

“…Understanding the factors associated with HIV infection among these women is important for developing interventions to target HIV testing and other initiatives for black women at high risk for infection, including efforts to prevent infection among the uninfected and promote early linkage to care and improved patient outcomes for those who are HIV infected. 13,14 Materials and Methods…”