Impaired Naive and Memory B-Cell Responsiveness to TLR9 Stimulation in Human Immunodeficiency Virus Infection

Abstract

Toll-like receptor 9 (TLR9) agonists such as unmethylated bacterial CpG DNAs activate B lymphocytes directly, potentially influencing their function and homeostasis. To assess B-cell responsiveness to TLR9 agonists in human immunodeficiency virus (HIV) disease, we examined the ability of naive and memory B cells to proliferation and to increase surface expression of CD80 in response to CpG oligonucleotides (ODN). CpG ODN induced expression of CD80 similarly in B cells from HIV-infected persons and from healthy controls. In contrast, proliferation responses to CpG ODN were markedly impaired in both naive and memory B-cell subsets from HIV-infected persons. Naive B-cell proliferation defects were related to plasma HIV RNA and, among memory B cells, to the frequencies of CD21-negative cells. Importantly, TLR9 mRNA levels were significantly diminished in freshly prepared naive B cells and especially so in memory B cells from HIV-positive viremic donors, suggesting a possible underlying mechanism for the observed functional impairments. Doseresponse studies indicated that optimal induction of CD80 expression was achieved with much lower concentrations of CpG ODN than optimal induction of proliferation. We propose that the relatively low threshold of activation that is required for CD80 induction by CpG ODN might explain the preservation of this response in B cells from HIV-infected persons despite diminished TLR9 expression. Impaired responsiveness to TLR9 agonists may contribute to defects in humoral immunity in HIV infection.

Loss of memory B cells during chronic HIV infection is driven by Foxo3a- and TRAIL-mediated apoptosis

“…Moreover, we found similar levels of proliferation in viable activated memory B cells from ST, EC, and HIV -subjects, as measured by CFSE dilution (Supplemental Figure 8). This is in accordance with results from previous studies (5,41,42), confirming that the decreased number of ASCs in ST subjects was not due to lower levels of proliferation but was the result of reduced survival of activated memory B cells.…”

“…These are manifested by polyclonal activation of undifferentiated naive B cells (1), induction of hypergammaglobulinemia (2), increased expression of activation markers (3), high frequencies of apoptotic cells (4), poor responsiveness to antigenic and mitogenic stimulation (5,6), and a progressive depletion of peripheral CD27 + memory B cells (7). Of note, this loss of memory B cells already occurs from the onset of acute infection (8,9).…”

Timing of HAART defines the integrity of memory B cells and the longevity of humoral responses in HIV-1 vertically-infected children

“…In this context, of particular interest is the observation that transitional B cells stimulated by CpG terminally differentiate into plasma cells producing natural antibodies with innate pneumoccoccal specificity (42). It has been recently shown that TLR9 responsiveness to CpG stimulation is diminished in HIV-1 disease (43). Despite these limitations, a positive but not significant trend of higher levels of pneumococcal antibody titers was observed in the early-treated group.…”

Relationship of Pneumocystis jiroveci Humoral Immunity to Prevention of Colonization and Chronic Obstructive Pulmonary Disease in a Primate Model of HIV Infection

“…Several studies of HIV ϩ patients report B-cell functional deficits and abnormalities that may contribute to poor responses to antigenic stimulation and result in their diminished vaccine responsiveness and increased susceptibility of opportunistic infections (12,28,37,39,61). The diminished humoral responses in HIV-infected individuals upon vaccination with carbohydrate antigens and T-independent antigens, such as the pneumococcal vaccine, may be due to a deficit in a particular subset of memory B cells, such as IgM memory cells (26) Several studies of HIV ϩ patients focus on recall responses to antigens or pathogens against which study participants have been vaccinated (37,61) or to antigens that they are not likely to be naturally exposed (i.e., tetanus toxoid) (13,26).…”