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. Author manuscript; available in PMC: 2009 Jul 10.
Published in final edited form as: J Allergy Clin Immunol. 2008 Jun 10;122(1):12–21. doi: 10.1016/j.jaci.2008.04.034

Pathogenic mechanisms of B-lymphocyte dysfunction in HIV disease

Susan Moir 1, Anthony S Fauci 1
PMCID: PMC2708937  NIHMSID: NIHMS101511  PMID: 18547629

Abstract

HIV disease is associated with abnormalities in all major lymphocyte populations, including B cells. Aberrancies in the B-cell compartment can be divided into 3 broad categories: changes that arise as a result of HIV-induced immune activation, changes that arise as a result of HIV-induced lymphopenia, and changes that arise independently of these 2 parameters. We review recent developments in all 3 categories of abnormalities and highlight how observations made in the early years of the HIV epidemic are better understood today in large part because of the advent of effective antiretroviral therapy. Insight into the mechanisms of B-cell dysfunction in HIV disease has also been achieved as a result of increased knowledge of the B-cell subpopulations as they exist in healthy individuals, compared with their abnormalities in HIV-infected individuals. A better understanding of the pathogenic mechanisms of B-cell abnormalities in HIV disease can potentially lead to new strategies for improving antibody responses against opportunistic pathogens that afflict HIV-infected individuals and against HIV itself, in the context of both HIV infection and an antibody-based HIV vaccine.

Keywords: HIV, B cells, immunopathogenesis, immune activation, lymphopenia, apoptosis

HIV infection leads to persistent viral replication, immune activation, loss of CD4+T cells, and disease progression in a majority of infected individuals who do not receive antiretroviral therapy (ART). Although CD4+T cells represent the primary target for HIV in terms of both direct and indirect effects of viral replication, varying degrees of perturbations related to HIV infection are observed in virtually all lymphocyte populations.1–4 Apart from the obvious CD4+ T lymphocytopenia, B cells were among the first dysfunctional lymphocyte populations to be described in patients with AIDS.5 These initial observations revealed that patients with AIDS exhibited hypergammaglobulinemia, and their B cells showed evidence of polyclonal B-cell hyperactivity in vivo, yet poor responsiveness to neoantigens in vivo and B-cell stimuli in vitro.5 These observations were seminal in establishing the concept that HIV disease leads to defects in B-cell function despite intense polyclonal B-cell activation.

Before the era of effective ART, insight into mechanisms of B-cell pathogenesis in HIV-infected individuals proved to be difficult because of the paucity of adequate controls of aviremic HIV-infected individuals; in addition, the process could not easily be modeled in vitro. The advent of effective ART in the mid 1990s not only provided a means of slowing and reversing disease progression but also provided new opportunities for investigating mechanisms of HIV pathogenesis longitudinally in the same patient during viremia and after therapy-induced suppression of virus replication. In this regard, the majority of advances regarding mechanisms of B-cell pathogenesis in HIV disease have been based on longitudinal as well as cross-sectional studies that compare the effects of ART on B cells. This review focuses on these studies by addressing the direct and indirect effects of HIV on B cells, the phenotypic and functional alterations of B cells associated with ongoing viral replication and CD4+ T-cell lymphopenia, and changes in B cells that appear to be independent of ongoing viral replication. The delineation of mechanisms of B-cell pathogenesis associated with various stages of HIV disease may help address some of the clinical consequences of B-cell dysfunction, including the increased incidence of B-cell neoplasms, increased autoimmune manifestations, and decreased humoral responses to specific antigens.

B-CELL HYPERACTIVATION IN HIV DISEASE

Many features of B-cell dysregulation in HIV disease suggest a prominent role for aberrant immune activation. These features include elevated serum levels of immunoglobulins and autoantibodies,6 extensive expansion in B-cell areas of lymphoid tissue,7,8 and an increased expression of activation, proliferation, and terminal differentiation markers on circulating B cells.5,9–11 As illustrated in Fig 1 and in data not shown, terminal differentiation of B cells is associated with a loss in the expression of CD20 and CD21, an increase in the size of B cells with prominent plasmacytoid features, and an increase in the expression of CD38 and CD27. In addition, HIV-induced immune activation of B cells is thought to be a contributing factor to the increased frequency of B-cell malignancies observed in HIV-infected individuals, which were especially observed before the widespread use of effective ART.12 Evidence for B-cell hyperactivity as a direct consequence of ongoing HIV replication came from studies demonstrating that many of the features associated with B-cell hyperactivity become attenuated after the reduction of HIV plasma viremia by ART.10,13–16 One of the first studies to illustrate this point clearly used both longitudinal and cross-sectional approaches to demonstrate that ART decreased both hypergammaglobulinemia and the frequency of B cells in the blood that spontaneously secreted immunoglobulins.17 An increased frequency of B cells undergoing terminal differentiation, as evidenced by phenotypic, functional, and morphologic changes consistent with the differentiation of B cells into plasma cells (Fig 1), has also been linked to HIV viremia.9 In addition, DNA microarray analyses performed on B cells isolated from HIV-viremic, HIV-aviremic, and HIV-negative individuals revealed that 24% of the genes found to be upregulated in HIV-viremic individuals but not the other 2 groups were associated with B-cell terminal differentiation (Fig 1).18 In this study, the potentially confounding effects of CD4+ lymphopenia in HIV-viremic individuals were controlled for by recruiting HIV-viremic and HIV-aviremic individuals with similar CD4+ T-cell counts. These findings thus underscore the direct role of HIV viremia in B-cell terminal differentiation. Of note, and as discussed in more detail below (see “Changes in B-cell subpopulations in HIV disease”), advanced HIV disease and profound CD4+ T-cell lymphopenia is associated with a waning of HIV-induced immune activation19 and a shift toward overexpression of immature/transitional B cells.20

FIG 1.

FIG 1

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Phenotypic and genotypic aberrancies associated with HIV viremia. A, Phenotypic profile of peripheral blood–derived B cells isolated from representative HIV-negative and HIV-viremic individuals illustrating decreased CD21 expression on B cells of the HIV-viremic individual. B, Electron micrograph illustrating presence of cells with plasmacytoid features in the CD21lo B-cell fraction of a representative HIV-viremic individual. Micrograph originally appeared in Moir S, Malaspina A, Ogwaro KM, Donoghue ET, Hallahan CW, Ehler LA, et al. HIV-1 induces phenotypic and functional perturbations of B cells in chronically infected individuals. Proc Natl Acad Sci U S A 2001;98:10362–7.9 C, Main findings from DNA microarray analyses performed on blood-derived B cells isolated from HIV-viremic individuals and compared with B cells isolated from HIV-aviremic and HIV-negative individuals.18 BCMA, B-cell maturation protein; IFI, IFN-induced family of genes; ISG, IFN-stimulated gene.

DIRECT INTERACTIONS BETWEEN HIV AND B CELLS

Although there is little evidence that HIV productively infects B cells in vivo, we have shown that B cells isolated from the blood and lymph nodes of HIV-infected individuals carry replication-competent virus on their surface.21 The interaction is mediated primarily through the binding of complement-opsonized HIV virions to CD21 expressed on the surface of B cells. These findings are consistent with other in vivo and in vitro studies demonstrating a prominent role for CD21 in the trapping of HIV virions coated with antibody and complement,22 the form of virus that is likely to predominate in vivo. The potential consequences of the direct binding of HIV to B cells include enhanced infectivity through virologic cross-talk between virion-bound B cells and target CD4+ T cells,23 and potential effects on B-cell responses stemming from the triggering of CD21 by bound virions.24,25 However, given the relatively low frequency of B cells carrying HIV in infected individuals contrasted with the high frequency of B-cell dysfunction, it is likely that B-cell dysfunction is predominantly driven by indirect effects of HIV on B cells. It is noteworthy that similar arguments have been made with regard to direct and indirect effects of HIV on CD4+ T cells.3

HIV has also been shown to bind to B cells through superantigen interactions between the viral envelope gp120 and the immunoglobulin variable heavy-chain family member 3 (VH3).26 Some investigators have shown depletion of VH3-expressing B cells in HIV-infected individuals,27 whereas others have either not confirmed these findings or found defects in the VH3 repertoire that appear unrelated to interactions with gp120.28,29 Furthermore, few studies were performed in the era of effective ART, and thus, evidence of changes in VH3-expressing B cells relative to ongoing viral replication and disease progression is lacking.

CHANGES IN B-CELL SUBPOPULATIONS IN HIV DISEASE

Many of the B-cell aberrations that have been reported in HIV disease are likely to reflect alterations in the frequencies of the various subpopulations of B cells that are present in the human body, or at least that are detectable in the peripheral blood (Table I). Given that the vast majority of these studies have been performed on B cells isolated from the peripheral blood, we restrict our comments to alterations in this compartment. Naive B cells constitute the largest B-cell subpopulation in the blood, followed by memory B cells, the frequency of which varies considerably among healthy individuals, yet appears to be surprisingly constant over time for a given healthy individual. Several studies have shown that the frequency of memory B cells is decreased in HIV-infected individuals.30,31 However, several confounding factors should be considered, in addition to the high variability among healthy donors that inherently makes it more difficult to compare groups of HIV-infected and HIV-negative individuals. Human memory B cells are most commonly defined by the expression of the CD27 cell-surface marker. However, CD27 is also a marker of B-cell activation and terminal differentiation,32 2 features that are overrepresented in HIV disease and not generally considered to represent true memory,33 especially given the short lifespan of most activated and differentiated lymphocyte populations circulating in the blood. Accordingly, additional markers should be included in studies on HIV-infected individuals to distinguish between resting memory B cells and other activated/differentiated subpopulations of B cells that also express CD27. One such marker is CD21, which can be used to distinguish between activated/differentiated (CD21lo) and resting (CD21hi) B cells (Fig 1). B cells undergoing terminal differentiation also lose expression of CD20 and express reduced levels of CD19, 2 additional features that need to be considered when assessing the totality of B cells expressing CD27, especially in HIV-viremic individuals. In these individuals, it is common to find similar levels of CD27 expression on both CD21lo and CD21hi B cells,18 and a total CD27 percentage that is not significantly different than the average 35% to 40% of CD27+ B cells in HIV-negative individuals.34 The significant differences arise once HIV-viremic individuals initiate ART. The CD27 component on activated B cells decreases substantially as these cells disappear because aberrant immune activation diminishes with therapy, whereas the CD27 component on resting B cells increases slightly.35 However, the percentage and number of CD27-expressing resting B cells (classic resting memory B cells) remain low in ART-treated individuals.30,36,37 Of note, there are also indications that early treatment of ART may prevent loss of memory B cells.38

TABLE I.

Alterations in B-cell subpopulations associated with HIV infection

Subpopulation Phenotype Properties In HIV disease Reversed by ART References
Immature/transitional CD10+/27−

  • High susceptibility to intrinsic apoptosis

  • Low proliferative response

 Expansion associated with lymphopenia and increased IL-7 Yes 20, 43, 48
Activated/mature CD21lo/10−

  • High susceptibility to extrinsic apoptosis

  • Plasmacytoid features

  • Spontaneous secretion of immunoglobulins

  • Increased expression of Ki-67

 Expansion associated with immune activation Yes 9, 15–18, 48
Resting/memory CD21hi/27+

  • Long-lived

  • Induced response to antigen

 Contraction No 30, 31, 35–37, 63–65
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Several B-cell subpopulations that are normally present at low frequencies in the peripheral blood of healthy individuals are expanded in HIV-infected individuals (Table I). Whereas the percentage of plasma cells (CD20−/CD21lo/CD27++/CD38+++) circulating in the blood of healthy individuals is typically below 1%, this percentage is increased several-fold in HIV-viremic individuals.18 In addition to plasma cells, mature/activated B cells, which have a similar phenotype to the recently described tonsil-derived memory B cells (CD20++/CD21lo/CD27−/+/CD38−/+),39 are overrepresented in the peripheral blood of HIV-viremic individuals (Fig 1).40 The percentage of these B cells is typically below 5% in healthy individuals and HIV-infected aviremic individuals, compared with more than 25% in HIV-viremic individuals. In a recent longitudinal study on chronically HIV-infected individuals,35 we found that before ART, the mean percentage of activated and terminally differentiated B cells in the peripheral blood was 29%. After 1 year of effective ART, that percentage dropped to 12%.

Finally, we and others have recently characterized immature/transitional B cells in the peripheral blood of healthy individuals and found their frequency to be significantly increased in various disease settings of immune deficiencies, including HIV infection (Table I).20,41,42 This subpopulation of B cells can be defined by the expression of CD10 in the absence of CD27. B cells coexpressing CD10 and CD27 represent mature germinal center B cells that normally circulate in the blood at a frequency of approximately 2%, a percentage that is not affected by disease status.20 In contrast, immature/transitional B cells account for more than 30% of peripheral blood B cells in active HIV disease, compared with approximately 10% in healthy individuals.20 In addition, this immature/transitional B-cell subpopulation can be further divided into less immature (CD21hi/CD10+) and a more immature (CD21lo/CD10++) B cells, the latter of which are rarely observed in the blood of healthy individuals, yet are very common in HIV-infected individuals with advanced disease. These individuals typically have very low CD4+T-cell counts. A similar expansion of immature/transitional B cells in individuals with idiopathic CD4+ T lymphocytopenia indicates that CD4+ T-cell lymphopenia in HIV disease drives the overrepresentation of immature/transitional B cells and not HIV viremia per se.43 The association between immature/transitional B cells and CD4+ T-cell lymphopenia also correlates with increased serum levels of IL-7, a cytokine involved in homeostatic compensation of lymphocyte subsets in HIV disease.44,45

INCREASED B-CELL DEATH IN HIV DISEASE

Cell death by apoptosis is an important component of immune activation and lymphocyte depletion in HIV disease.46 Two major pathways of apoptosis exist: the intrinsic pathway arises from an insufficiency in survival factors that result in mitochondrial-driven apoptosis, whereas the extrinsic pathway arises from the triggering of a death receptor.47 In HIV disease, both these pathways likely contribute to increased B-cell death,18,48 and B-cell depletion that we and others have documented.35,49,50 On the one hand, immature/transitional B cells are highly susceptible to intrinsic apoptosis as a result of low expression of members of the Bcl-2 family associated with survival, including Bcl-2 and Bcl-xL (Fig 2).48 On the other hand, mature/activated B cells are highly susceptible to extrinsic apoptosis as a result of increased expression of CD95 and increased apoptosis in the presence of CD95 ligand (Fig 2).18,48 Considering that both immature/transitional and mature/activated B cells are overrepresented in HIV-infected individuals with ongoing viral replication and that effective ART results in a decrease in these overrepresented apoptosis-prone B-cell subpopulations concomitant with an increase in B-cell numbers,35 it is fair to suggest that the B-cell lymphopenia observed in HIV disease is in part a result of increased B-cell death by apoptosis.

FIG 2.

FIG 2

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HIV disease is associated with increased B-cell turnover and increased B-cell death by intrinsic and extrinsic apoptosis. A, Identification of B-cell subpopulations in the peripheral blood of a representative HIV-infected individual with active disease. B, Increased expression of CD95 on CD10−/CD21lo mature/activated B cells correlates with increased susceptibility to CD95-mediated extrinsic apoptosis. C, CD10−/CD21lo mature/activated B cells also express increased levels of the cell-cycling marker Ki-67. Decreased expression of (D) Bcl-2 and (E) Bcl-xL in CD10+ immature/transitional B cells is associated with increased susceptibility to intrinsic apoptosis. These profiles originally appeared in Ho J, Moir S, Malaspina A, Howell ML, Wang W, DiPoto AC, et al. Two overrepresented B cell populations in HIV-infected individuals undergo apoptosis by different mechanisms. Proc Natl Acad Sci U S A 2006;103:19436–41.48 Max, Maximum.

The high levels of immune activation and cell turnover induced by ongoing HIV replication contribute to increased cell death by extrinsic apoptosis. In HIV and SIV disease, increased cell turnover is well documented for CD4+ and CD8+ T cells and to a lesser extent for B cells.51–56 Within the B-cell compartment, mature/activated B cells express increased levels of the cell cycle marker Ki-67 (Fig 2),48 suggesting that this subpopulation of B cells arises as a result of HIV-induced B-cell turnover. In addition, mature/activated B cells express increased levels of activation markers, including CD80, CD86, and CD38, collectively suggesting that these would be the cells most prone to proliferation-induced and activation-induced extrinsic apoptosis. Of the numerous death receptors that can mediate extrinsic apoptosis, CD95 was the most overexpressed death receptor on B cells of HIV-viremic individuals, as determined by DNA microarray analysis.18 CD95 is also one of many genes shown to be induced after type I IFN treatment.57 Given that IFN-induced genes are prominently featured in the list of genes upregulated in HIV infection, which includes the genes in B cells of HIV-viremic individuals,18 it is not surprising that CD95 is among these upregulated genes. Phenotypic analyses have also revealed that the increase in CD95 expression is concentrated on mature/activated B cells, the same B-cell subpopulation expressing increased levels of Ki-67 and activation markers. Furthermore, functional analyses have demonstrated that levels of CD95 expression on B cells of HIV-infected individuals correlate with susceptibility to CD95 ligand–mediated apoptosis and that this extrinsic form of apoptosis is directly correlated to HIV viremia.18 Collectively, the data from our studies and other reports strongly suggest that ongoing HIV replication is associated with the appearance of apoptosis-prone subpopulations of B cells that arise from increased cell turnover and activation.18,38,48,58,59 On balance, these events are likely to contribute to B-cell lymphopenia in the peripheral blood of HIV-viremic individuals that we and others have reported.35,49,50

FUNCTIONAL ALTERATIONS OF B CELLS IN HIV DISEASE

The effects of HIV infection on B-cell function can be divided into 2 broad categories. The first category relates to changes that directly reflect in vivo phenomena, such as hypergammaglobulinemia, increased autoantibody levels, and poor antibody responses to specific antigens. The second category relates to changes that are inferred from ex vivo analysis of B cells isolated from HIV-infected individuals. There have been substantial advances in the latter category over the period of the past 25 years as new techniques and a better understanding of B-cell development have helped to dissect the various elements of HIV-induced B-cell dysfunction.

Several studies have confirmed the early observation that although B cells of HIV-infected individuals with active disease exhibit numerous signs of increased activation in vivo, they respond poorly ex vivo to B-cell stimuli.5 All the early ex vivo observations were based on analyses performed on unfractionated B-cells, and the precise effects of HIV viremia were difficult to assess. With more recent data based on B-cell fractionation and control of HIV viremia by ART, the early observations can now best be explained by HIV viremia inducing the expansion of terminally differentiated B cells with secretion of high levels of immunoglobulins, loss of responsiveness to stimuli, and a high propensity to cell death.9,18 In addition, the overrepresentation of immature/transitional B cells, especially in patients with advanced CD4+ T-cell lymphopenia, can also help explain the unresponsiveness of B cells ex vivo to B-cell stimuli because immature/transitional B cells have been shown to respond poorly to stimulation and to die rapidly by intrinsic apoptosis.20,48 Given that more than 50% of peripheral blood B cells isolated from chronically HIV-viremic individuals are composed of immature/transitional and mature/activated B-cell subpopulations,35 such a skewing of the B-cell compartment provides a compelling explanation for the poor overall B-cell responses that have been reported in vivo and ex vivo.

Loss of B-cell function can also be investigated by reconstituting the events of cognate interactions that occur between B cells and CD4+ T cells after antigenic stimulation. Once stimulated, B cells acquire antigen-presenting cell capacities, which then enable them to provide help to CD4+ T cells. This occurs in part through stimulatory interactions between CD80/CD86 receptors, which are upregulated after B-cell activation, and CD28 on responder CD4+T cells.60 B-cell antigen-presenting cell function is inefficient in HIV-viremic individuals, as evidenced by the inability of activated B cells to provide CD80/CD86-mediated stimulatory signals to autologous CD4+T cells.61 Furthermore, CD4+ T-cell help given to B cells has also been shown to be defective in HIV-viremic individuals as a result of an impaired interaction between CD40 ligand on the T cells and CD40 on the B cells.62 In both of these studies, the reduction of HIV plasma viremia by ART was associated with a normalization of responses resulting from bidirectional interactions between B cells and CD4+T cells. Given that normalization of the representation of B-cell subpopulations also occurs during ART, it is reasonable to suggest that impaired bidirectional interactions between B cells and CD4+ T cells in HIV-viremic individuals are at least in part a result of skewing toward unresponsive B-cell subpopulations.

One aspect of B-cell dysfunction in HIV disease that does not appear to be normalized by ART is the loss of memory B cells. This loss correlates with a reduced frequency of immunogen-specific memory B cells after immunization in HIV-infected individuals that does not normalize with ART.63,64 Many of these reported defects in antigen-specific memory B-cell responses, particularly those that are T-cell–dependent, might result from defects in the CD4+ T-cell compartment of HIV-infected individuals. However, there is also evidence for memory B-cell deficiencies in HIV-infected individuals against CD4+ T-cell–independent immunogens such as pneumococcal polysaccharides.65 These defects have been associated with a reduced frequency of IgM+ memory B cells, the subpopulation of B cells thought to be important for memory B-cell responses against pneumococcal infection.66 In pediatric HIV infection, deficiencies in B cells and humoral responses to various childhood vaccines have also been described. Decline in CD19+ B-cell counts has been reported in pediatric HIV disease, and there are some indications that an irreversible loss of CD27+ memory B cells also occurs in pediatric HIV infection. 49,67,68 These observations are consistent with poor antibody and B-cell memory responses in pediatric HIV infection to both T-cell–dependent and T-cell–independent antigens that are not fully reversed by ART.69,70 These observations may also help explain the high risk of bacterial infections that is seen in pediatric HIV disease.69,71,72 Thus, several defects in the memory B-cell compartment of HIV-infected individuals appear to occur independently of ART. However, one open question is whether initiation of ART during acute HIV infection rather than after prolonged periods of viremia can prevent the lost of memory B-cell frequency and function.

Finally, one very important aspect of B-cell function in HIV disease that has received relatively little attention is the induction of HIV-specific B cells in infected individuals. High frequencies of B cells actively secreting antibodies against HIV are observed in the peripheral blood of HIV-viremic individuals, along with high levels anti-HIV antibodies in the serum.11,17 However, as polyclonal B-cell activation and hypergammaglobulinemia decrease with the reduction of HIV viremia by ART, so do frequencies of HIV-specific B cells and anti-HIV antibodies. Given the strong indications from SIV models that antibodies can contribute to the control of viral replication,73–75 it is important to understand the mechanisms involved in the rise and fall of HIV-specific B-cell responses in infected individuals and whether early intervention can lead to an effective antibody response. Ideally, insights from these observations can help in the design of an effective antibody-based HIV vaccine. Vaccine strategies that elicit B cells to produce broadly neutralizing antibodies against HIV are being investigated, along with a variety of approaches that fall beyond the scope of this review (see reviews76,77). The characterization of broadly neutralizing antibodies isolated from HIV-infected individuals and related advances in immunogen design represent some of the more recent approaches being considered for an antibody-based HIV vaccine.78–80 However, whether the elusive process by which neutralizing anti-HIV B-cell responses arise in infected individuals can be reproduced with a vaccine strategy remains to be determined.

CONCLUSION

In summary, HIV infection in a majority of untreated individuals leads to persistent viral replication and progressive CD4+ T-cell lymphopenia. Persistent HIV replication is associated with increased immune activation that manifests itself in the B-cell compartment as hypergammaglobulinemia, polyclonal B-cell activation, induction of terminal differentiation of B cells, increased levels of autoantibodies, and increased frequency of B-cell malignancies. CD4+ T cell lymphopenia and increased serum levels of IL-7 in HIV-infected individuals with advancing disease are associated with an expansion of immature/transitional B cells. In addition, HIV infection is associated with a decrease in CD27+ resting memory B cells. The overall effect of these changes in the B-cell compartment is a decreased capacity to proliferate in response to B-cell stimuli, a decreased capacity to respond to neoantigens and recall antigens, and a decreased capacity to generate antigen-specific memory B cells.

Future efforts should include the following: 1) evaluating whether early initiation of ART leads to a normalization of memory B-cell function in HIV-infected individuals, 2) increasing our understanding of the anti-HIV antibody response relative to B-cell function, and 3) evaluating new vaccine strategies aimed at enhancing antibody responses to a variety of immunogens in immunocompromised, HIV-infected individuals. These strategies include the addition of adjuvants such as Toll-like receptor agonists, which may both lower the response threshold to immunogens and modulate the quality of the response. As individuals living with HIV grow older, it will become important to consider these strategies in light of an immune system that is affected by both HIV and age. Finally, there are also concerns that rates of cancer, including those of B-cell origin, remain high in the HIV-infected population, indicating the need for a better understanding of pathways of immune surveillance and regulation in HIV disease.

Acknowledgments

The Editors wish to acknowledge Seema Aceves, MD, PhD, for preparing this glossary.

Abbreviations

ART

Antiretroviral therapy

VH3

Variable heavy-chain family member 3

GLOSSARY

B-CELL TERMINAL DIFFERENTIATION

B-cell development can be simplified as (1) proB, H-chain rearrangement begins

(2) preB

H-chain rearrangement complete, pre–B-cell receptor expressed

(3) immature B

H and L–chain rearrangement complete, surface IgM expressed

(4) mature B

surface IgM and IgD expressed

(5) activated B cells

antigen responsive

(6) plasma cells

no longer express surface immunoglobulin but secrete large quantities of antibody. Memory B cells are generated in germinal centers, are CD20+CD27+, and can rapidly differentiate into plasma cells

CD10

CD10 is also known as the common acute lymphoblastic leukemia antigen (CALLA) and is expressed on early lymphoid precursors, as well as some epithelial cells, and neutrophils. CD10 can be a marker associated with cancers of the skin, pancreas, and kidney

CD19

An immunoglobulin superfamily member, CD19 is present on B-cell precursors and mature B cells but decreased on plasma cells. CD9 can be considered a marker of B-cell maturation

CD20

CD20 is a calcium channel protein present on B cells but not plasma cells that is involved in B-cell activation and proliferation. Rituximab targets CD20 and is used to treat non-Hodgkin lymphoma, rheumatoid arthritis, and other autoimmune disorders such as autoimmune cytopenias and SLE

CD21

Also known as complement receptor 2, CD21 is present on mature B cells and binds complement fragment C3d as well as EBV. CD21 is involved in B-cell proliferation and activation and IgE production on interaction with CD23 (the low-affinity IgE receptor)

CD27

CD27 is a TNF-α receptor family member present on activated and memory B cells and plasma cells that mediates costimulatory signals. HIV-infected individuals can have specific deficiency of CD27+ memory B cells, especially IgM memory B cells. This finding could correlate with poor polysaccharide response seen in HIV-positive patients

CD80/86:CD28, CD40:CD40 ligand

Interactions between T cells and B cells or antigen-presenting cells that are required for T-cell activation can occur through CD80/86:CD28 or CD40:CD40L. T cells that do not get a second (or costimulatory) signal become anergic. CD40 is expressed on mature B cells, and CD40 signaling results in increased CD80/86 expression with subsequent interaction with CD28 and signaling through the phosphatidylinositol (PI) 3 kinase–Ras–mitogen-activated protein kinase pathway. CD40 triggering of B cells is essential for their ability to class-switch and make high-affinity antibodies. Blockade of the CD80/86 with abatacept or belatacept is used in treating autoimmune diseases such as rheumatoid arthritis and transplant rejection

CD95,CD95 ligand

CD95 and CD95L are also known as Fas and Fas ligand, respectively. CD95 is expressed mainly on activated T cells, B cells, and eosinophils and is a member of the TNF receptor superfamily. The ability to induce apoptosis lies in the death domain. Binding of Fas-associated death domain (FADD) protein recruits caspase 8 and caspase 10, which are proapoptotic signaling molecules to the death-induced signaling complex (DISC). Mutations in Fas, Fas ligand, caspase 10, and caspase 8 are associated with immune deficiency associated with auto-immunity syndromes, autoimmune lymphoproliferative syndrome 1a, 1b, 2a, and 2b

DNA MICROARRAY

Also known as gene chips, DNA microarrays look simultaneously at changes in expression in a large number of genes. DNA oligonucleotides are fixed on a solid matrix. mRNA is reverse-transcribed to cDNA and incubated with the array

gp120

Initial binding of HIV to target cells occurs via gp120 and CD4. Binding results in a conformational change in the viral envelope, exposing binding sites for other coreceptors involved in viral entry. Essential chemokine coreceptor CCR5 or CXCR4 interacts with HIV, which allows the envelope protein gp41 to complete viral-host cell membrane fusion

IL-7

A proliferation signal for T and B cells, IL-7 signals through the IL-7 receptor, which is composed of the IL-7 receptor α and the common gamma chain (γc). The γc is also used by IL-2, IL-4, IL-9, IL-15, IL-21, and IL-46, and mutations in γc as well as in the IL-7 receptor lead to severe combined immunodeficiency. IL-7 promotes the survival of lymphocytes by regulating the Bcl-2 family of proapoptotic and antiapoptotic factors and may be therapeutically useful in conditions associated with lymphopenia

SUPERANTIGEN

B-cell superantigens interact with immunoglobulin outside of the antigen binding site and are capable of activating large numbers of B cells, resulting in a polyclonal response. Superantigens for B cells include Staphylococcus aureus protein A and HIV gp120. Super-antigens for T cells bind to the Vβ region of the T-cell receptor and crosslink it to MHC independent of specific antigen recognition

References

  • 1.De Milito A. B lymphocyte dysfunctions in HIV infection. Curr HIV Res. 2004;2:11–21. doi: 10.2174/1570162043485068. [DOI] [PubMed] [Google Scholar]
  • 2.Fauci AS, Mavilio D, Kottilil S. NK cells in HIV infection: paradigm for protection or targets for ambush. Nat Rev Immunol. 2005;5:835–43. doi: 10.1038/nri1711. [DOI] [PubMed] [Google Scholar]
  • 3.Grossman Z, Meier-Schellersheim M, Paul WE, Picker LJ. Pathogenesis of HIV infection: what the virus spares is as important as what it destroys. Nat Med. 2006;12:289–95. doi: 10.1038/nm1380. [DOI] [PubMed] [Google Scholar]
  • 4.Papagno L, Spina CA, Marchant A, Salio M, Rufer N, Little S, et al. Immune activation and CD8+ T-cell differentiation towards senescence in HIV-1 infection. PLoS Biol. 2004;2:E20. doi: 10.1371/journal.pbio.0020020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Lane HC, Masur H, Edgar LC, Whalen G, Rook AH, Fauci AS. Abnormalities of B-cell activation and immunoregulation in patients with the acquired immunodeficiency syndrome. N Engl J Med. 1983;309:453–8. doi: 10.1056/NEJM198308253090803. [DOI] [PubMed] [Google Scholar]
  • 6.Ng VL. B-lymphocytes and autoantibody profiles in HIV disease. Clin Rev Allergy Immunol. 1996;14:367–84. doi: 10.1007/BF02771753. [DOI] [PubMed] [Google Scholar]
  • 7.Racz P, Tenner-Racz K, van Vloten F, Schmidt H, Dietrich M, Gluckman JC, et al. Lymphatic tissue changes in AIDS and other retrovirus infections: tools and insights. Lymphology. 1990;23:85–91. [PubMed] [Google Scholar]
  • 8.Pantaleo G, Graziosi C, Demarest JF, Cohen OJ, Vaccarezza M, Gantt K, et al. Role of lymphoid organs in the pathogenesis of human immunodeficiency virus (HIV) infection. Immunol Rev. 1994;140:105–30. doi: 10.1111/j.1600-065x.1994.tb00867.x. [DOI] [PubMed] [Google Scholar]
  • 9.Moir S, Malaspina A, Ogwaro KM, Donoghue ET, Hallahan CW, Ehler LA, et al. HIV-1 induces phenotypic and functional perturbations of B cells in chronically infected individuals. Proc Natl Acad Sci U S A. 2001;98:10362–7. doi: 10.1073/pnas.181347898. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Fournier AM, Fondere JM, Alix-Panabieres C, Merle C, Baillat V, Huguet MF, et al. Spontaneous secretion of immunoglobulins and anti-HIV-1 antibodies by in vivo activated B lymphocytes from HIV-1-infected subjects: monocyte and natural killer cell requirement for in vitro terminal differentiation into plasma cells. Clin Immunol. 2002;103:98–109. doi: 10.1006/clim.2001.5195. [DOI] [PubMed] [Google Scholar]
  • 11.Shirai A, Cosentino M, Leitman-Klinman SF, Klinman DM. Human immunodeficiency virus infection induces both polyclonal and virus-specific B cell activation. J Clin Invest. 1992;89:561–6. doi: 10.1172/JCI115621. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Martinez-Maza O, Breen EC. B-cell activation and lymphoma in patients with HIV. Curr Opin Oncol. 2002;14:528–32. doi: 10.1097/00001622-200209000-00009. [DOI] [PubMed] [Google Scholar]
  • 13.Chong Y, Nabeshima S, Furusyo N, Murata M, Yamaji K, Hayashi J. Downregulation of CXCR5 in CD27- B cells of HIV-1 infected patients. J Med Virol. 2004;73:362–7. doi: 10.1002/jmv.20099. [DOI] [PubMed] [Google Scholar]
  • 14.Jacobson MA, Khayam-Bashi H, Martin JN, Black D, Ng V. Effect of long-term highly active antiretroviral therapy in restoring HIV-induced abnormal B-lymphocyte function. J Acquir Immune Defic Syndr. 2002;31:472–7. doi: 10.1097/00126334-200212150-00003. [DOI] [PubMed] [Google Scholar]
  • 15.Nilssen DE, Oktedalen O, Brandtzaeg P. Intestinal B cell hyperactivity in AIDS is controlled by highly active antiretroviral therapy. Gut. 2004;53:487–93. doi: 10.1136/gut.2003.027854. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Notermans DW, de Jong JJ, Goudsmit J, Bakker M, Roos MT, Nijholt L, et al. Potent antiretroviral therapy initiates normalization of hypergammaglobulinemia and a decline in HIV type 1-specific antibody responses. AIDS Res Hum Retroviruses. 2001;17:1003–8. doi: 10.1089/088922201300343681. [DOI] [PubMed] [Google Scholar]
  • 17.Morris L, Binley JM, Clas BA, Bonhoeffer S, Astill TP, Kost R, et al. HIV-1 antigen-specific and -nonspecific B cell responses are sensitive to combination antiretroviral therapy. J Exp Med. 1998;188:233–45. doi: 10.1084/jem.188.2.233. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Moir S, Malaspina A, Pickeral OK, Donoghue ET, Vasquez J, Miller NJ, et al. Decreased survival of B cells of HIV-viremic patients mediated by altered expression of receptors of the TNF superfamily. J Exp Med. 2004;200:587–99. [PubMed] [Google Scholar]
  • 19.Margolick JB, Munoz A, Donnenberg AD, Park LP, Galai N, Giorgi JV, et al. Failure of T-cell homeostasis preceding AIDS in HIV-1 infection. The Multicenter AIDS Cohort Study. Nat Med. 1995;1:674–80. doi: 10.1038/nm0795-674. [DOI] [PubMed] [Google Scholar]
  • 20.Malaspina A, Moir S, Ho J, Wang W, Howell ML, O’Shea MA, et al. Appearance of immature/transitional B cells in HIV-infected individuals with advanced disease: correlation with increased IL-7. Proc Natl Acad Sci U S A. 2006;103:2262–7. doi: 10.1073/pnas.0511094103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Moir S, Malaspina A, Li Y, Chun TW, Lowe T, Adelsberger J, et al. B cells of HIV-1-infected patients bind virions through CD21-complement interactions and transmit infectious virus to activated T cells. J Exp Med. 2000;192:637–46. doi: 10.1084/jem.192.5.637. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Stoiber H, Speth C, Dierich MP. Role of complement in the control of HIV dynamics and pathogenesis. Vaccine. 2003;21(suppl 2):S77–82. doi: 10.1016/s0264-410x(03)00203-2. [DOI] [PubMed] [Google Scholar]
  • 23.Malaspina A, Moir S, Nickle DC, Donoghue ET, Ogwaro KM, Ehler LA, et al. Human immunodeficiency virus type 1 bound to B cells: relationship to virus replicating in CD4+ T cells and circulating in plasma. J Virol. 2002;76:8855–63. doi: 10.1128/JVI.76.17.8855-8863.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Rickert RC. Regulation of B lymphocyte activation by complement C3 and the B cell coreceptor complex. Curr Opin Immunol. 2005;17:237–43. doi: 10.1016/j.coi.2005.03.001. [DOI] [PubMed] [Google Scholar]
  • 25.Dorner T, Radbruch A. Antibodies and B cell memory in viral immunity. Immunity. 2007;27:384–92. doi: 10.1016/j.immuni.2007.09.002. [DOI] [PubMed] [Google Scholar]
  • 26.Berberian L, Goodglick L, Kipps TJ, Braun J. Immunoglobulin VH3 gene products: natural ligands for HIV gp120. Science. 1993;261:1588–91. doi: 10.1126/science.7690497. [DOI] [PubMed] [Google Scholar]
  • 27.Juompan L, Lambin P, Zouali M. Selective alterations of the antibody response to HIV-1. Appl Biochem Biotechnol. 1998;75:139–50. doi: 10.1007/BF02787714. [DOI] [PubMed] [Google Scholar]
  • 28.Scamurra RW, Miller DJ, Dahl L, Abrahamsen M, Kapur V, Wahl SM, et al. Impact of HIV-1 infection on VH3 gene repertoire of naive human B cells. J Immunol. 2000;164:5482–91. doi: 10.4049/jimmunol.164.10.5482. [DOI] [PubMed] [Google Scholar]
  • 29.Margolin DH, Reimann KA, Sodroski J, Karlsson GB, Tenner-Racz K, Racz P, et al. Immunoglobulin V(H) usage during primary infection of rhesus monkeys with chimeric simian-human immunodeficiency viruses. J Virol. 1997;71:8582–91. doi: 10.1128/jvi.71.11.8582-8591.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.De Milito A, Morch C, Sonnerborg A, Chiodi F. Loss of memory (CD27) B lymphocytes in HIV-1 infection. AIDS. 2001;15:957–64. doi: 10.1097/00002030-200105250-00003. [DOI] [PubMed] [Google Scholar]
  • 31.Nagase H, Agematsu K, Kitano K, Takamoto M, Okubo Y, Komiyama A, et al. Mechanism of hypergammaglobulinemia by HIV infection: circulating memory B-cell reduction with plasmacytosis. Clin Immunol. 2001;100:250–9. doi: 10.1006/clim.2001.5054. [DOI] [PubMed] [Google Scholar]
  • 32.Avery DT, Ellyard JI, Mackay F, Corcoran LM, Hodgkin PD, Tangye SG. Increased expression of CD27 on activated human memory B cells correlates with their commitment to the plasma cell lineage. J Immunol. 2005;174:4034–42. doi: 10.4049/jimmunol.174.7.4034. [DOI] [PubMed] [Google Scholar]
  • 33.Anderson SM, Tomayko MM, Shlomchik MJ. Intrinsic properties of human and murine memory B cells. Immunol Rev. 2006;211:280–94. doi: 10.1111/j.0105-2896.2006.00398.x. [DOI] [PubMed] [Google Scholar]
  • 34.Klein U, Rajewsky K, Kuppers R. Human immunoglobulin (Ig)M+IgD+ peripheral blood B cells expressing the CD27 cell surface antigen carry somatically mutated variable region genes: CD27 as a general marker for somatically mutated (memory) B cells. J Exp Med. 1998;188:1679–89. doi: 10.1084/jem.188.9.1679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Moir S, Malaspina A, Ho J, Wang W, DiPoto AC, O’Shea MA, et al. Normalization of B cell counts and subpopulations following antiretroviral therapy in chronic HIV disease. J Infect Dis. 2008;197:572–9. doi: 10.1086/526789. [DOI] [PubMed] [Google Scholar]
  • 36.D’Orsogna LJ, Krueger RG, McKinnon EJ, French MA. Circulating memory B-cell subpopulations are affected differently by HIV infection and antiretroviral therapy. AIDS. 2007;21:1747–52. doi: 10.1097/QAD.0b013e32828642c7. [DOI] [PubMed] [Google Scholar]
  • 37.Chong Y, Ikematsu H, Kikuchi K, Yamamoto M, Murata M, Nishimura M, et al. Selective CD27+ (memory) B cell reduction and characteristic B cell alteration in drug-naive and HAART-treated HIV type 1-infected patients. AIDS Res Hum Retroviruses. 2004;20:219–26. doi: 10.1089/088922204773004941. [DOI] [PubMed] [Google Scholar]
  • 38.Titanji K, Chiodi F, Bellocco R, Schepis D, Osorio L, Tassandin C, et al. Primary HIV-1 infection sets the stage for important B lymphocyte dysfunctions. AIDS. 2005;19:1947–55. doi: 10.1097/01.aids.0000191231.54170.89. [DOI] [PubMed] [Google Scholar]
  • 39.Ehrhardt GR, Hsu JT, Gartland L, Leu CM, Zhang S, Davis RS, et al. Expression of the immunoregulatory molecule FcRH4 defines a distinctive tissue-based population of memory B cells. J Exp Med. 2005;202:783–91. doi: 10.1084/jem.20050879. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Moir S, Ho J, Malaspina A, Wang W, DiPoto A, O’Shea MA, et al. Evidence for HIV-associated B-cell exhaustion in a dysfunctional memory B-cell compartment in HIV-infected viremic individuals. J Exp Med. 2008 doi: 10.1084/jem.20072683. In press. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Sims GP, Ettinger R, Shirota Y, Yarboro CH, Illei GG, Lipsky PE. Identification and characterization of circulating human transitional B cells. Blood. 2005;105:4390–8. doi: 10.1182/blood-2004-11-4284. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Cuss AK, Avery DT, Cannons JL, Yu LJ, Nichols KE, Shaw PJ, et al. Expansion of functionally immature transitional B cells is associated with human-immunodeficient states characterized by impaired humoral immunity. J Immunol. 2006;176:1506–16. doi: 10.4049/jimmunol.176.3.1506. [DOI] [PubMed] [Google Scholar]
  • 43.Malaspina A, Moir S, Chaitt DG, Rehm CA, Kottilil S, Falloon J, et al. Idiopathic CD4+ T lymphocytopenia is associated with increases in immature/transitional B cells and serum levels of IL-7. Blood. 2007;109:2086–8. doi: 10.1182/blood-2006-06-031385. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Napolitano LA, Grant RM, Deeks SG, Schmidt D, De Rosa SC, Herzenberg LA, et al. Increased production of IL-7 accompanies HIV-1-mediated T-cell depletion: implications for T-cell homeostasis. Nat Med. 2001;7:73–9. doi: 10.1038/83381. [DOI] [PubMed] [Google Scholar]
  • 45.Fry TJ, Connick E, Falloon J, Lederman MM, Liewehr DJ, Spritzler J, et al. A potential role for interleukin-7 in T-cell homeostasis. Blood. 2001;97:2983–90. doi: 10.1182/blood.v97.10.2983. [DOI] [PubMed] [Google Scholar]
  • 46.McCune JM. The dynamics of CD4+ T-cell depletion in HIV disease. Nature. 2001;410:974–9. doi: 10.1038/35073648. [DOI] [PubMed] [Google Scholar]
  • 47.Siegel RM. Caspases at the crossroads of immune-cell life and death. Nat Rev Immunol. 2006;6:308–17. doi: 10.1038/nri1809. [DOI] [PubMed] [Google Scholar]
  • 48.Ho J, Moir S, Malaspina A, Howell ML, Wang W, DiPoto AC, et al. Two overrepresented B cell populations in HIV-infected individuals undergo apoptosis by different mechanisms. Proc Natl Acad Sci U S A. 2006;103:19436–41. doi: 10.1073/pnas.0609515103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Bekker V, Scherpbier H, Beld M, Piriou E, van Breda A, Lange J, et al. Epstein-Barr virus infects B and non-B lymphocytes in HIV-1-infected children and adolescents. J Infect Dis. 2006;194:1323–30. doi: 10.1086/508197. [DOI] [PubMed] [Google Scholar]
  • 50.Soriano-Sarabia N, Leal M, Delgado C, Molina-Pinelo S, De Felipe B, Ruiz-Mateos E, et al. Effect of hepatitis C virus coinfection on humoral immune alterations in naive HIV-infected adults on HAART: a three year follow-up study. J Clin Immunol. 2005;25:296–302. doi: 10.1007/s10875-005-3864-1. [DOI] [PubMed] [Google Scholar]
  • 51.De Boer RJ, Mohri H, Ho DD, Perelson AS. Turnover rates of B cells, T cells, and NK cells in simian immunodeficiency virus-infected and uninfected rhesus macaques. J Immunol. 2003;170:2479–87. doi: 10.4049/jimmunol.170.5.2479. [DOI] [PubMed] [Google Scholar]
  • 52.Hazenberg MD, Stuart JW, Otto SA, Borleffs JC, Boucher CA, de Boer RJ, et al. T-cell division in human immunodeficiency virus (HIV)-1 infection is mainly due to immune activation: a longitudinal analysis in patients before and during highly active antiretroviral therapy (HAART) Blood. 2000;95:249–55. [PubMed] [Google Scholar]
  • 53.Kovacs JA, Lempicki RA, Sidorov IA, Adelsberger JW, Herpin B, Metcalf JA, et al. Identification of dynamically distinct subpopulations of T lymphocytes that are differentially affected by HIV. J Exp Med. 2001;194:1731–41. doi: 10.1084/jem.194.12.1731. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 54.Lempicki RA, Kovacs JA, Baseler MW, Adelsberger JW, Dewar RL, Natarajan V, et al. Impact of HIV-1 infection and highly active antiretroviral therapy on the kinetics of CD4+ and CD8+ T cell turnover in HIV-infected patients. Proc Natl Acad Sci U S A. 2000;97:13778–83. doi: 10.1073/pnas.250472097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Mohri H, Bonhoeffer S, Monard S, Perelson AS, Ho DD. Rapid turnover of T lymphocytes in SIV-infected rhesus macaques. Science. 1998;279:1223–7. doi: 10.1126/science.279.5354.1223. [DOI] [PubMed] [Google Scholar]
  • 56.Sachsenberg N, Perelson AS, Yerly S, Schockmel GA, Leduc D, Hirschel B, et al. Turnover of CD4+ and CD8+ T lymphocytes in HIV-1 infection as measured by Ki-67 antigen. J Exp Med. 1998;187:1295–303. doi: 10.1084/jem.187.8.1295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57.Der SD, Zhou A, Williams BR, Silverman RH. Identification of genes differentially regulated by interferon alpha, beta, or gamma using oligonucleotide arrays. Proc Natl Acad Sci U S A. 1998;95:15623–8. doi: 10.1073/pnas.95.26.15623. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Samuelsson A, Sonnerborg A, Heuts N, Coster J, Chiodi F. Progressive B cell apoptosis and expression of Fas ligand during human immunodeficiency virus type 1 infection. AIDS Res Hum Retroviruses. 1997;13:1031–8. doi: 10.1089/aid.1997.13.1031. [DOI] [PubMed] [Google Scholar]
  • 59.Muro-Cacho CA, Pantaleo G, Fauci AS. Analysis of apoptosis in lymph nodes of HIV-infected persons: intensity of apoptosis correlates with the general state of activation of the lymphoid tissue and not with stage of disease or viral burden. J Immunol. 1995;154:5555–66. [PubMed] [Google Scholar]
  • 60.Greenwald RJ, Freeman GJ, Sharpe AH. The B7 family revisited. Annu Rev Immunol. 2005;23:515–48. doi: 10.1146/annurev.immunol.23.021704.115611. [DOI] [PubMed] [Google Scholar]
  • 61.Malaspina A, Moir S, Kottilil S, Hallahan CW, Ehler LA, Liu S, et al. Deleterious effect of HIV-1 plasma viremia on B cell costimulatory function. J Immunol. 2003;170:5965–72. doi: 10.4049/jimmunol.170.12.5965. [DOI] [PubMed] [Google Scholar]
  • 62.Moir S, Ogwaro KM, Malaspina A, Vasquez J, Donoghue ET, Hallahan CW, et al. Perturbations in B cell responsiveness to CD4+ T cell help in HIV-infected individuals. Proc Natl Acad Sci U S A. 2003;100:6057–62. doi: 10.1073/pnas.0730819100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Malaspina A, Moir S, Orsega SM, Vasquez J, Miller NJ, Donoghue ET, et al. Compromised B cell responses to influenza vaccination in HIV-infected individuals. J Infect Dis. 2005;191:1442–50. doi: 10.1086/429298. [DOI] [PubMed] [Google Scholar]
  • 64.Titanji K, De Milito A, Cagigi A, Thorstensson R, Grutzmeier S, Atlas A, et al. Loss of memory B cells impairs maintenance of long-term serologic memory during HIV-1 infection. Blood. 2006;108:1580–7. doi: 10.1182/blood-2005-11-013383. [DOI] [PubMed] [Google Scholar]
  • 65.Hart M, Steel A, Clark SA, Moyle G, Nelson M, Henderson DC, et al. Loss of discrete memory B cell subsets is associated with impaired immunization responses in HIV-1 infection and may be a risk factor for invasive pneumococcal disease. J Immunol. 2007;178:8212–20. doi: 10.4049/jimmunol.178.12.8212. [DOI] [PubMed] [Google Scholar]
  • 66.Kruetzmann S, Rosado MM, Weber H, Germing U, Tournilhac O, Peter HH, et al. Human immunoglobulin M memory B cells controlling Streptococcus pneumoniae infections are generated in the spleen. J Exp Med. 2003;197:939–45. doi: 10.1084/jem.20022020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Shearer WT, Easley KA, Goldfarb J, Rosenblatt HM, Jenson HB, Kovacs A, et al. Prospective 5-year study of peripheral blood CD4, CD8, and CD19/CD20 lymphocytes and serum Igs in children born to HIV-1 women. The P(2)C(2) HIV Study Group. J Allergy Clin Immunol. 2000;106:559–66. doi: 10.1067/mai.2000.109433. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 68.Bekker V, Scherpbier H, Pajkrt D, Jurriaans S, Zaaijer H, Kuijpers TW. Persistent humoral immune defect in highly active antiretroviral therapy-treated children with HIV-1 infection: loss of specific antibodies against attenuated vaccine strains and natural viral infection. Pediatrics. 2006;118:e315–22. doi: 10.1542/peds.2005-2616. [DOI] [PubMed] [Google Scholar]
  • 69.Bliss SJ, O’Brien KL, Janoff EN, Cotton MF, Musoke P, Coovadia H, et al. The evidence for using conjugate vaccines to protect HIV-infected children against pneumococcal disease. Lancet Infect Dis. 2008;8:67–80. doi: 10.1016/S1473-3099(07)70242-6. [DOI] [PubMed] [Google Scholar]
  • 70.Obaro SK, Pugatch D, Luzuriaga K. Immunogenicity and efficacy of childhood vaccines in HIV-1-infected children. Lancet Infect Dis. 2004;4:510–8. doi: 10.1016/S1473-3099(04)01106-5. [DOI] [PubMed] [Google Scholar]
  • 71.Dankner WM, Lindsey JC, Levin MJ. Correlates of opportunistic infections in children infected with the human immunodeficiency virus managed before highly active antiretroviral therapy. Pediatr Infect Dis J. 2001;20:40–8. doi: 10.1097/00006454-200101000-00008. [DOI] [PubMed] [Google Scholar]
  • 72.Hatherill M. Sepsis predisposition in children with human immunodeficiency virus. Pediatr Crit Care Med. 2005;6:S92–8. doi: 10.1097/01.PCC.0000161579.39050.6B. [DOI] [PubMed] [Google Scholar]
  • 73.Mascola JR, Lewis MG, Stiegler G, Harris D, VanCott TC, Hayes D, et al. Protection of macaques against pathogenic simian/human immunodeficiency virus 89. 6PD by passive transfer of neutralizing antibodies. J Virol. 1999;73:4009–18. doi: 10.1128/jvi.73.5.4009-4018.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74.Miller CJ, Genesca M, Abel K, Montefiori D, Forthal D, Bost K, et al. Antiviral antibodies are necessary for control of simian immunodeficiency virus replication. J Virol. 2007;81:5024–35. doi: 10.1128/JVI.02444-06. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 75.Baba TW, Liska V, Hofmann-Lehmann R, Vlasak J, Xu W, Ayehunie S, et al. Human neutralizing monoclonal antibodies of the IgG1 subtype protect against mucosal simian-human immunodeficiency virus infection. Nat Med. 2000;6:200–6. doi: 10.1038/72309. [DOI] [PubMed] [Google Scholar]
  • 76.Johnston MI, Fauci AS. An HIV vaccine: evolving concepts. N Engl J Med. 2007;356:2073–81. doi: 10.1056/NEJMra066267. [DOI] [PubMed] [Google Scholar]
  • 77.Letvin NL. Progress and obstacles in the development of an AIDS vaccine. Nat Rev Immunol. 2006;6:930–9. doi: 10.1038/nri1959. [DOI] [PubMed] [Google Scholar]
  • 78.Montefiori D, Sattentau Q, Flores J, Esparza J, Mascola J. Antibody-based HIV-1 vaccines: recent developments and future directions. PLoS Med. 2007;4:e348. doi: 10.1371/journal.pmed.0040348. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 79.Li Y, Migueles SA, Welcher B, Svehla K, Phogat A, Louder MK, et al. Broad HIV-1 neutralization mediated by CD4-binding site antibodies. Nat Med. 2007;13:1032–4. doi: 10.1038/nm1624. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 80.Karlsson Hedestam GB, Fouchier RA, Phogat S, Burton DR, Sodroski J, Wyatt RT. The challenges of eliciting neutralizing antibodies to HIV-1 and to influenza virus. Nat Rev Microbiol. 2008;6:143–55. doi: 10.1038/nrmicro1819. [DOI] [PubMed] [Google Scholar]

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