Bone Marrow Plasma Cells Are a Primary Source of Serum HIV-1–Specific Antibodies in Chronically Infected Individuals

Montezuma-Rusca, Jairo M.; Moir, Susan; Kardava, Lela; Buckner, Clarisa M.; Louie, Aaron; Kim, Leo J.Y.; Santich, Brian H.; Wang, Wei; Fankuchen, Olivia R.; Diaz, Gabriela; Daub, Janine; Rosenzweig, Sergio D.; Chun, Tae‐Wook; Li, Yuxing; Braylan, Raul C.; Calvo, Katherine R.; Fauci, Anthony S.

doi:10.4049/jimmunol.1402424

Cited by 15 publications

(13 citation statements)

References 49 publications

(66 reference statements)

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“…The bone marrow is the most likely source of serum antibodies, and even in the setting of immune-activating effects of chronic HIV viremia that lead to increased plasmacytosis in tissues and blood, 11,15,58,61,63,96,148,151,160 we have demonstrated that there remains a strong correlation between frequencies of HIV-specific antibodies in the serum and HIV-specific plasma cells in the bone marrow. 69 It is noteworthy that we did not find a correlation between serum levels of HIV-specific antibodies and HIV-specific memory B cells in the peripheral blood. While these analyses were not performed on elite controllers, a study that investigated such a cohort also found a discordance between CD4bsspecific memory B cells in the peripheral blood and antibodies in the serum of the same specificity, with the latter being much lower than the former.…”

Section: Lessons From Elite Controllers and Long-term Non-progressorscontrasting

confidence: 52%

“…Our previous studies have demonstrated that despite the numerous alterations in B-cell dynamics and differentiation that occur in HIV infection, especially in the setting of chronic HIV viremia ( Fig. 1), there remains a strong correlation between frequencies of HIV-specific plasma cells in the bone marrow and frequencies of HIV-specific antibodies in the peripheral blood (69). These observations suggest that despite HIV-induced aberrant immune activation and dysregulation of B cells, including extensive secondary lymphoid tissue hyperplasia (70, 71), the dynamics of plasma-cell homing to the bone marrow and release of antibody into circulation appear to remain intact.…”

Section: Populations Of Human B Cells and Their Relevance To Hiv Infementioning

confidence: 99%

“…This study also remains one of very few that investigated and demonstrated related clones of 3BNC117 among circulating memory B cells, plasma cells in the bone marrow and serum-derived antibodies. The bone marrow is the most likely source of serum antibodies and we have demonstrated that even in the setting of immune activating effects of chronic HIV viremia that lead to increased plasmacytosis in tissues and blood (11, 15, 58, 61, 63, 96, 147, 150, 159), there remains a strong correlation between frequencies of HIV-specific antibodies in the serum and HIV-specific plasma cells in the bone marrow (69). It is noteworthy that we did not find a correlation between serum levels of HIV-specific antibodies and HIV-specific memory B cells in the peripheral blood.…”

Section: Correlates Of a Strong B-cell Response Against Hivmentioning

confidence: 99%

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B‐cell responses to HIV infection

Moir

Fauci

2017

Immunological Reviews

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144

153

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Summary The induction of neutralizing antibodies directed against the human immunodeficiency virus (HIV) has received considerable attention in recent years, in part driven by renewed interest and opportunities for antibody-based strategies for prevention such as passive transfer of antibodies and the development of preventive vaccines, as well as immune-based therapeutic interventions. Advances in the ability to screen, isolate and characterize HIV-specific antibodies have led to the identification of a new generation of potent broadly neutralizing antibodies (bNAbs). The majority of these antibodies have been isolated from B cells of chronically HIV-infected individuals with detectable viremia. In this review, we provide insight into the phenotypic and functional attributes of human B cells, with a focus on HIV-specific memory B cells and plasmablasts/cells that are responsible for sustaining humoral immune responses against HIV. We discuss the abnormalities in B cells that occur in HIV infection both in the peripheral blood and lymphoid tissues, especially in the setting of persisting viremia. Finally, we consider the opportunities and drawbacks of intensively interrogating antibodies isolated from HIV-infected individuals to guide strategies aimed at developing effective antibody-based vaccine and therapeutic interventions for HIV.

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Section: Lessons From Elite Controllers and Long-term Non-progressorscontrasting

confidence: 52%

Section: Populations Of Human B Cells and Their Relevance To Hiv Infementioning

confidence: 99%

Section: Correlates Of a Strong B-cell Response Against Hivmentioning

confidence: 99%

See 1 more Smart Citation

B‐cell responses to HIV infection

Moir

Fauci

2017

Immunological Reviews

Self Cite

144

153

View full text Add to dashboard Cite

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“…Similarly, high numbers of plasma cells were observed at the site of infection for pulmonary TB in non-human primates ( 24 ). The disparity between plasma cell (increased) and total B-cell (decreased) numbers that we observed in HIV-infected TB tissues was also found in the bone marrow of HIV-infected individuals ( 26 ). To explore consequences of increased plasma cells, we measured antibody responses and found increased total IgM and IgG, especially IgG1, in HIV-positive TB patient serum.…”

Section: Discussionsupporting

confidence: 62%

Cellular Architecture of Spinal Granulomas and the Immunological Response in Tuberculosis Patients Coinfected with HIV

et al. 2017

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Mycobacterium tuberculosis (M.tb) and HIV are individually responsible for the most deaths worldwide among all infectious agents, and coinfection with M.tb and HIV is a significant public health challenge in the developing world. Although the lung is the primary target organ for tuberculosis (TB), M.tb can also cause extrapulmonary tuberculosis (EPTB) such as in the bones and joints. Treatment of EPTB is much more challenging than treatment of pulmonary TB. The hallmark of the host immune response against TB is the formation of organized structures called granulomas that are infiltrated with immune cells and are rich in cytokines and chemokines. Inside granulomas, the host confines the M.tb bacteria to a particular region of the organ and avoids dispersion. In this study, we analyzed immune cells in bone granulomas of patients with EPTB that are also coinfected with HIV. We found that HIV-infected TB patients have dispersed bone granulomas, with reduced T cell numbers and a concomitant increase in plasma cells. Additionally, HIV-infected patients exhibited dramatically increased serum levels of IgM and IgG1 antibodies, which is indicative of T-cell-independent B-cell activation and mucosal T-cell activation, respectively. Interestingly, we also observed that CD29+ stem cells are increased in HIV–TB coinfection, suggesting a link with HIV infection. Therefore, our work provides new insights into the architecture of spinal TB granulomas and the role of B-cells and humoral immunity against a highly infectious intracellular pathogen. We propose that our findings will inform biomarker identification for EPTB and possibly the development of related therapeutics and/or vaccines to protect HIV-infected patients against disseminated TB.

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“…Duplicate measurements were averaged. Serum HIV neutralization profiles of breadth and potency were determined against the cross-clade panel of pseudoviruses shown in Supplemental Table 1 and performed by Monogram, as described previously (74). Pools of CD4bs mAbs grouped within each individual source by family or population were also evaluated for potency against the same cross-clade panel of pseudoviruses.…”

Section: Methodsmentioning

confidence: 99%

Maturational characteristics of HIV-specific antibodies in viremic individuals

Meffre¹,

Louie²,

Bannock³

et al. 2016

JCI Insight

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Despite the rare appearance of potent HIV-neutralizing mAbs in infected individuals requiring prolonged affinity maturation, little is known regarding this process in the majority of viremic individuals. HIV-infected individuals with chronic HIV viremia have elevated numbers of nonconventional tissue-like memory (TLM) B cells that predominate in blood over conventional resting memory (RM) B cells. Accordingly, we investigated affinity maturation in these 2 memory B cell populations. Analysis of IgG-expressing TLM B cells revealed a higher number of cell divisions compared with RM B cells; however, TLM B cells paradoxically displayed significantly lower frequencies of somatic hypermutation (SHM). To assess Ab reactivity in TLM and RM B cells, single-cell cloning was performed on HIV envelope CD4–binding site–sorted (CD4bs-sorted) B cells from 3 individuals with chronic HIV viremia. Several clonal families were present among the 127 cloned recombinant mAbs, with evidence of crosstalk between TLM and RM B cell populations that was largely restricted to non-VH4 families. Despite evidence of common origins, SHM frequencies were significantly decreased in TLM-derived mAbs compared with SHM frequencies in RM-derived mAbs. However, both cell populations had lower frequencies of SHMs than did broadly neutralizing CD4bs–specific mAbs. There was a significant correlation between SHM frequencies and the HIV-neutralizing capacities of the mAbs. Furthermore, HIV neutralization was significantly higher in the RM-derived mAbs compared with that seen in the TLM-derived mAbs, and both SHM frequencies and neutralizing capacity were lowest in TLM-derived mAbs with high polyreactivity. Thus, deficiencies in memory B cells that arise during chronic HIV viremia provide insight into the inadequacy of the Ab response in viremic individuals.

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Bone Marrow Plasma Cells Are a Primary Source of Serum HIV-1–Specific Antibodies in Chronically Infected Individuals

Cited by 15 publications

References 49 publications

B‐cell responses to HIV infection

B‐cell responses to HIV infection

Cellular Architecture of Spinal Granulomas and the Immunological Response in Tuberculosis Patients Coinfected with HIV

Maturational characteristics of HIV-specific antibodies in viremic individuals

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