Breadth of Human Immunodeficiency Virus-Specific Neutralizing Activity in Sera: Clustering Analysis and Association with Clinical Variables

Doria‐Rose, Nicole A.; Klein, Rachel M.; Daniels, Marcus G.; O’Dell, Sijy; Nason, Martha; Lapedes, Alan S.; Bhattacharya, Tanmoy; Migueles, Stephen A.; Wyatt, Richard T.; Korber, Bette T.; Mascola, John R.; Connors, Mark

doi:10.1128/jvi.01482-09

Cited by 297 publications

(334 citation statements)

References 36 publications

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“…Of note, using a similar technique, Doria-Rose et al reported that plasmablasts were expanded in peripheral blood of HIV ϩ PBMCs and accounted for most of the antigen-specific antibody-secreting cells (ASC) in HIVinfected samples. However, they only found a relationship between development of bNAbs and viral load, and not Env-specific ASC, CD4 ϩ T cell count, or years since diagnosis (2). Thus, the present findings builds upon those of Kardava et al, who reported no significant associations between CD4 T cells (frequency or count) and percent RM Env-specific B cells (17).…”

Section: Discussionsupporting

confidence: 81%

“…To study the impact of antigenemia on HIV-specific B cells, we next used a Histagged HIV Env gp120 protein probe study the approximate frequency of gp120-specific B cells between progressors, HIV EC, and HIV VC by flow cytometry, as previously described (2). Healthy donors were assessed as negative controls.…”

Section: Bulk B Cells Are Expanded In Uncontrolled Hiv Infection But mentioning

confidence: 99%

“…Attempts to induce such bNAbs through vaccination have mostly been ineffective. Interestingly, in natural infection, serologic breadth develops only under conditions that seem counterintuitive to efficient B cell maturation processes, such as years of chronic immune activation, loss of CD4 T cells, high levels of exhaustion marker expression, and other phenotypic lymphocyte abnormalities (2)(3)(4)(5). In addition, high viral loads and coevolution of viral quasispecies have been implicated in the development of serologic breadth, suggesting that constant immune activation and antigen recognition may play a key role in HIV antibody maturation processes.…”

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confidence: 99%

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Preservation of Peripheral T Follicular Helper Cell Function in HIV Controllers

Buranapraditkun

Pissani

Teigler

et al. 2017

J Virol

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The maturation process of high-affinity antibodies is a result of intricate interactions between B cells and follicular helper T (Tfh) cells occurring in lymphoid germinal centers. HIV infection induces significant chronic immune activation, phenotypic skewing, and inflammation driven by years of continuous viral replication. High levels of viremia as well as immune activation and dysfunction have been demonstrated to have a perturbing impact on the B cell memory compartment and contribute to B cell exhaustion. Counterintuitively, the factors associated with perturbation of the B cell compartment seem to be favorable for the generation of highly affinity-matured Env-specific antibodies in a minority of HIV-infected individuals. Thus, the impact of HIV antigenemia on B cells and Tfh cell interactions warrants further exploration. We therefore studied immunophenotypes of HIV-specific B cells in individuals with differing levels of viral control using HIV Env gp120 probes and characterized the functionality of matched T cells in peripheral blood. While CXCR5 ϩ CD4 ϩ T cells were significantly diminished in HIV progressors, we found that a small subset of gp120-specific interleukin-21 (IL-21)-secreting CXCR5 ϩ CD4 ϩ T cells were significantly associated with gp120-specific B cell frequencies. In contrast, neither bulk CXCR5 ϩ CD4 ϩ T cells nor other HIV antigen specificities were associated with gp120-specific B cell levels. HIV-specific B cells derived from elite controllers displayed greater amounts of gp120-specific B cells in the resting memory subset, whereas HIV-specific B cells in progressors accumulated in tissue-like and activated memory subsets. Furthermore, CXCR5 ϩ CD4 ϩ T cells from elite controllers showed a stronger ex vivo capacity to induce B cell maturation and immunoglobulin class switching than cells from HIV progressors.IMPORTANCE Dissecting the factors that are involved in B cell maturation and antibody development is important for HIV vaccine design. In this study, we found that HIV Env-specific CXCR5 ϩ CD4 ϩ T cells that secrete interleukin-21 are strongly associated with B cell memory phenotypes and function. Moreover, we found that the immune responses of HIV controllers showed intrinsically better helper activity than those of HIV progressors.

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Section: Discussionsupporting

confidence: 81%

Section: Bulk B Cells Are Expanded In Uncontrolled Hiv Infection But mentioning

confidence: 99%

mentioning

confidence: 99%

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Preservation of Peripheral T Follicular Helper Cell Function in HIV Controllers

Buranapraditkun

Pissani

Teigler

et al. 2017

J Virol

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“…Further supporting this point, while X5 was originally considered broadly neutralizing, it has relatively poor neutralizing breadth against various HIV-1 isolates compared to the other antibodies tested here (27) yet demonstrates good breadth as a CAR. Regardless, because BNAbs seem to be escaped by HIV-1 Env variation in their original hosts (28)(29)(30), viral variability and escape may remain a barrier to the therapeutic implementation of BNAb-based CARs.…”

Section: Discussionmentioning

confidence: 99%

HIV-1-Specific Chimeric Antigen Receptors Based on Broadly Neutralizing Antibodies

Ali

Kitchen

Chen

et al. 2016

J Virol

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Although the use of chimeric antigen receptors (CARs) based on single-chain antibodies for gene immunotherapy of cancers is increasing due to promising recent results, the earliest CAR therapeutic trials were done for HIV-1 infection in the late 1990s. This approach utilized a CAR based on human CD4 as a binding domain and was abandoned for a lack of efficacy. The growing number of HIV-1 broadly neutralizing antibodies (BNAbs) offers the opportunity to generate novel CARs that may be more active and revisit this modality for HIV-1 immunotherapy. We used sequences from seven well-defined BNAbs varying in binding sites and generated single-chain-antibody-based CARs. These CARs included 10E8, 3BNC117, PG9, PGT126, PGT128, VRC01, and X5. Each novel CAR exhibited conformationally relevant expression on the surface of transduced cells, mediated specific proliferation and killing in response to HIV-1-infected cells, and conferred potent antiviral activity (reduction of viral replication in log 10 units) to transduced CD8 ؉ T lymphocytes. The antiviral activity of these CARs was reproducible but varied according to the strain of virus. These findings indicated that BNAbs are excellent candidates for developing novel CARs to consider for the immunotherapeutic treatment of HIV-1. R ecent years have seen a surge in immunotherapeutic approaches for treating malignancy, including numerous promising human trials of chimeric antigen receptor (CAR) gene therapy to generate tumor-specific T cells, based on the importance of CD8 ϩ T lymphocytes (CTLs) in tumor surveillance and malignant cell clearance through cytotoxicity. The general approach has been to identify monoclonal antibodies that bind a tumor cell surface antigen and use a single-chain version of the antibody as an artificial T cell receptor by genetic fusion to the CD3 chain signaling domain. As opposed to native T cell receptors (TCRs), CARs have the advantage of being major histocompatibility complex (MHC) unrestricted and therefore broadly applicable across human individuals and are also unaffected by tumor cell immune evasion through MHC downregulation. IMPORTANCE While chimeric antigen receptors (CARsNotably, one of the earliest tested clinical applications of CARs was for the treatment of HIV-1 infection. In 1994, Roberts et al. designed two virus-specific CARs using CD4 or a single-chain antibody as the binding domain for recombinant gp120 on the surface of cells (1), and these CARs were shown subsequently to have the direct capacity to kill HIV-1-infected cells and suppress viral replication at levels similar to those of HIV-1-specific CTL clones isolated from infected persons (2). Based on these data, the CD4-based CAR, consisting of the CD4 extracellular and transmembrane domains fused to the CD3 intracellular signaling domain (CD4 Ϫ ), was advanced to clinical trials starting in the late 1990s, using retroviral transduction of autologous peripheral blood T lymphocytes and reinfusion. Unfortunately, this effort was abandoned after these trials showed...

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“…Breadth of plasma neutralizing activity develops incrementally,48 and evidence suggests that protracted exposure to HIV‐1 Env is required 22, 23, 24, 47, 48, 49, 50. Neutralization breadth is not an all‐or‐nothing phenomenon—in one study, about half of a cohort of 205 chronically infected persons were capable of neutralizing about half of a panel of 219 hard‐to‐neutralize (tier 2) HIV‐1 isolates 45.…”

Section: Development Of Broadly Neutralizing Antibodies In Hiv‐1 Infementioning

confidence: 99%

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

Borrow

Moody

2017

Immunological Reviews

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SummaryInduction of broadly neutralizing antibodies (bnAbs) capable of inhibiting infection with diverse variants of human immunodeficiency virus type 1 (HIV‐1) is a key, as‐yet‐unachieved goal of prophylactic HIV‐1 vaccine strategies. However, some HIV‐infected individuals develop bnAbs after approximately 2‐4 years of infection, enabling analysis of features of these antibodies and the immunological environment that enables their induction. Distinct subsets of CD4+ T cells play opposing roles in the regulation of humoral responses: T follicular helper (Tfh) cells support germinal center formation and provide help for affinity maturation and the development of memory B cells and plasma cells, while regulatory CD4+ (Treg) cells including T follicular regulatory (Tfr) cells inhibit the germinal center reaction to limit autoantibody production. BnAbs exhibit high somatic mutation frequencies, long third heavy‐chain complementarity determining regions, and/or autoreactivity, suggesting that bnAb generation is likely to be highly dependent on the activity of CD4+ Tfh cells, and may be constrained by host tolerance controls. This review discusses what is known about the immunological environment during HIV‐1 infection, in particular alterations in CD4+ Tfh, Treg, and Tfr populations and autoantibody generation, and how this is related to bnAb development, and considers the implications for HIV‐1 vaccine design.

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Breadth of Human Immunodeficiency Virus-Specific Neutralizing Activity in Sera: Clustering Analysis and Association with Clinical Variables

Cited by 297 publications

References 36 publications

Preservation of Peripheral T Follicular Helper Cell Function in HIV Controllers

Preservation of Peripheral T Follicular Helper Cell Function in HIV Controllers

HIV-1-Specific Chimeric Antigen Receptors Based on Broadly Neutralizing Antibodies

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

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