Trends in Immunology
Volume 35, Issue 11, November 2014, Pages 549-561
Journal home page for Trends in Immunology

Feature Review
Antibody B cell responses in HIV-1 infection

https://doi.org/10.1016/j.it.2014.08.007Get rights and content

Highlights

  • bNAbs possess unique molecular features and thus, rarely develop in HIV+ patients.

  • bNAbs have different antiviral properties, and can bypass viral defense mechanisms.

  • bNAbs are generated through a co-evolution process with diversifying HIV-1 viruses.

  • bNAbs offer promising therapeutic opportunities to treat HIV-1 infection in humans.

  • Studying bNAbs biology is essential in trying to design HIV-1 vaccine strategies.

In rare cases, B cells can supply HIV-1-infected individuals with unconventional antibodies equipped to neutralize the wide diversity of viral variants. Innovations in single-cell cloning, high-throughput sequencing, and structural biology methods have enabled the capture and thorough characterization of these exceptionally potent broadly neutralizing antibodies (bNAbs). Here, I review the recent findings in humoral responses to HIV-1, focusing on the interplay between naturally occurring bNAbs and the virus both at systemic and mucosal levels. In this context, I discuss how an improved understanding of bNAb generation may provide invaluable insight into the fundamental mechanisms governing adaptive B cell responses to viruses, and how this knowledge is currently contributing to the development of vaccine and therapeutic strategies against HIV-1.

Section snippets

Antibodies against HIV-1

More than a century ago, Von Behring and Kitasato provided the first evidence on the role of the humoral response in host protection against infectious agents using serum therapy experiments against diphtheria and tetanus toxins [1]. ‘Briefly expressed, serum therapy works through anti-bodies’ explained Emil Von Behring (http://www.nobelprize.org). We now know that antibodies are valuable immunotherapeutics for a wide range of infectious diseases 2, 3, that they can confer mother-to-child

Systemic and mucosal antibody responses to HIV-1

The initial antibody response to HIV-1 can be detected as immune complexes as early as ∼1 week post-infection [15]. In the following days, circulating anti-gp41 antibodies are produced, followed by production of anti-gp120 antibodies a few weeks later, but none of these antibodies are capable of neutralizing the infecting viral strain (autologous virus) [15]. The first autologous neutralizing antibodies appear several months post-infection and although they are unable to neutralize heterologous

Multiple viral strategies for disrupting and evading the immune response

HIV-1 infection induces major perturbations in B cell development, physiology, and function that likely interfere with the establishment of a normal antiviral humoral response. Deregulation of B cell differentiation and function during HIV-1 infection is now well documented and consists of a variety of abnormalities, which are also associated with pathological changes in lymphoid tissues supporting B cell immune response (follicular hyperplasia and germinal centers alterations) such as: (i) B

Features of HIV-1 neutralizing antibodies

In the early 1990s, first-generation HIV-1 bNAbs were isolated using Epstein–Barr virus transformation and phage display methods 77, 78, 79, 80, 81, 82. Their extensive molecular characterization improved our knowledge of the host immune response to HIV-1 by identifying important sites of vulnerability, antibody structure-to-function relations, and numerous viral escape mechanisms as described above [83]. Nevertheless, the uncommon nature of the antibodies (unnatural IgH and IgL pairing for

Development of next generation HIV-1 bNAbs

Genetic and biological host factors that determine or influence the generation of HIV-1 bNAbs are not fully understood, and are an area of active investigation. From an immunological standpoint, genetic predisposition to the natural control of HIV-1 (HIV-1 controller phenotype) is principally linked to certain HLA class I alleles predicted to enable efficient effector CD8+ T cell responses [106]. Whether specific genetic traits are associated with the development of bNAbs in Elite neutralizers

Antiviral activity of broadly HIV-1 neutralizing antibodies and therapeutic potential

The antiviral activity of HIV-1 antibodies is typically measured in vitro using cell-free pseudovirus particles and reporter cell lines, such as the HeLa-derived TzMbl cell [137]. In these assays, which measure the inhibition of free virus binding to cellular receptors and/or of viral fusion (Figure 4), first-generation bNAbs can achieve neutralization breadth but only several orders of magnitude less than the recently isolated bNAbs, which can neutralize up to 95% of HIV-1 strains at low

Concluding remarks

Humoral immune responses are fundamental to the host protection against pathogens, and rely on the extraordinary diversity of antibody molecules that ensure the recognition of a theoretically infinite number of foreign antigens. Since the beginning of the AIDS epidemic 30 years ago, intensive research efforts have been engaged to dissect the interplay between HIV-1 and neutralizing antibodies. However, only recently did the discovery and characterization at a molecular level of broadly

Acknowledgments

We are grateful to Jean-Philippe Julien and Ian A. Wilson (The Scripps Research Institute) for providing us the structural model used in Figure 2, and to Caroline Eden (Icahn School of Medicine at Mount Sinai) for helpful comments and manuscript editing. This work was supported by the European Research Council (ERC) – Seventh Framework Program (ERC-2013-StG 337146). H.M. was supported by the G5 Institut Pasteur Program and the Milieu Intérieur Program (ANR-10-LABX-69-01).

Glossary

Germinal centers
germinal centers are specialized microenvironments within secondary lymphoid organs that support the maturation, proliferation, and differentiation of B lymphocytes during T cell dependent immune responses. These microanatomical structures are divided into light and dark zones; in the dark zone, B cells expand and diversify their antigen receptors through somatic hypermutation (that potentially increases antibody affinity) and class-switching (that alters antibody effector

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