Broadly neutralizing HIV-1 antibodies

Broadly Neutralizing HIV-1 Antibodies (bNAbs) are neutralizing antibodies which neutralize multiple HIV-1 viral strains.[1] bNAbs are unique in that they target conserved epitopes of the virus, meaning the virus may mutate, but the targeted epitopes will still exist.[2] In contrast, non-bNAbs are specific for individual viral strains with unique epitopes. The discovery of bNAbs has led to an important area of research, namely, discovery of a vaccine, not only limited to HIV, but also other rapidly mutating viruses like Influenza.

Characteristics

The following table shows the characteristics of various HIV-1 bNAbs[3]

Viral Epitope Antibody binding characteristics Antibody clonal family Year published
MPER of gp41Contiguous sequence2F51992
Contiguous sequence4E101994
Contiguous sequenceM66.62011
Contiguous sequenceCAP206-CH122011
Contiguous sequence10E8 l2012
V1V2-glycanPeptidoglycanPG9, PG162009
PeptidoglycanCH01–042011
PeptidoglycanPGT 141–1452011
Outer domain glycanGlycan only2G121994
V3-glycanPeptidoglycanPGT121–1232011
PeptidoglycanPGT125–1312011
PeptidoglycanPGT135–1372011
CD4 binding siteCDRH3 loopb121991
CDRH3 loopHJ162010
CDRH3 loopCH103–1062013
Mimics CD4 via CDRH2VRC01–032010
Mimics CD4 via CDRH2VRC-PG04, 04b2011
Mimics CD4 via CDRH2VRC-CH30–342011
Mimics CD4 via CDRH23BNC117, 3BNC602011
Mimics CD4 via CDRH2NIH45–462011
Mimics CD4 via CDRH212A12, 12A212011
Mimics CD4 via CDRH28ANC131, 1342011, 2015
Mimics CD4 via CDRH21NC9, 1B25302011, 2015

Online databases like bNAber and LANL constantly report and update the discovery of new HIV bNAbs.

History of HIV bNAbs

In 1990, researchers identified the first HIV bNAb, far more powerful than any antibody seen before. They described the exact viral component, or epitope that triggered the antibody. Six amino acids at the tip of HIV's surface protein, gp120, were responsible. The first bNAb turned out to be clinically irrelevant, but in 1994 another team isolated a bNAb that worked on cells taken from patients. This antibody attached to a "conserved" portion of gp120 that outlasts many of its mutations, affecting 17/24 tested strains at low doses. Another bNAb was discovered that acted on protein gp41 across many strains. Antibodies require antigens to trigger them and these were not originally identified.[4]

Over time more bNAbs were isolated, while single cell antibody cloning made it possible to produce large quantities of the antibodies for study. Low levels of bNAbs are now found in up to 25% of HIV patients. bNAbs evolve over years, accumulating some three times as many mutations as other antibodies.[4]

By 2006, researchers had identified a few so-called "broadly neutralizing antibodies" (bNAbs) that worked on multiple HIV strains. They analyzed 1800 blood samples from HIV-infected people from Africa, South Asia and the English-speaking world. They individually probed 30,000 of one woman's antibody-producing B cells and isolated two that were able to stop more than 70% of 162 divergent HIV strains from establishing an infection. Since 2009, researchers have identified more than 50 HIV bNAbs.[4] Integrated web resource BNAber, focused on broadly neutralizing HIV-1 antibodies, has recently been introduced.[5]

In 2006, a Malawian man joined a study within weeks of becoming infected. Over a year, he repeatedly donated blood, which researchers used to create a timeline of changes in his virus' gp120, his antibody response and the ultimate emergence of a bNAb. Researchers want to direct this evolution in other subjects to achieve similar results. A screen of massive gp120 libraries led to one that strongly bound both an original antibody and the mature bNAb that evolved from it. Giving patients a modified gp120 that contains little more than the epitope that both antibodies target could act to "prime" the immune system, followed by a booster that contains trimer spikes in the most natural configuration possible. However, it is still under study whether bNAbs could prevent HIV infection.[4]

In 2009, researchers isolated and characterized the first HIV bNAbs seen in a decade. The two broadest neutralizers were PGT151 and PGT152. They could block about two-thirds of a large panel of HIV strains. Unlike most other bNAbs, these antibodies do not bind to known epitopes, on Env or on Env's subunits (gp120 or gp41). Instead, they attach to parts of both. Gp120 and gp41 assemble as a trimer. The bNAbs binding site occurs only on the trimer structure, the form of Env that invades host cells.[6]

Recent years have seen an increase in HIV-1 bNAb discovery.

References
  1. Eroshkin, AM; LeBlanc, A; Weekes, D; et al. (January 2014). "bNAber: database of broadly neutralizing HIV antibodies". Nucleic Acids Res. 42 (Database issue): D1133–9. doi:10.1093/nar/gkt1083. PMC 3964981. PMID 24214957..
  2. Scheid, J. F.; Mouquet, H.; Feldhahn, N.; Seaman, M. S.; Velinzon, K.; Pietzsch, J.; Nussenzweig, M. C. (2009). "Broad diversity of neutralizing antibodies isolated from memory B cells in HIV-infected individuals". Nature. 458 (7238): 636–40. Bibcode:2009Natur.458..636S. doi:10.1038/nature07930. PMID 19287373.
  3. Mascola, JR; Haynes, BF (2013). "HIV-1 neutralizing antibodies: understanding nature's pathways". Immunol Rev. 254 (1): 225–44. doi:10.1111/imr.12075. PMC 3738265. PMID 23772623.
  4. Cohen, J. (2013). "Bound for Glory". Science. 341 (6151): 1168–1171. Bibcode:2013Sci...341.1168C. doi:10.1126/science.341.6151.1168. PMID 24030996.
  5. "bnaber.org". Archived from the original on 2013-12-28. Retrieved 2017-12-16.
  6. "Scientists find new point of attack on HIV for vaccine development". Research & Development. 2014-04-24. Retrieved 2016-06-11.
This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.