Broadly Neutralizing Antibodies for HIV-1 Prevention

Walsh, Stephen R.; Seaman, Michael S.

doi:10.3389/fimmu.2021.712122

Cited by 55 publications

(65 citation statements)

References 131 publications

(176 reference statements)

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“…This suggests that there may be certain properties within the viral variants that infected the donors CAP206 and RV217.40512 (the donor from whom the VRC42 lineage was isolated) that gave rise to multiple MPER responses. Due to the highly conserved nature of the MPER, bNAbs targeting this region tend to be among the broadest antibodies isolated to date [39]. Sequential immunogens designed based on variants identified in CAP206 and/or RV217.40512 may enable the development of such responses in a vaccine setting.…”

Section: Discussionmentioning

confidence: 99%

Dependence on a variable residue limits the breadth of an HIV MPER neutralizing antibody, despite convergent evolution with broadly neutralizing antibodies

Scheepers

Kgagudi

Mzindle

et al. 2022

Preprint

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Broadly neutralizing antibodies (bNAbs) that target the membrane-proximal external region (MPER) of HIV gp41 envelope, such as 4E10 and VRC42.01, can neutralize >95% of viruses. These two MPER-directed monoclonal antibodies share germline antibody genes ( IGHV1-69 and IGKV3-20) and form a bNAb epitope class. Furthermore, convergent evolution within these two lineages towards a 111.2 GW 111.3 motif in the CDRH3 is known to enhance neutralization potency. We have previously isolated an MPER neutralizing antibody, CAP206-CH12, that uses these same germline heavy and light chain genes but lacks breadth (neutralizing only 6% of heterologous viruses). Longitudinal sequencing of the CAP206-CH12 lineage over three years revealed similar convergent evolution towards 111.2 GW 111.3 among some lineage members. Mutagenesis of CAP206-CH12 from 111.2 GL 111.3 to 111.2 GW 111.3 modestly improved neutralization breadth (by 9%) and potency (3-fold), but did not reach the levels of breadth and potency of VRC42.01 and 4E10. To explore the lack of potency/breadth, viral mutagenesis was performed to map the CAP206-CH12 epitope. This indicated that CAP206-CH12 is dependent on D 674 , a highly variable residue at the solvent-exposed elbow of MPER. In contrast, VRC42.01 and 4E10 were dependent on highly conserved residues (W 672 , F 673 , T 676 , and W 680 ) facing the hydrophobic patch of the MPER. Therefore, while CAP206-CH12, VRC42.01, and 4E10 share germline genes and show some evidence of convergent evolution, their dependence on different amino acids, which impacts orientation of binding to the MPER, result in differences in breadth and potency. These data have implications for the design of HIV vaccines directed at the MPER epitope.

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Section: Discussionmentioning

confidence: 99%

Dependence on a variable residue limits the breadth of an HIV MPER neutralizing antibody, despite convergent evolution with broadly neutralizing antibodies

Scheepers

Kgagudi

Mzindle

et al. 2022

Preprint

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“…Although several standard virus panels such as the 12-strain ‘global’ panel ( 64 ) and the 118-strain multi-clade panel ( 87 ) have already been established, there is currently no consensus panel. As a consequence, the 291 antibodies were tested against different or only partially overlapping viral panels, making it difficult to compare them in terms of breadth and potency ( 88 ). Neutralization data against the global and the 118 multi-clade panel were downloaded separately from the CATNAP database.…”

Section: Methodsmentioning

confidence: 99%

Probabilities of HIV-1 bNAb development in healthy and chronically infected individuals

Kreer

Lupo

Ercanoglu

et al. 2022

Preprint

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HIV-1 broadly neutralizing antibodies (bNAbs) are able to suppress viremia and prevent infection. Their induction by vaccination is therefore a major goal. However, in contrast to antibodies that neutralize other pathogens, HIV-1-specific bNAbs frequently carry uncommon molecular characteristics that might prevent their induction. Here, we performed unbiased sequence analyses of B cell receptor repertoires from 57 healthy and 46 chronically HIV-1- or HCV-infected individuals and learned probabilistic models to predict the likelihood of bNAb development. We show that lower probabilities for bNAbs are predictive of higher HIV-1 neutralization activity. Moreover, ranking of bNAbs by their probabilities allowed to identify highly potent antibodies with superior generation probabilities as preferential targets for vaccination approaches. Importantly, we found equal bNAb probabilities across infected and healthy donors. This implies that chronic infection is not a prerequisite for the generation of bNAbs, fostering the hope that HIV-1 vaccines can induce bNAb development in healthy individuals.

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“…Research has also shown that broadly neutralizing antibodies (bNAbs) can control HIV replication [ 212 – 217 ]. All bnAbs target the HIV-1 Envelope (Env) glycoprotein 120 (gp120) and gp41 [ 218 ]. The first-generation bNabs (b12, 447-52D, 2G12, 17b, 2F5, 4E10 and Z13) [ 219 – 221 ] generated little clinical effect on HIV [ 222 ].…”

Section: Hiv Cure Strategiesmentioning

confidence: 99%

“…The first-generation bNabs (b12, 447-52D, 2G12, 17b, 2F5, 4E10 and Z13) [ 219 – 221 ] generated little clinical effect on HIV [ 222 ]. Next, antibodies targeting the CD4 binding site (VRC01, 3BNC117, VRC01-LS, and VRC07-523LS), the glycan-rich V3 loop (10–1074 and PGT121), the V2-glycan site (PGDM1400, CAP256-VRC26.25) and MPER epitope (10E8) were identified [ 218 , 223 , 224 ]. All these bNAbs have shown different levels of protection against Simian Immunodeficiency Virus (SHIV) [ 225 – 228 ].…”

Section: Hiv Cure Strategiesmentioning

confidence: 99%

“…Research has shown that combining two or more bNAbs is effective in enhancing a broad viral coverage [ 229 – 233 ]. bnAbs against HIV have shown significant promise for their potential use in the control of HIV, [ 218 , 223 ], however, one setback is to identify combinations of bnAbs that will increase the breadth to cover circulating variants [ 218 , 234 ]. In terms of HIV cure or remission, bNAbs could be given to patients who are virologically suppressed on ART to keep the virus undetected after withdrawal of ART.…”

Section: Hiv Cure Strategiesmentioning

confidence: 99%

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HIV cure strategies: which ones are appropriate for Africa?

Abana

Lamptey

Bonney

et al. 2022

Cell. Mol. Life Sci.

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Although combination antiretroviral therapy (ART) has reduced mortality and improved lifespan for people living with HIV, it does not provide a cure. Patients must be on ART for the rest of their lives and contend with side effects, unsustainable costs, and the development of drug resistance. A cure for HIV is, therefore, warranted to avoid the limitations of the current therapy and restore full health. However, this cure is difficult to find due to the persistence of latently infected HIV cellular reservoirs during suppressive ART. Approaches to HIV cure being investigated include boosting the host immune system, genetic approaches to disable co-receptors and the viral genome, purging cells harboring latent HIV with latency-reversing latency agents (LRAs) (shock and kill), intensifying ART as a cure, preventing replication of latent proviruses (block and lock) and boosting T cell turnover to reduce HIV-1 reservoirs (rinse and replace). Since most people living with HIV are in Africa, methods being developed for a cure must be amenable to clinical trials and deployment on the continent. This review discusses the current approaches to HIV cure and comments on their appropriateness for Africa.

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Broadly Neutralizing Antibodies for HIV-1 Prevention

Cited by 55 publications

References 131 publications

Dependence on a variable residue limits the breadth of an HIV MPER neutralizing antibody, despite convergent evolution with broadly neutralizing antibodies

Dependence on a variable residue limits the breadth of an HIV MPER neutralizing antibody, despite convergent evolution with broadly neutralizing antibodies

Probabilities of HIV-1 bNAb development in healthy and chronically infected individuals

HIV cure strategies: which ones are appropriate for Africa?

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