Broad and potent cross clade neutralizing antibodies with multiple specificities in the plasma of HIV-1 subtype C infected individuals

Cheedarla, Narayanaiah; Precilla, K L; Babu, Hemalatha; Vijayan, Kamalakannan; Ashokkumar, Manickam; Padmapriyadarsini, Chandrasekaran; Kailasam, Nandagopal; Sundaramurthi, Jagadish Chandrabose; Swaminathan, Soumya; Viswanath, Buddolla; Vaniambadi, S. Kalyanaraman; Ramanathan, V. D.; Hanna, Luke Elizabeth

doi:10.1038/srep46557

Cited by 8 publications

(32 citation statements)

References 55 publications

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“…A follow-up blood sample was obtained from 5 of the 12 individuals identified to have broad cross-clade neutralization property in our previous study ( 1 ); follow-up sample could not be obtained from the remaining 7 individuals. The follow-up time point was 4 years after the initial screening, which was within 3 years from the time of initial diagnosis of HIV infection.…”

Section: Methodsmentioning

confidence: 99%

“…CD4+ and CD8+ T-lymphocyte counts were determined on the day of sample collection, by flow cytometry as described earlier using a FACS count flow cytometer (Becton-Dickinson) ( 1 ).…”

Section: Methodsmentioning

confidence: 99%

“…In a previous study, we screened a cohort of ( n = 101) HIV-1 subtype C-infected individuals and identified 12 individuals whose plasma exhibited broad cross-clade neutralization (BCN) activity against HIV ( 1 ). In the present study, we describe the evolution of the bNAb response in a subset of these individuals in terms of breadth, potency, and neutralization specificity.…”

Section: Introductionmentioning

confidence: 99%

“…Identification and characterization of these bNAbs and understanding their evolution dynamics are critical for obtaining useful clues for the development of an effective HIV vaccine. Very recently, we published a study in which we identified 12 HIV-1 subtype C-infected individuals from India whose plasma showed potent and broad cross-clade neutralization (BCN) ability ( 1 ). In the present study, we report our findings on the evolution of host bNAb response over a period of 4 years in a subset of these individuals.…”

mentioning

confidence: 99%

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Evolution of Neutralization Response in HIV-1 Subtype C-Infected Individuals Exhibiting Broad Cross-Clade Neutralization of HIV-1 Strains

et al. 2018

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Strain-specific neutralizing antibodies develop in all human immunodeficiency virus type 1 (HIV-1)-infected individuals. However, only 10–30% of infected individuals produce broadly neutralizing antibodies (bNAbs). Identification and characterization of these bNAbs and understanding their evolution dynamics are critical for obtaining useful clues for the development of an effective HIV vaccine. Very recently, we published a study in which we identified 12 HIV-1 subtype C-infected individuals from India whose plasma showed potent and broad cross-clade neutralization (BCN) ability (1). In the present study, we report our findings on the evolution of host bNAb response over a period of 4 years in a subset of these individuals. Three of the five individuals (NAB033, NAB059, and NAB065) demonstrated a significant increase (p < 0.05) in potency. Interestingly, two of the three samples also showed a significant increase in CD4 binding site-specific antibody response, maintained stable CD4+ T cell counts (>350 cells/mm3) and continued to remain ART-naïve for more than 10 years after initial diagnosis, implying a strong clinical correlation with the development and evolution of broadly neutralizing antibody response against HIV-1.

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Section: Methodsmentioning

confidence: 99%

“…CD4+ and CD8+ T-lymphocyte counts were determined on the day of sample collection, by flow cytometry as described earlier using a FACS count flow cytometer (Becton-Dickinson) ( 1 ).…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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Evolution of Neutralization Response in HIV-1 Subtype C-Infected Individuals Exhibiting Broad Cross-Clade Neutralization of HIV-1 Strains

et al. 2018

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“…Plasma from a subtype-C HIV-infected elite neutralizer (numeric identity: NAB059) was used for epitope mapping studies using our approach. The NAB059 elite neutralizer exhibited extraordinarily high titers against a panel of Tier-3 pseudoviruses (26,27), which are the hardest to neutralize. Epitope mapping was also carried out using sera from guinea pigs immunized with an HIV-1 candidate vaccine, a trimeric cyclic permutant (CycP) of gp120 (28) which elicited Tier-2 neutralization activity against a global panel of HIV-1 isolates (29).…”

Section: Polyclonal Epitope Specificity Mapping Using Excyslibmentioning

confidence: 99%

A facile method of mapping HIV-1 neutralizing epitopes using chemically masked cysteines and deep sequencing

Datta

Chowdhury

Manjunath

et al. 2020

Preprint

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13Identification of specific epitopes targeted by neutralizing antibodies is essential to advance 14 epitope-based vaccine design strategies. We report a methodology for rapid epitope mapping 15 of neutralizing antibodies against HIV-1 Env at single residue resolution, using viral 16 neutralization assays and deep sequencing. We extended our methodology to map multiple 17 specificities of epitopes targeted in polyclonal sera, elicited in immunized animals as well as 18 in HIV-We recently described a methodology to decipher epitopes of monoclonal antibody panels 35 using yeast surface display, Cys labeling and deep sequencing 1, 2 . Here we built on this to map 36 epitopes of neutralizing monoclonal antibodies and polyclonal sera against the HIV-1 virus. 37 The design of an effective vaccine against HIV-1 has met with limited success so far, because 38 of the inability of immunogens to elicit broadly neutralizing antibodies (bNAbs) targeted to the 39 trimeric envelope (Env) glycoprotein, the sole viral antigen on the surface of the virus. Most 40 bNAbs isolated from infected individuals are directed to one of the major sites of vulnerability 41 on Env: V1/V2 loop apex, V3 loop, CD4-binding site, centre of the gp120 silent face, gp120-42 gp41 subunit interface, gp41 fusion peptide and membrane proximal external region (MPER) 43 of gp41. 44 We developed a facile methodology for mapping neutralizing HIV-1 epitopes at single residue 45 resolution. To this end, a library of single-site Cys mutations were engineered at selected 46 solvent-exposed sites in the Env glycoprotein on the surface of the virus. Cys mutants were 47 covalently labeled using a Cys reactive reagent (Maleimide-PEG2-Biotin) that masks epitope 48 residues, followed by infection of the labeled mutant viruses in mammalian cells in the 49 presence of bNAbs. Subsequently, deep sequencing of the env gene from bNAb-resistant 50 viruses was used to delineate epitopes ( Figure 1). We focused our epitope mapping efforts to 51 the Env ectodomain of the clade B, CCR5-tropic primary HIV-1 isolate JRFL, which has been 52 extensively characterized both biochemically and structurally, and is used as a model primary 53 virus. 54A total of 81 solvent-exposed residues (Table S1) were selected from the X-ray crystal structure 55 of the pre-fusion HIV-1 Env ectodomain using a combined criterion of >30% solvent 56 accessibility and sidechain-sidechain centroid distance >8 Å ( Figure S1). This led to the 57 identification of a set of solvent-exposed residues which collectively exhibit uniform surface 58 coverage of the Env trimer ( Figure S2). These Env residues were mutated to Cys in the pLAI-59 JRFL molecular clone, pooled in equimolar quantities to create a plasmid DNA library, and 60 transfected in HEK293T cells to produce the Exposed Cys Library, a library of single-site Cys 61 mutant viruses. Wt Env lacks free Cys residues. In single-cycle and multi-cycle infectivity 62 assays, the Exposed Cys Library retained significant viral infectivity ( Figure S3) and ...

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HIV/AIDS Prevention

Reynolds¹,

Quinn²,

Sendagire³

2024

Manson's Tropical Diseases

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Broad and potent cross clade neutralizing antibodies with multiple specificities in the plasma of HIV-1 subtype C infected individuals

Cited by 8 publications

References 55 publications

Evolution of Neutralization Response in HIV-1 Subtype C-Infected Individuals Exhibiting Broad Cross-Clade Neutralization of HIV-1 Strains

Evolution of Neutralization Response in HIV-1 Subtype C-Infected Individuals Exhibiting Broad Cross-Clade Neutralization of HIV-1 Strains

A facile method of mapping HIV-1 neutralizing epitopes using chemically masked cysteines and deep sequencing

HIV/AIDS Prevention

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