Neutralization resistant HIV-1 primary isolates from antiretroviral naïve chronically infected children in India

Makhdoomi, Muzamil Ashraf; Singh, Deepti; Pananghat, Ambili Nair; Lodha, Rakesh; Kabra, S. K.; Luthra, Kalpana

doi:10.1016/j.virol.2016.09.011

Cited by 7 publications

(12 citation statements)

References 77 publications

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“…Recently, we and others observed the longitudinal evolution of plasma cross-neutralization antibody response with multiple epitope specificities in select antiretroviral naïve HIV-1 clade C (HIV-1C) chronically infected children (5,6). The clade C primary isolates that we established from some of these chronically infected children were relatively resistant to some of the tested second generation adult bnAbs (18). From this cohort of HIV-1 infected antiretroviral naive children that were longitudinally studied, we identified and characterised herein a pair of genetically identical twins, who were infected at the time of birth by vertical transmission.…”

Section: Discussionmentioning

confidence: 99%

“…Chronically infected children have been shown to have potent plasma bnAbs with diverse epitope specificities (5,6). In our pediatric cohort of antiretroviral naïve HIV-1C infected long term non-progressors (LTNPs) characterized for plasma antibody responses (6,13–18), we identified a pair of antiretroviral naive HIV-1C infected children AIIMS_329 and AIIMS_330, defined herein as genetically identical twins by their identical HLA haplotypes, who had acquired the infection at birth by vertical transmission. Both twins AIIMS_329 and AIIMS_330 developed potent plasma neutralizing antibodies, with the latter showing elite neutralizing activity since first sampling.…”

Section: Introductionmentioning

confidence: 99%

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Viral characteristics associated with sustenance of elite neutralizing activity in chronically HIV-1C infected monozygotic pediatric twins

Mishra

Makhdoomi

Sharma

et al. 2018

Preprint

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15Importance 37Chronically HIV-1 infected children that develop elite neutralizing activity are suitable can-38 didates to understand the mechanisms that lead to the co-evolution of virus and antibody re-39 sponse. Here, we evaluated the alterations in virus and antibody responses over time in chron-40 ically HIV-1C infected monozygotic pediatric twins, AIIMS_329 and AIIMS_330, who had 41 acquired the infection by vertical transmission. AIIMS_330 retained the elite plasma neutral-42izing activity throughout, while in AIIMS_329, the potency decreased post 90 months of age. 43The corresponding viral pool from post 90-month samples in AIIMS_330 showed varied sus-44 ceptibility, while that in AIIMS_329, developed resistance to bnAbs and autologous plasma 45antibodies. The findings of this study, conducted in twin children of same genetic make-up 46 and infected at birth with a single source of HIV-1C, suggest that a viral pool with varied 47 susceptibility to antibodies could have been one of the factors responsible for sustained elite 48 neutralizing activity in AIIMS_330. 49 Keywords 50Epitope mapping, HIV-1C envelope, pediatric HIV-1C infection, broadly neutralizing anti-51 bodies, V2-glycan, V3-glycan, pediatric elite neutralizers. 52

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Viral characteristics associated with sustenance of elite neutralizing activity in chronically HIV-1C infected monozygotic pediatric twins

Mishra

Makhdoomi

Sharma

et al. 2018

Preprint

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“…Chronically HIV-1-infected children have been shown to have potent plasma bnAbs with diverse epitope specificities (5,6). In our pediatric cohort of antiretroviral-naive HIC-1 clade C (HIV-1C)-infected children previously characterized for plasma antibody responses (6,(13)(14)(15)(16)(17)(18), we identified a pair of chronically infected antiretroviral-naive HIV-1C-infected children, AIIMS_329 and AIIMS_330, defined herein as genetically identical twins by their identical HLA phenotypes, who had acquired the infection at birth by vertical transmission. Both twins AIIMS_329 and AIIMS_330 developed potent plasma neutralizing antibodies (nAbs), with the latter showing elite neutralizing activity since the first sampling.…”

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confidence: 99%

Viral Characteristics Associated with Maintenance of Elite Neutralizing Activity in Chronically HIV-1 Clade C-Infected Monozygotic Pediatric Twins

Mishra

Makhdoomi

Sharma

et al. 2019

J Virol

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Broad and potent neutralizing antibodies (bnAbs) with multiple epitope specificities evolve in HIV-1-infected children. Herein, we studied two antiretroviral-naive chronically HIV-1 clade C-infected monozygotic pediatric twins, AIIMS_329 and AIIMS_330, with potent plasma bnAbs. Elite plasma neutralizing activity was observed since the initial sampling at 78 months of age in AIIMS_330 and persisted throughout, while in AIIMS_329 it was seen at 90 months of age, after which the potency decreased over time. We evaluated potential viral characteristics associated with the varied immune profiles by generating single genome-amplified pseudoviruses. The AIIMS_329 viruses generated from the 90-month time point were neutralization sensitive to bnAbs and contemporaneous plasma antibodies, while viruses from the 112-month and 117-month time points were resistant to most bnAbs and contemporaneous plasma. AIIMS_329 viruses developed resistance to plasma neutralizing antibodies (nAbs) plausibly by N160 glycan loss and V1 and V4 loop lengthening. The viruses generated from AIIMS_330 (at 90 and 117 months) showed varied susceptibility to bnAbs and autologous contemporaneous plasma antibodies, while the viruses of the 112-month time point, at which the plasma nAb specificities mapped to the V2 glycan, V3 glycan, and CD4 binding site (CD4bs), were resistant to contemporaneous plasma antibodies as well as to most bnAbs. Chimeric viruses were constructed from 90-month-time-point PG9-sensitive AIIMS_329 and AIIMS_330 viruses with swapped V1V2 regions of their respective evolved viruses (at 112 and 117 months), which led to higher resistance to neutralization by PG9 and autologous plasma antibodies. We observed the evolution of a viral pool in the AIIMS_330 donor comprising plasma antibody neutralization-sensitive or -resistant diverse autologous viruses that may have contributed to the development and maintenance of elite neutralizing activity. IMPORTANCE Herein, we report the longitudinal development of bnAbs in a pair of chronically HIV-1 clade C-infected monozygotic pediatric twins, AIIMS_329 and AIIMS_330, who acquired the infection by vertical transmission. The plasma from both donors, sharing a similar genetic makeup and infecting virus, showed the evolvement of bnAbs targeting common epitopes in the V2 and V3 regions of the envelope, suggesting that bnAb development in these twins may perhaps be determined by specific sequences in the shared virus that can guide the development of immunogens aimed at eliciting V2 and V3 bNAbs. Characterization of the neutralization-sensitive and -resistant viruses coevolving with bNAbs in the contemporaneous AIIMS_330 plasma provides information toward understanding the viral alterations that may have contributed to the development of resistance to bnAbs. Further longitudinal studies in more monozygotic and dizygotic twin pairs will help in delineating the role of host and viral factors that may contribute to the development of bnAbs.

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“…The tier 2 viruses 92RW020 (clade A), QZ4589 (subtype_B), JRCSF (subtype_B) and DU422.1 (subtype_C) were neutralized by D11 and C11 scFv monoclonals at significantly low IC50 values. The D11 scFv neutralized 10/16 subtype_C Indian primary isolates tested434445 (mostly known to be resistant viruses). The C11 scFv achieved IC50 titers for 27 viruses, D11 scFv for 33 viruses, 1F6 scFv for 19 viruses, out of the 50 viruses tested (Table 2).…”

Section: Resultsmentioning

confidence: 99%

“…The neutralization profiling of INDO-SA 2007 is recently published and that of INDO-SA 0030 was unpublished data. Briefly, different dilutions of scFv monoclonals (100 μg/ml–0.09 μg/ml) were incubated with 200 TCID of the pseudoviruses/primary isolates444565 (derived from PBMCs of HIV-1 infected Indian donors) for 1 h at 37 °C. Then TZM-bl cells were trypsinized and seeded at 10 4 cells/well (in DMEM, containing 25 ug/ml DEAE Dextran).…”

Section: Methodsmentioning

confidence: 99%

Cross-neutralizing anti-HIV-1 human single chain variable fragments(scFvs) against CD4 binding site and N332 glycan identified from a recombinant phage library

Khan

Kumar

Thiruvengadam

et al. 2017

Sci Rep

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More than 50% of HIV-1 infection globally is caused by subtype_C viruses. Majority of the broadly neutralizing antibodies (bnAbs) targeting HIV-1 have been isolated from non-subtype_C infected donors. Mapping the epitope specificities of bnAbs provides useful information for vaccine design. Recombinant antibody technology enables generation of a large repertoire of monoclonals with diverse specificities. We constructed a phage recombinant single chain variable fragment (scFv) library with a diversity of 7.8 × 108 clones, using a novel strategy of pooling peripheral blood mononuclear cells (PBMCs) of six select HIV-1 chronically infected Indian donors whose plasma antibodies exhibited potent cross neutralization efficiency. The library was panned and screened by phage ELISA using trimeric recombinant proteins to identify viral envelope specific clones. Three scFv monoclonals D11, C11 and 1F6 selected from the library cross neutralized subtypes A, B and C viruses at concentrations ranging from 0.09 μg/mL to 100 μg/mL. The D11 and 1F6 scFvs competed with mAbs b12 and VRC01 demonstrating CD4bs specificity, while C11 demonstrated N332 specificity. This is the first study to identify cross neutralizing scFv monoclonals with CD4bs and N332 glycan specificities from India. Cross neutralizing anti-HIV-1 human scFv monoclonals can be potential candidates for passive immunotherapy and for guiding immunogen design.

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Neutralization resistant HIV-1 primary isolates from antiretroviral naïve chronically infected children in India

Cited by 7 publications

References 77 publications

Viral characteristics associated with sustenance of elite neutralizing activity in chronically HIV-1C infected monozygotic pediatric twins

Viral characteristics associated with sustenance of elite neutralizing activity in chronically HIV-1C infected monozygotic pediatric twins

Viral Characteristics Associated with Maintenance of Elite Neutralizing Activity in Chronically HIV-1 Clade C-Infected Monozygotic Pediatric Twins

Cross-neutralizing anti-HIV-1 human single chain variable fragments(scFvs) against CD4 binding site and N332 glycan identified from a recombinant phage library

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