HIV-1 co-receptor usage and variable loop contact impacts V3 loop bnAb susceptibility

Registre, Ludy; Moreau, Yvetane; Ataca, Sila; Pulukuri, Surya; Henrich, Timothy J.; Lin, Nina; Sagar, Manish

doi:10.1101/568469

Cited by 3 publications

(2 citation statements)

References 60 publications

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“…Furthermore, the magnitude of the breast milk IgG or breast milk supernatant ADCC did not associate with transmission when the analysis was restricted to the women with high plasma virus levels (greater than 4.6 log 10 copies per milliliter), as in the previous study. 12 Similar to our previous reports, 6,22 AUC estimates were directly correlated to the percentage decrease observed at the highest tested plasma/antibody dilution (p < 0.0001, r > 0.91 in all cases). In aggregate, higher ADCC and a combination of ADCC plus nAb responses in the exposed individual against the exposure strains associate with lower HIV-1 acquisition.…”

Section: Infant Adcc Responses Are Associated With Lower Transmissionsupporting

confidence: 88%

Pre-existing infant antibody-dependent cellular cytotoxicity associates with reduced HIV-1 acquisition and lower morbidity

Thomas¹,

Moreau²,

Jiang³

et al. 2021

Cell Reports Medicine

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In humans, pre-existing anti-HIV-1 neutralizing antibodies (nAbs) have not been associated with decreased HIV-1 acquisition. Here, we evaluate antibody-dependent cellular cytotoxicity (ADCC) present in pre-transmission infant and maternal plasma and breast milk (BM) against the contemporaneous maternal HIV-1 variants. HIV-1-exposed uninfected compared with HIV-1-exposed infected infants have higher ADCC and a combination of ADCC and nAb responses against their corresponding mother's strains. ADCC does not correlate with nAbs, suggesting they are independent activities. The infected infants with high ADCC compared with low ADCC, but not those with higher ADCC plus nAbs, have lower morbidity up to 1 year after birth. A higher IgA to IgG ratio, observed in BM supernatants and in a higher proportion of the infected compared with the uninfected infants, associates with lower ADCC. Against the exposure strains, ADCC, more than nAbs, associates with both lower mother-to-child transmission and decreased post-infection infant morbidity.

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Section: Infant Adcc Responses Are Associated With Lower Transmissionsupporting

confidence: 88%

Pre-existing infant antibody-dependent cellular cytotoxicity associates with reduced HIV-1 acquisition and lower morbidity

Thomas¹,

Moreau²,

Jiang³

et al. 2021

Cell Reports Medicine

Self Cite

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“…Viral pellets were resuspended in PBS, tittered on TZM-bl cells, aliquoted, and stored at -80 o C until use. 4102-61 is a replication competent HIV-1 clone produced in transfected 293T cells and passaged on primary CD4 T cells 86 . NLCI is an X4-tropic HIV-1 IMC expressing NL4.3 Env and an mCherry reporter in the nef locus with Nef expression restored by the use of an internal ribosome entry site (IRES) 87 .…”

Section: Cell Lines Lectins Anti-env Mabs and Virusesmentioning

confidence: 99%

HIV-1 interaction with an O-glycan-specific bacterial lectin enhances virus infectivity and resistance to neutralization by antibodies

Heindel,

Acosta,

Goff

et al. 2024

Preprint

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Bacteria dysbiosis has been associated with an increased risk of HIV-1 transmission and acquisition. The prevalent idea is that bacteria dysbiosis compromises mucosal integrity and promotes inflammatory conditions to cause recruitment and activation of immune cells that harbor or are targeted by HIV-1. However, it is also possible that HIV-1 directly binds bacteria or bacterial products to impact virus infectivity and transmissibility. This study evaluated HIV-1 interactions with bacteria through glycan-binding lectins. The StreptococcalSiglec-like lectin SLBR-N, which is part of the fimbriae shrouding the bacteria surface and recognizes α2,3 sialyated O-linked glycans, was noted for its ability to enhance HIV-1 infectivity in the context of cell-free infection and cell-to-cell transfer. Enhancing effects were recapitulated with O-glycan-binding plant lectins, signifying the importance of O-glycans. Conversely, N-glycan-binding bacterial lectins FimH and Msl had no effect. SLBR-N was demonstrated to capture and transfer infectious HIV-1 virions, bind to O-glycans on HIV-1 Env, and increase HIV-1 resistance to broadly neutralizing antibodies targeting different regions of Env. Hence, this study highlights the potential contribution of O-glycans in promoting HIV-1 infection through the exploitation of O-glycan-binding lectins from commensal bacteria at the mucosa.

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HIV-1 Coreceptor Usage and Variable Loop Contact Impact V3 Loop Broadly Neutralizing Antibody Susceptibility

Registre

Moreau

Ataca

et al. 2020

J Virol

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In clinical trials, HIV-1 broadly neutralizing antibodies (bnAbs) effectively lower plasma viremia and delay virus reemergence. The presence of less neutralization-susceptible strains prior to treatment decreases the efficacy of these antibody-based treatments, but neutralization sensitivity often cannot be predicted by sequence analysis alone. We found that phenotypically confirmed CXCR4-utilizing strains are less neutralization sensitive, especially to variable loop 3 (V3 loop)-directed bnAbs, than exclusively CCR5-utilizing strains in some, but not all, cases. Homology modeling suggested that the primary V3 loop bnAb epitope is equally accessible among CCR5- and CXCR4-using strains, although variants that exclusively use CXCR4 have V3 loop protrusions that interfere with CCR5 receptor interactions. Homology modeling also showed that among some, but not all, envelopes with decreased neutralization sensitivity, V1 loop orientation interfered with V3 loop-directed bnAb binding. Thus, there are likely different structural reasons for the coreceptor usage restriction and the different bnAb susceptibilities. Importantly, we show that individuals harboring envelopes with higher likelihood of using CXCR4 or greater predicted V1 loop interference have faster virus rebound and a lower maximum decrease in plasma viremia, respectively, after treatment with a V3 loop bnAb. Knowledge of receptor usage and homology models may be useful in developing future algorithms that predict treatment efficacy with V3 loop bnAbs. IMPORTANCE The efficacy of HIV-1 broadly neutralizing antibody (bnAb) therapies may be compromised by the preexistence of less susceptible variants. Sequence-based methods are needed to predict pretreatment variants’ neutralization sensitivities. HIV-1 strains that exclusively use the CXCR4 receptor rather than the CCR5 receptor are less neutralization susceptible, especially to variable loop 3 (V3 loop) bnAbs in some, but not all, instances. While the inability to utilize the CCR5 receptor maps to a predicted protrusion in the envelope V3 loop, this viral determinant does not directly influence V3 loop bnAb sensitivity. Homology modeling predicts that contact between the envelope V1 loop and the antibody impacts V3 loop bnAb susceptibility in some cases. Among pretreatment envelopes, increased probability of using CXCR4 and greater predicted V1 interference are associated with faster virus rebound and a smaller decrease in the plasma virus level, respectively, after V3 loop bnAb treatment. Receptor usage information and homology models may be useful for predicting V3 loop bnAb therapy efficacy.

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HIV-1 co-receptor usage and variable loop contact impacts V3 loop bnAb susceptibility

Cited by 3 publications

References 60 publications

Pre-existing infant antibody-dependent cellular cytotoxicity associates with reduced HIV-1 acquisition and lower morbidity

Pre-existing infant antibody-dependent cellular cytotoxicity associates with reduced HIV-1 acquisition and lower morbidity

HIV-1 interaction with an O-glycan-specific bacterial lectin enhances virus infectivity and resistance to neutralization by antibodies

HIV-1 Coreceptor Usage and Variable Loop Contact Impact V3 Loop Broadly Neutralizing Antibody Susceptibility

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