Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 226
Filtrar
1.
Sci Transl Med ; 16(748): eadn0223, 2024 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-38753806

RESUMEN

A protective HIV vaccine will likely need to induce broadly neutralizing antibodies (bnAbs). Vaccination with the germline-targeting immunogen eOD-GT8 60mer adjuvanted with AS01B was found to induce VRC01-class bnAb precursors in 97% of vaccine recipients in the IAVI G001 phase 1 clinical trial; however, heterologous boost immunizations with antigens more similar to the native glycoprotein will be required to induce bnAbs. Therefore, we designed core-g28v2 60mer, a nanoparticle immunogen to be used as a first boost after eOD-GT8 60mer priming. We found, using a humanized mouse model approximating human conditions of VRC01-class precursor B cell diversity, affinity, and frequency, that both protein- and mRNA-based heterologous prime-boost regimens induced VRC01-class antibodies that gained key mutations and bound to near-native HIV envelope trimers lacking the N276 glycan. We further showed that VRC01-class antibodies induced by mRNA-based regimens could neutralize pseudoviruses lacking the N276 glycan. These results demonstrated that heterologous boosting can drive maturation toward VRC01-class bnAb development and supported the initiation of the IAVI G002 phase 1 trial testing mRNA-encoded nanoparticle prime-boost regimens.


Asunto(s)
Vacunas contra el SIDA , Anticuerpos Neutralizantes , Anticuerpos Anti-VIH , Animales , Humanos , Vacunas contra el SIDA/inmunología , Anticuerpos Neutralizantes/inmunología , Anticuerpos Anti-VIH/inmunología , Ratones , Vacunación , Inmunización Secundaria , VIH-1/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/prevención & control , Anticuerpos ampliamente neutralizantes/inmunología
2.
Sci Immunol ; 9(95): eadn0622, 2024 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-38753808

RESUMEN

Germline-targeting (GT) protein immunogens to induce VRC01-class broadly neutralizing antibodies (bnAbs) to the CD4-binding site of the HIV envelope (Env) have shown promise in clinical trials. Here, we preclinically validated a lipid nanoparticle-encapsulated nucleoside mRNA (mRNA-LNP) encoding eOD-GT8 60mer as a soluble self-assembling nanoparticle in mouse models. In a model with three humanized B cell lineages bearing distinct VRC01-precursor B cell receptors (BCRs) with similar affinities for eOD-GT8, all lineages could be simultaneously primed and undergo diversification and affinity maturation without exclusionary competition. Boosts drove precursor B cell participation in germinal centers; the accumulation of somatic hypermutations, including in key VRC01-class positions; and affinity maturation to boost and native-like antigens in two of the three precursor lineages. We have preclinically validated a prime-boost regimen of soluble self-assembling nanoparticles encoded by mRNA-LNP, demonstrating that multiple lineages can be primed, boosted, and diversified along the bnAb pathway.


Asunto(s)
Anticuerpos ampliamente neutralizantes , Nanopartículas , ARN Mensajero , Animales , Ratones , Humanos , ARN Mensajero/inmunología , ARN Mensajero/genética , Nanopartículas/química , Anticuerpos ampliamente neutralizantes/inmunología , Anticuerpos Anti-VIH/inmunología , Lípidos/inmunología , Infecciones por VIH/inmunología , Vacunas contra el SIDA/inmunología , Anticuerpos Neutralizantes/inmunología , VIH-1/inmunología , Femenino , Anticuerpos Monoclonales , Liposomas
4.
Science ; 384(6697): eadj8321, 2024 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-38753769

RESUMEN

Germline-targeting immunogens hold promise for initiating the induction of broadly neutralizing antibodies (bnAbs) to HIV and other pathogens. However, antibody-antigen recognition is typically dominated by heavy chain complementarity determining region 3 (HCDR3) interactions, and vaccine priming of HCDR3-dominant bnAbs by germline-targeting immunogens has not been demonstrated in humans or outbred animals. In this work, immunization with N332-GT5, an HIV envelope trimer designed to target precursors of the HCDR3-dominant bnAb BG18, primed bnAb-precursor B cells in eight of eight rhesus macaques to substantial frequencies and with diverse lineages in germinal center and memory B cells. We confirmed bnAb-mimicking, HCDR3-dominant, trimer-binding interactions with cryo-electron microscopy. Our results demonstrate proof of principle for HCDR3-dominant bnAb-precursor priming in outbred animals and suggest that N332-GT5 holds promise for the induction of similar responses in humans.


Asunto(s)
Vacunas contra el SIDA , Anticuerpos ampliamente neutralizantes , Regiones Determinantes de Complementariedad , Centro Germinal , Anticuerpos Anti-VIH , Animales , Humanos , Vacunas contra el SIDA/inmunología , Linfocitos B/inmunología , Anticuerpos ampliamente neutralizantes/inmunología , Regiones Determinantes de Complementariedad/inmunología , Microscopía por Crioelectrón , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología , Centro Germinal/inmunología , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/prevención & control , VIH-1/inmunología , Cadenas Pesadas de Inmunoglobulina/inmunología , Cadenas Pesadas de Inmunoglobulina/genética , Macaca mulatta , Células B de Memoria/inmunología
6.
Science ; 384(6697): eadk0582, 2024 May 17.
Artículo en Inglés | MEDLINE | ID: mdl-38753770

RESUMEN

Germline-targeting (GT) HIV vaccine strategies are predicated on deriving broadly neutralizing antibodies (bnAbs) through multiple boost immunogens. However, as the recruitment of memory B cells (MBCs) to germinal centers (GCs) is inefficient and may be derailed by serum antibody-induced epitope masking, driving further B cell receptor (BCR) modification in GC-experienced B cells after boosting poses a challenge. Using humanized immunoglobulin knockin mice, we found that GT protein trimer immunogen N332-GT5 could prime inferred-germline precursors to the V3-glycan-targeted bnAb BG18 and that B cells primed by N332-GT5 were effectively boosted by either of two novel protein immunogens designed to have minimum cross-reactivity with the off-target V1-binding responses. The delivery of the prime and boost immunogens as messenger RNA lipid nanoparticles (mRNA-LNPs) generated long-lasting GCs, somatic hypermutation, and affinity maturation and may be an effective tool in HIV vaccine development.


Asunto(s)
Vacunas contra el SIDA , Anticuerpos ampliamente neutralizantes , Centro Germinal , Anticuerpos Anti-VIH , VIH-1 , Inmunización Secundaria , Nanopartículas , Vacunas de ARNm , Animales , Humanos , Ratones , Vacunas contra el SIDA/inmunología , Linfocitos B/inmunología , Anticuerpos ampliamente neutralizantes/inmunología , Reacciones Cruzadas , Técnicas de Sustitución del Gen , Centro Germinal/inmunología , Anticuerpos Anti-VIH/inmunología , Proteína gp120 de Envoltorio del VIH/inmunología , Proteína gp120 de Envoltorio del VIH/química , Proteína gp120 de Envoltorio del VIH/genética , Infecciones por VIH/inmunología , Infecciones por VIH/prevención & control , VIH-1/inmunología , VIH-1/genética , Liposomas , Células B de Memoria/inmunología , Receptores de Antígenos de Linfocitos B/inmunología , Receptores de Antígenos de Linfocitos B/genética , Hipermutación Somática de Inmunoglobulina , Vacunas de ARNm/inmunología , Femenino , Ratones Endogámicos C57BL
7.
JCI Insight ; 9(10)2024 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-38775156

RESUMEN

Since its emergence, SARS-CoV-2 has been continuously evolving, hampering the effectiveness of current vaccines against COVID-19. mAbs can be used to treat patients at risk of severe COVID-19. Thus, the development of broadly protective mAbs and an understanding of the underlying protective mechanisms are of great importance. Here, we isolated mAbs from donors with breakthrough infection with Omicron subvariants using a single-B cell screening platform. We identified a mAb, O5C2, which possesses broad-spectrum neutralization and antibody-dependent cell-mediated cytotoxic activities against SARS-CoV-2 variants, including EG.5.1. Single-particle analysis by cryo-electron microscopy revealed that O5C2 targeted an unusually large epitope within the receptor-binding domain of spike protein that overlapped with the angiotensin-converting enzyme 2 binding interface. Furthermore, O5C2 effectively protected against BA.5 Omicron infection in vivo by mediating changes in transcriptomes enriched in genes involved in apoptosis and interferon responses. Our findings provide insights into the development of pan-protective mAbs against SARS-CoV-2.


Asunto(s)
Anticuerpos Antivirales , COVID-19 , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , SARS-CoV-2/inmunología , Humanos , COVID-19/inmunología , COVID-19/virología , Anticuerpos Antivirales/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/química , Animales , Ratones , Enzima Convertidora de Angiotensina 2/metabolismo , Enzima Convertidora de Angiotensina 2/inmunología , Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/inmunología , Microscopía por Crioelectrón , Epítopos/inmunología , Anticuerpos ampliamente neutralizantes/inmunología , Citotoxicidad Celular Dependiente de Anticuerpos/inmunología , Femenino
8.
Front Immunol ; 15: 1340619, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38711498

RESUMEN

To design new CARs targeting hepatitis B virus (HBV), we isolated human monoclonal antibodies recognizing the HBV envelope proteins from single B cells of a patient with a resolved infection. HBV-specific memory B cells were isolated by incubating peripheral blood mononuclear cells with biotinylated hepatitis B surface antigen (HBsAg), followed by single-cell flow cytometry-based sorting of live, CD19+ IgG+ HBsAg+ cells. Amplification and sequencing of immunoglobulin genes from single memory B cells identified variable heavy and light chain sequences. Corresponding immunoglobulin chains were cloned into IgG1 expression vectors and expressed in mammalian cells. Two antibodies named 4D06 and 4D08 were found to be highly specific for HBsAg, recognized a conformational and a linear epitope, respectively, and showed broad reactivity and neutralization capacity against all major HBV genotypes. 4D06 and 4D08 variable chain fragments were cloned into a 2nd generation CAR format with CD28 and CD3zeta intracellular signaling domains. The new CAR constructs displayed a high functional avidity when expressed on primary human T cells. CAR-grafted T cells proved to be polyfunctional regarding cytokine secretion and killed HBV-positive target cells. Interestingly, background activation of the 4D08-CAR recognizing a linear instead of a conformational epitope was consistently low. In a preclinical model of chronic HBV infection, murine T cells grafted with the 4D06 and the 4D08 CAR showed on target activity indicated by a transient increase in serum transaminases, and a lower number of HBV-positive hepatocytes in the mice treated. This study demonstrates an efficient and fast approach to identifying pathogen-specific monoclonal human antibodies from small donor cell numbers for the subsequent generation of new CARs.


Asunto(s)
Antígenos de Superficie de la Hepatitis B , Virus de la Hepatitis B , Humanos , Virus de la Hepatitis B/inmunología , Virus de la Hepatitis B/genética , Animales , Ratones , Antígenos de Superficie de la Hepatitis B/inmunología , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/metabolismo , Anticuerpos Monoclonales/inmunología , Inmunoterapia Adoptiva , Hepatitis B/inmunología , Hepatitis B/virología , Anticuerpos ampliamente neutralizantes/inmunología , Linfocitos B/inmunología , Linfocitos T/inmunología
9.
EBioMedicine ; 104: 105151, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38728839

RESUMEN

BACKGROUND: People living with HIV (PLWH) with multidrug-resistant (MDR) viruses have limited therapeutic options and present challenges regarding clinical management. Recent studies have shown that passive transfer of combination broadly neutralizing antibodies (bNAbs) against HIV and anti-domain 1 CD4 antibody UB-421 can sustain virologic suppression in PLWH in the absence of antiretroviral therapy (ART). Yet studies addressing the therapeutic potential of these antibodies and/or detailed characterization of immunologic and virologic parameters in PLWH with MDR HIV are lacking. METHODS: We examined levels of immune activation and exhaustion markers on CD8+ T cells and the intact HIV proviral DNA burden in 11 PLWH with MDR viruses. For comparison purposes, we included a control group consisting of 27 ART-naïve viremic PLWH. In addition, we determined the sensitivity of infectious viral isolates obtained from the participants against eight bNAbs (3BNC117, 10-1074, VRC01, VRC07, N6, 10E8, PGDM1400, and PGT121) and two anti-CD4 antibodies (ibalizumab and UB-421) using a TZM-bl-based neutralization/suppression assay. FINDINGS: The level of intact HIV proviral DNA was comparable between the two groups (P = 0.29). The levels of activation and exhaustion markers PD-1 (P = 0.0019), TIGIT (P = 0.0222), 2B4 (P = 0.0015), CD160 (P = 0.0015), and CD38+/HLA-DR+ (P = 0.0138) were significantly lower in the MDR group. The infectious viral isolates from each study participant with MDR HIV were resistant to at least 2 bNAbs; however, they were sensitive to at least one of the CD4-binding and non-CD4-binding site antibodies. The majority of participants had ibalizumab-sensitive viruses although the isolates from some participants showed reduced sensitivity to ibalizumab. Notably, none of the 93 viral isolates obtained from the participants were resistant to UB-421. INTERPRETATION: Our data suggest that combination therapy with HIV-specific bNAbs and/or UB-421 in the presence of optimized background therapy could potentially provide sustained virologic suppression in PLWH with MDR HIV. However, this therapeutic strategy needs to be evaluated in human clinical trials. FUNDING: Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.


Asunto(s)
Anticuerpos Neutralizantes , Anticuerpos ampliamente neutralizantes , Anticuerpos Anti-VIH , Infecciones por VIH , VIH-1 , Humanos , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Infecciones por VIH/tratamiento farmacológico , VIH-1/inmunología , Masculino , Femenino , Adulto , Anticuerpos Neutralizantes/inmunología , Persona de Mediana Edad , Anticuerpos ampliamente neutralizantes/inmunología , Anticuerpos Anti-VIH/inmunología , Antígenos CD4/metabolismo , Antígenos CD4/inmunología , Farmacorresistencia Viral Múltiple , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Carga Viral , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo
10.
Nat Immunol ; 25(6): 1083-1096, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38816616

RESUMEN

Current prophylactic human immunodeficiency virus 1 (HIV-1) vaccine research aims to elicit broadly neutralizing antibodies (bnAbs). Membrane-proximal external region (MPER)-targeting bnAbs, such as 10E8, provide exceptionally broad neutralization, but some are autoreactive. Here, we generated humanized B cell antigen receptor knock-in mouse models to test whether a series of germline-targeting immunogens could drive MPER-specific precursors toward bnAbs. We found that recruitment of 10E8 precursors to germinal centers (GCs) required a minimum affinity for germline-targeting immunogens, but the GC residency of MPER precursors was brief due to displacement by higher-affinity endogenous B cell competitors. Higher-affinity germline-targeting immunogens extended the GC residency of MPER precursors, but robust long-term GC residency and maturation were only observed for MPER-HuGL18, an MPER precursor clonotype able to close the affinity gap with endogenous B cell competitors in the GC. Thus, germline-targeting immunogens could induce MPER-targeting antibodies, and B cell residency in the GC may be regulated by a precursor-competitor affinity gap.


Asunto(s)
Afinidad de Anticuerpos , Linfocitos B , Centro Germinal , Anticuerpos Anti-VIH , VIH-1 , Centro Germinal/inmunología , Animales , Ratones , Humanos , Linfocitos B/inmunología , VIH-1/inmunología , Anticuerpos Anti-VIH/inmunología , Afinidad de Anticuerpos/inmunología , Anticuerpos Neutralizantes/inmunología , Infecciones por VIH/inmunología , Vacunas contra el SIDA/inmunología , Receptores de Antígenos de Linfocitos B/metabolismo , Receptores de Antígenos de Linfocitos B/inmunología , Técnicas de Sustitución del Gen , Ratones Transgénicos , Anticuerpos ampliamente neutralizantes/inmunología , Ratones Endogámicos C57BL
11.
Nat Immunol ; 25(6): 1073-1082, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38816615

RESUMEN

A key barrier to the development of vaccines that induce broadly neutralizing antibodies (bnAbs) against human immunodeficiency virus (HIV) and other viruses of high antigenic diversity is the design of priming immunogens that induce rare bnAb-precursor B cells. The high neutralization breadth of the HIV bnAb 10E8 makes elicitation of 10E8-class bnAbs desirable; however, the recessed epitope within gp41 makes envelope trimers poor priming immunogens and requires that 10E8-class bnAbs possess a long heavy chain complementarity determining region 3 (HCDR3) with a specific binding motif. We developed germline-targeting epitope scaffolds with affinity for 10E8-class precursors and engineered nanoparticles for multivalent display. Scaffolds exhibited epitope structural mimicry and bound bnAb-precursor human naive B cells in ex vivo screens, protein nanoparticles induced bnAb-precursor responses in stringent mouse models and rhesus macaques, and mRNA-encoded nanoparticles triggered similar responses in mice. Thus, germline-targeting epitope scaffold nanoparticles can elicit rare bnAb-precursor B cells with predefined binding specificities and HCDR3 features.


Asunto(s)
Vacunas contra el SIDA , Anticuerpos Neutralizantes , Anticuerpos Anti-VIH , Proteína gp41 de Envoltorio del VIH , Infecciones por VIH , VIH-1 , Macaca mulatta , Animales , Humanos , Proteína gp41 de Envoltorio del VIH/inmunología , Anticuerpos Anti-VIH/inmunología , Ratones , Vacunas contra el SIDA/inmunología , Anticuerpos Neutralizantes/inmunología , VIH-1/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/prevención & control , Infecciones por VIH/virología , Vacunación , Anticuerpos ampliamente neutralizantes/inmunología , Linfocitos B/inmunología , Nanopartículas/química , Femenino , Regiones Determinantes de Complementariedad/inmunología , Epítopos/inmunología
12.
Immunity ; 57(5): 1141-1159.e11, 2024 May 14.
Artículo en Inglés | MEDLINE | ID: mdl-38670113

RESUMEN

Broadly neutralizing antibodies (bnAbs) targeting the hemagglutinin (HA) stem of influenza A viruses (IAVs) tend to be effective against either group 1 or group 2 viral diversity. In rarer cases, intergroup protective bnAbs can be generated by human antibody paratopes that accommodate the conserved glycan differences between the group 1 and group 2 stems. We applied germline-engaging nanoparticle immunogens to elicit a class of cross-group bnAbs from physiological precursor frequency within a humanized mouse model. Cross-group protection depended on the presence of the human bnAb precursors within the B cell repertoire, and the vaccine-expanded antibodies enriched for an N55T substitution in the CDRH2 loop, a hallmark of the bnAb class. Structurally, this single mutation introduced a flexible fulcrum to accommodate glycosylation differences and could alone enable cross-group protection. Thus, broad IAV immunity can be expanded from the germline repertoire via minimal antigenic input and an exceptionally simple antibody development pathway.


Asunto(s)
Anticuerpos Neutralizantes , Anticuerpos Antivirales , Virus de la Influenza A , Vacunas contra la Influenza , Infecciones por Orthomyxoviridae , Vacunación , Animales , Ratones , Humanos , Anticuerpos Antivirales/inmunología , Vacunas contra la Influenza/inmunología , Virus de la Influenza A/inmunología , Anticuerpos Neutralizantes/inmunología , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/prevención & control , Glicoproteínas Hemaglutininas del Virus de la Influenza/inmunología , Sustitución de Aminoácidos , Linfocitos B/inmunología , Gripe Humana/inmunología , Gripe Humana/prevención & control , Anticuerpos ampliamente neutralizantes/inmunología
13.
Cell Host Microbe ; 32(5): 693-709.e7, 2024 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-38670093

RESUMEN

A major goal of HIV-1 vaccine development is the induction of broadly neutralizing antibodies (bnAbs). Although success has been achieved in initiating bnAb B cell lineages, design of boosting immunogens that select for bnAb B cell receptors with improbable mutations required for bnAb affinity maturation remains difficult. Here, we demonstrate a process for designing boosting immunogens for a V3-glycan bnAb B cell lineage. The immunogens induced affinity-matured antibodies by selecting for functional improbable mutations in bnAb precursor knockin mice. Moreover, we show similar success in prime and boosting with nucleoside-modified mRNA-encoded HIV-1 envelope trimer immunogens, with improved selection by mRNA immunogens of improbable mutations required for bnAb binding to key envelope glycans. These results demonstrate the ability of both protein and mRNA prime-boost immunogens for selection of rare B cell lineage intermediates with neutralizing breadth after bnAb precursor expansion, a key proof of concept and milestone toward development of an HIV-1 vaccine.


Asunto(s)
Vacunas contra el SIDA , Anticuerpos Neutralizantes , Linfocitos B , Anticuerpos Anti-VIH , VIH-1 , Vacunas contra el SIDA/inmunología , Vacunas contra el SIDA/genética , Animales , Anticuerpos Anti-VIH/inmunología , VIH-1/inmunología , VIH-1/genética , Ratones , Anticuerpos Neutralizantes/inmunología , Linfocitos B/inmunología , Humanos , Infecciones por VIH/inmunología , Infecciones por VIH/prevención & control , Anticuerpos ampliamente neutralizantes/inmunología , Mutación , Desarrollo de Vacunas , Inmunización Secundaria , Productos del Gen env del Virus de la Inmunodeficiencia Humana/inmunología , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genética
14.
Clin Microbiol Rev ; 37(2): e0015222, 2024 Jun 13.
Artículo en Inglés | MEDLINE | ID: mdl-38687039

RESUMEN

SUMMARYThe human immunodeficiency virus (HIV) epidemic remains a formidable global health concern, with 39 million people living with the virus and 1.3 million new infections reported in 2022. Despite anti-retroviral therapy's effectiveness in pre-exposure prophylaxis, its global adoption is limited. Broadly neutralizing antibodies (bNAbs) offer an alternative strategy for HIV prevention through passive immunization. Historically, passive immunization has been efficacious in the treatment of various diseases ranging from oncology to infectious diseases. Early clinical trials suggest bNAbs are safe, tolerable, and capable of reducing HIV RNA levels. Although challenges such as bNAb resistance have been noted in phase I trials, ongoing research aims to assess the additive or synergistic benefits of combining multiple bNAbs. Researchers are exploring bispecific and trispecific antibodies, and fragment crystallizable region modifications to augment antibody efficacy and half-life. Moreover, the potential of other antibody isotypes like IgG3 and IgA is under investigation. While promising, the application of bNAbs faces economic and logistical barriers. High manufacturing costs, particularly in resource-limited settings, and logistical challenges like cold-chain requirements pose obstacles. Preliminary studies suggest cost-effectiveness, although this is contingent on various factors like efficacy and distribution. Technological advancements and strategic partnerships may mitigate some challenges, but issues like molecular aggregation remain. The World Health Organization has provided preferred product characteristics for bNAbs, focusing on optimizing their efficacy, safety, and accessibility. The integration of bNAbs in HIV prophylaxis necessitates a multi-faceted approach, considering economic, logistical, and scientific variables. This review comprehensively covers the historical context, current advancements, and future avenues of bNAbs in HIV prevention.


Asunto(s)
Anticuerpos Anti-VIH , Infecciones por VIH , Humanos , Infecciones por VIH/prevención & control , Infecciones por VIH/inmunología , Anticuerpos Anti-VIH/inmunología , Anticuerpos Anti-VIH/uso terapéutico , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/uso terapéutico , Anticuerpos ampliamente neutralizantes/inmunología , Anticuerpos ampliamente neutralizantes/uso terapéutico , Inmunización Pasiva/métodos , VIH-1/inmunología
15.
J Virol ; 98(3): e0172023, 2024 Mar 19.
Artículo en Inglés | MEDLINE | ID: mdl-38412036

RESUMEN

The rational design of HIV-1 immunogens to trigger the development of broadly neutralizing antibodies (bNAbs) requires understanding the viral evolutionary pathways influencing this process. An acute HIV-1-infected individual exhibiting >50% plasma neutralization breadth developed neutralizing antibody specificities against the CD4-binding site (CD4bs) and V1V2 regions of Env gp120. Comparison of pseudoviruses derived from early and late autologous env sequences demonstrated the development of >2 log resistance to VRC13 but not to other CD4bs-specific bNAbs. Mapping studies indicated that the V3 and CD4-binding loops of Env gp120 contributed significantly to developing resistance to the autologous neutralizing response and that the CD4-binding loop (CD4BL) specifically was responsible for the developing resistance to VRC13. Tracking viral evolution during the development of this cross-neutralizing CD4bs response identified amino acid substitutions arising at only 4 of 11 known VRC13 contact sites (K282, T283, K421, and V471). However, each of these mutations was external to the V3 and CD4BL regions conferring resistance to VRC13 and was transient in nature. Rather, complete resistance to VRC13 was achieved through the cooperative expression of a cluster of single amino acid changes within and immediately adjacent to the CD4BL, including a T359I substitution, exchange of a potential N-linked glycosylation (PNLG) site to residue S362 from N363, and a P369L substitution. Collectively, our data characterize complex HIV-1 env evolution in an individual developing resistance to a VRC13-like neutralizing antibody response and identify novel VRC13-associated escape mutations that may be important to inducing VRC13-like bNAbs for lineage-based immunogens.IMPORTANCEThe pursuit of eliciting broadly neutralizing antibodies (bNAbs) through vaccination and their use as therapeutics remains a significant focus in the effort to eradicate HIV-1. Key to our understanding of this approach is a more extensive understanding of bNAb contact sites and susceptible escape mutations in HIV-1 envelope (env). We identified a broad neutralizer exhibiting VRC13-like responses, a non-germline restricted class of CD4-binding site antibody distinct from the well-studied VRC01-class. Through longitudinal envelope sequencing and Env-pseudotyped neutralization assays, we characterized a complex escape pathway requiring the cooperative evolution of four amino acid changes to confer complete resistance to VRC13. This suggests that VRC13-class bNAbs may be refractory to rapid escape and attractive for therapeutic applications. Furthermore, the identification of longitudinal viral changes concomitant with the development of neutralization breadth may help identify the viral intermediates needed for the maturation of VRC13-like responses and the design of lineage-based immunogens.


Asunto(s)
Anticuerpos ampliamente neutralizantes , Infecciones por VIH , Humanos , Aminoácidos , Anticuerpos ampliamente neutralizantes/inmunología , Antígenos CD4/genética , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genética , Epítopos , Anticuerpos Anti-VIH , Antígenos VIH , Proteína gp120 de Envoltorio del VIH/genética , Seropositividad para VIH , VIH-1/genética , Vacunas contra el SIDA/inmunología
16.
J Virol ; 98(1): e0152223, 2024 Jan 23.
Artículo en Inglés | MEDLINE | ID: mdl-38169306

RESUMEN

Understanding how different amino acids affect the HIV-1 envelope (Env) trimer will greatly help the design and development of vaccines that induce broadly neutralizing antibodies (bnAbs). A tryptophan residue at position 375 that opens the CD4 binding site without modifying the trimer apex was identified using our saturation mutagenesis strategy. 375W was introduced into a large panel of 27 transmitted/founder, acute stage, chronic infection, and AIDS macrophage-tropic and non-macrophage-tropic primary envelopes from different clades (A, B, C, D, and G) as well as complex and circulating recombinants. We evaluated soluble CD4 and monoclonal antibody neutralization of WT and mutant Envs together with macrophage infection. The 375W substitution increased sensitivity to soluble CD4 in all 27 Envs and macrophage infection in many Envs including an X4 variant. Importantly, 375W did not impair or abrogate neutralization by potent bnAbs. Variants that were already highly macrophage tropic were compromised for macrophage tropism, indicating that other structural factors are involved. Of note, we observed a macrophage-tropic (clade G) and intermediate macrophage-tropic (clades C and D) primary Envs from the blood and not from the central nervous system (CNS), indicating that such variants could be released from the brain or evolve outside the CNS. Our data also indicate that "intermediate" macrophage-tropic variants should belong to a new class of HIV-1 tropism. These Envs infected macrophages more efficiently than non-macrophage-tropic variants without reaching the high levels of macrophage-tropic brain variants. In summary, we show that 375W is ideal for inclusion into HIV-1 vaccines, increasing Env binding to CD4 for widely diverse Envs from different clades and disease stages.IMPORTANCESubstitutions exposing the CD4 binding site (CD4bs) on HIV-1 trimers but still occluding non-neutralizing, immunogenic epitopes are desirable to develop HIV-1 vaccines. If such substitutions induce similar structural changes in trimers across diverse clades, they could be exploited for the development of multi-clade envelope (Env) vaccines. We show that the 375W substitution increases CD4 affinity for envelopes of all clades, circulating recombinant forms, and complex Envs tested, independent of disease stage. Clade B and C Envs with an exposed CD4bs were described for macrophage-tropic strains from the central nervous system (CNS). Here, we show that intermediate (clades C and D) and macrophage-tropic (clade G) envelopes can be detected outside the CNS. Vaccines targeting the CD4bs will be particularly effective against such strains and CNS disease.


Asunto(s)
Infecciones por VIH , VIH-1 , Tropismo Viral , Productos del Gen env del Virus de la Inmunodeficiencia Humana , Humanos , Anticuerpos ampliamente neutralizantes/inmunología , Productos del Gen env del Virus de la Inmunodeficiencia Humana/genética , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/prevención & control , VIH-1/genética , Mutación , Desarrollo de Vacunas , Macrófagos/virología , Antígenos CD4
17.
J Virol ; 97(9): e0071023, 2023 09 28.
Artículo en Inglés | MEDLINE | ID: mdl-37681958

RESUMEN

The envelope (Env) glycoproteins on HIV-1 virions are the sole target of broadly neutralizing antibodies (bNAbs) and the focus of vaccines. However, many cross-reactive conserved epitopes are often occluded on virus particles, contributing to the evasion of humoral immunity. This study aimed to identify the Env epitopes that are exposed/occluded on HIV-1 particles and to investigate the mechanisms contributing to their masking. Using a flow cytometry-based assay, three HIV-1 isolates, and a panel of antibodies, we show that only select epitopes, including V2i, the gp120-g41 interface, and gp41-MPER, are accessible on HIV-1 particles, while V3, V2q, and select CD4bs epitopes are masked. These epitopes become accessible after allosteric conformational changes are induced by the pre-binding of select Abs, prompting us to test if similar conformational changes are required for these Abs to exhibit their neutralization capability. We tested HIV-1 neutralization where the virus-mAb mix was pre-incubated/not pre-incubated for 1 hour prior to adding the target cells. Similar levels of neutralization were observed under both assay conditions, suggesting that the interaction between virus and target cells sensitizes the virions for neutralization via bNAbs. We further show that lectin-glycan interactions can also expose these epitopes. However, this effect is dependent on the lectin specificity. Given that, bNAbs are ideal for providing sterilizing immunity and are the goal of current HIV-1 vaccine efforts, these data offer insight on how HIV-1 may occlude these vulnerable epitopes from the host immune response. In addition, the findings can guide the formulation of effective antibody combinations for therapeutic use. IMPORTANCE The human immunodeficiency virus (HIV-1) envelope (Env) glycoprotein mediates viral entry and is the sole target of neutralizing antibodies. Our data suggest that antibody epitopes including V2q (e.g., PG9, PGT145), CD4bs (e.g., VRC01, 3BNC117), and V3 (2219, 2557) are masked on HIV-1 particles. The PG9 and 2219 epitopes became accessible for binding after conformational unmasking was induced by the pre-binding of select mAbs. Attempts to understand the masking mechanism led to the revelation that interaction between virus and host cells is needed to sensitize the virions for neutralization by broadly neutralizing antibodies (bNAbs). These data provide insight on how bNAbs may gain access to these occluded epitopes to exert their neutralization effects and block HIV-1 infection. These findings have important implications for the way we evaluate the neutralizing efficacy of antibodies and can potentially guide vaccine design.


Asunto(s)
Anticuerpos ampliamente neutralizantes , Epítopos de Linfocito B , Anticuerpos Anti-VIH , Infecciones por VIH , VIH-1 , Interacciones Microbiota-Huesped , Humanos , Anticuerpos Monoclonales/inmunología , Anticuerpos ampliamente neutralizantes/inmunología , Anticuerpos Anti-VIH/inmunología , Proteína gp120 de Envoltorio del VIH/inmunología , Proteína gp120 de Envoltorio del VIH/metabolismo , Infecciones por VIH/inmunología , Infecciones por VIH/patología , Infecciones por VIH/virología , VIH-1/química , VIH-1/inmunología , VIH-1/metabolismo , Lectinas/metabolismo , Epítopos de Linfocito B/inmunología , Epítopos de Linfocito B/metabolismo , Vacunas contra el SIDA/química , Vacunas contra el SIDA/inmunología , Virión/química , Virión/inmunología , Virión/metabolismo , Polisacáridos/metabolismo
20.
JAMA ; 329(7): 527-528, 2023 02 21.
Artículo en Inglés | MEDLINE | ID: mdl-36723948

RESUMEN

This Medical News article discusses a clinical trial for an HIV vaccine that uses germline targeting, a novel technique to induce rare immune cell precursors of broadly neutralizing antibodies.


Asunto(s)
Vacunas contra el SIDA , Anticuerpos ampliamente neutralizantes , Infecciones por VIH , VIH-1 , Humanos , Vacunas contra el SIDA/inmunología , Vacunas contra el SIDA/uso terapéutico , Anticuerpos Neutralizantes/inmunología , Anticuerpos ampliamente neutralizantes/inmunología , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/prevención & control
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA