Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 17 de 17
Filtrar
1.
PLoS Pathog ; 18(11): e1010945, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36395347

RESUMO

Broadly neutralizing antibodies (bNAbs) have remarkable breadth and potency against most HIV-1 subtypes and are able to prevent HIV-1 infection in animal models. However, bNAbs are extremely difficult to induce by vaccination. Defining the developmental pathways towards neutralization breadth can assist in the design of strategies to elicit protective bNAb responses by vaccination. Here, HIV-1 envelope glycoproteins (Env)-specific IgG+ B cells were isolated at various time points post infection from an HIV-1 infected elite neutralizer to obtain monoclonal antibodies (mAbs). Multiple antibody lineages were isolated targeting distinct epitopes on Env, including the gp120-gp41 interface, CD4-binding site, silent face and V3 region. The mAbs each neutralized a diverse set of HIV-1 strains from different clades indicating that the patient's remarkable serum breadth and potency might have been the result of a polyclonal mixture rather than a single bNAb lineage. High-resolution cryo-electron microscopy structures of the neutralizing mAbs (NAbs) in complex with an Env trimer generated from the same individual revealed that the NAbs used multiple strategies to neutralize the virus; blocking the receptor binding site, binding to HIV-1 Env N-linked glycans, and disassembly of the trimer. These results show that diverse NAbs can complement each other to achieve a broad and potent neutralizing serum response in HIV-1 infected individuals. Hence, the induction of combinations of moderately broad NAbs might be a viable vaccine strategy to protect against a wide range of circulating HIV-1 viruses.


Assuntos
Soropositividade para HIV , HIV-1 , Animais , Anticorpos Amplamente Neutralizantes , Microscopia Crioeletrônica , Anticorpos Monoclonais , Proteína gp120 do Envelope de HIV
2.
Nat Commun ; 13(1): 4515, 2022 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-35922441

RESUMO

A major goal of current HIV-1 vaccine design efforts is to induce broadly neutralizing antibodies (bNAbs). The VH1-2-derived bNAb IOMA directed to the CD4-binding site of the HIV-1 envelope glycoprotein is of interest because, unlike the better-known VH1-2-derived VRC01-class bNAbs, it does not require a rare short light chain complementarity-determining region 3 (CDRL3). Here, we describe three IOMA-class NAbs, ACS101-103, with up to 37% breadth, that share many characteristics with IOMA, including an average-length CDRL3. Cryo-electron microscopy revealed that ACS101 shares interactions with those observed with other VH1-2 and VH1-46-class bNAbs, but exhibits a unique binding mode to residues in loop D. Analysis of longitudinal sequences from the patient suggests that a transmitter/founder-virus lacking the N276 glycan might have initiated the development of these NAbs. Together these data strengthen the rationale for germline-targeting vaccination strategies to induce IOMA-class bNAbs and provide a wealth of sequence and structural information to support such strategies.


Assuntos
Infecções por HIV , HIV-1 , Anticorpos Neutralizantes , Antígenos Virais , Sítios de Ligação , Anticorpos Amplamente Neutralizantes , Antígenos CD4/imunologia , Regiões Determinantes de Complementaridade , Microscopia Crioeletrônica , Glicoproteínas , Anticorpos Anti-HIV , Humanos
3.
J Virol ; 96(1): e0155221, 2022 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-34669426

RESUMO

The human immunodeficiency virus type 1 (HIV-1) trimeric envelope glycoprotein (Env) is heavily glycosylated, creating a dense glycan shield that protects the underlying peptidic surface from antibody recognition. The absence of conserved glycans, due to missing potential N-linked glycosylation sites (PNGS), can result in strain-specific, autologous neutralizing antibody (NAb) responses. Here, we sought to gain a deeper understanding of the autologous neutralization by introducing holes in the otherwise dense glycan shields of the AMC011 and AMC016 SOSIP trimers. Specifically, when we knocked out the N130 and N289 glycans, which are absent from the well-characterized B41 SOSIP trimer, we observed stronger autologous NAb responses. We also analyzed the highly variable NAb responses induced in rabbits by diverse SOSIP trimers from subtypes A, B, and C. Statistical analysis, using linear regression, revealed that the cumulative area exposed on a trimer by glycan holes correlates with the magnitude of the autologous NAb response. IMPORTANCE Forty years after the first description of HIV-1, the search for a protective vaccine is still ongoing. The sole target for antibodies that can neutralize the virus are the trimeric envelope glycoproteins (Envs) located on the viral surface. The glycoprotein surface is covered with glycans that shield off the underlying protein components from recognition by the immune system. However, the Env trimers of some viral strains have holes in the glycan shield. Immunized animals developed antibodies against such glycan holes. These antibodies are generally strain specific. Here, we sought to gain a deeper understanding of what drives these specific immune responses. First, we show that strain-specific neutralizing antibody responses can be increased by creating artificial holes in the glycan shield. Second, when studying a diverse set of Env trimers with different characteristics, we found that the surface area of the glycan holes contributes prominently to the induction of strain-specific neutralizing antibodies.


Assuntos
Infecções por HIV/imunologia , HIV-1/imunologia , Polissacarídeos/metabolismo , Multimerização Proteica , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/metabolismo , Vacinas contra a AIDS/imunologia , Aminoácidos/química , Aminoácidos/imunologia , Aminoácidos/metabolismo , Animais , Anticorpos Neutralizantes/imunologia , Formação de Anticorpos/imunologia , Antígenos Virais/imunologia , Glicosilação , Anticorpos Anti-HIV/imunologia , Infecções por HIV/metabolismo , Infecções por HIV/virologia , HIV-1/genética , Interações Hospedeiro-Patógeno , Humanos , Imunização , Modelos Moleculares , Conformação Proteica , Multimerização Proteica/imunologia , Coelhos , Deleção de Sequência , Relação Estrutura-Atividade , Produtos do Gene env do Vírus da Imunodeficiência Humana/química , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética
4.
Cell Rep ; 35(1): 108933, 2021 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-33826885

RESUMO

Artificial glycan holes on recombinant Env-based vaccines occur when a potential N-linked glycosylation site (PNGS) is under-occupied, but not on their viral counterparts. Native-like SOSIP trimers, including clinical candidates, contain such holes in the glycan shield that induce strain-specific neutralizing antibodies (NAbs) or non-NAbs. To eliminate glycan holes and mimic the glycosylation of native BG505 Env, we replace all 12 NxS sequons on BG505 SOSIP with NxT. All PNGS, except N133 and N160, are nearly fully occupied. Occupancy of the N133 site is increased by changing N133 to NxS, whereas occupancy of the N160 site is restored by reverting the nearby N156 sequon to NxS. Hence, PNGS in close proximity, such as in the N133-N137 and N156-N160 pairs, affect each other's occupancy. We further apply this approach to improve the occupancy of several Env strains. Increasing glycan occupancy should reduce off-target immune responses to vaccine antigens.


Assuntos
HIV-1/metabolismo , Polissacarídeos/metabolismo , Multimerização Proteica , Produtos do Gene env do Vírus da Imunodeficiência Humana/química , Produtos do Gene env do Vírus da Imunodeficiência Humana/metabolismo , Animais , Células CHO , Cricetulus , Microscopia Crioeletrônica , Glicosilação , Células HEK293 , Hexosiltransferases/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Modelos Moleculares , Polissacarídeos/química , Solubilidade , Produtos do Gene env do Vírus da Imunodeficiência Humana/ultraestrutura
5.
J Virol ; 94(24)2020 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-32999024

RESUMO

The induction of broadly neutralizing antibodies (bNAbs) is a major goal in vaccine research. HIV-1-infected individuals that develop exceptionally strong bNAb responses, termed elite neutralizers, can inform vaccine design by providing blueprints for the induction of similar bNAb responses. We describe a new recombinant native-like envelope glycoprotein (Env) SOSIP trimer, termed AMC009, based on the viral founder sequences of an elite neutralizer. The subtype B AMC009 SOSIP protein formed stable native-like trimers that displayed multiple bNAb epitopes. Overall, its structure at 4.3-Å resolution was similar to that of BG505 SOSIP.664. The AMC009 trimer resembled one from a second elite neutralizer, AMC011, in having a dense and complete glycan shield. When tested as immunogens in rabbits, the AMC009 trimers did not induce autologous neutralizing antibody (NAb) responses efficiently while the AMC011 trimers did so very weakly, outcomes that may reflect the completeness of their glycan shields. The AMC011 trimer induced antibodies that occasionally cross-neutralized heterologous tier 2 viruses, sometimes at high titer. Cross-neutralizing antibodies were more frequently elicited by a trivalent combination of AMC008, AMC009, and AMC011 trimers, all derived from subtype B viruses. Each of these three individual trimers could deplete the NAb activity from the rabbit sera. Mapping the polyclonal sera by electron microscopy revealed that antibodies of multiple specificities could bind to sites on both autologous and heterologous trimers. These results advance our understanding of how to use Env trimers in multivalent vaccination regimens and the immunogenicity of trimers derived from elite neutralizers.IMPORTANCE Elite neutralizers, i.e., individuals who developed unusually broad and potent neutralizing antibody responses, might serve as blueprints for HIV-1 vaccine design. Here, we studied the immunogenicity of native-like recombinant envelope glycoprotein (Env) trimers based on viral sequences from elite neutralizers. While immunization with single trimers from elite neutralization did not recapitulate the breadth and potency of neutralization observed in these infected individuals, a combination of three subtype B Env trimers from elite neutralizers resulted in some neutralization breadth within subtype B viruses. These results should guide future efforts to design vaccines to induce broadly neutralizing antibodies.


Assuntos
Anticorpos Neutralizantes/imunologia , Antígenos Virais/imunologia , Anticorpos Anti-HIV/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , Vacinas contra a AIDS/imunologia , Animais , Anticorpos Neutralizantes/química , Antígenos Virais/química , Microscopia Crioeletrônica , Epitopos/imunologia , Glicoproteínas , Infecções por HIV/virologia , Imunização , Coelhos , Proteínas Recombinantes/imunologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética
6.
Viruses ; 11(4)2019 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-31027215

RESUMO

Understanding the factors involved in the development of broadly neutralizing antibody (bNAb) responses in natural infection can guide vaccine design aimed at eliciting protective bNAb responses. Most of the studies to identify and study the development of bNAb responses have been performed in individuals who had become infected via homo- or heterosexual HIV-1 transmission; however, the prevalence and characteristics of bNAb responses in injecting drug users (IDUs) have been underrepresented. We retrospectively studied the prevalence of bNAb responses in HIV-1 infected individuals in the Amsterdam Cohort, including 50 male and 35 female participants who reported injecting drug use as the only risk factor. Our study revealed a significantly lower prevalence of bNAb responses in females compared to males. Gender, transmission route and CD4+ count at set point, but not viral load, were independently associated with the development of bNAb responses in IDUs. To further explore the influences of gender in the setting of IDU, we also looked into the Swiss 4.5k Screen. There we observed lower bNAb responses in female IDUs as well. These results reveal that the emergence of bNAbs may be dependent on multiple factors, including gender. Therefore, the effect of gender on the development of bNAb responses is a factor that should be taken into account when designing vaccine efficacy trials.


Assuntos
Anticorpos Neutralizantes/sangue , Usuários de Drogas , Anticorpos Anti-HIV/sangue , Infecções por HIV/imunologia , Abuso de Substâncias por Via Intravenosa/virologia , Contagem de Linfócito CD4 , Feminino , Infecções por HIV/transmissão , HIV-1 , Humanos , Masculino , Prevalência , Estudos Retrospectivos , Fatores Sexuais , Carga Viral
7.
J Exp Med ; 214(9): 2573-2590, 2017 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-28847869

RESUMO

Induction of broadly neutralizing antibodies (bNAbs) by HIV-1 envelope glycoprotein immunogens would be a major advance toward an effective vaccine. A critical step in this process is the activation of naive B cells expressing germline (gl) antibody precursors that have the potential to evolve into bNAbs. Here, we reengineered the BG505 SOSIP.664 glycoprotein to engage gl precursors of bNAbs that target either the trimer apex or the CD4-binding site. The resulting BG505 SOSIP.v4.1-GT1 trimer binds multiple bNAb gl precursors in vitro. Immunization experiments in knock-in mice expressing gl-VRC01 or gl-PGT121 show that this trimer activates B cells in vivo, resulting in the secretion of specific antibodies into the sera. A crystal structure of the gl-targeting trimer at 3.2-Å resolution in complex with neutralizing antibodies 35O22 and 9H+109L reveals a native-like conformation and the successful incorporation of design features associated with binding of multiple gl-bNAb precursors.


Assuntos
Anticorpos Neutralizantes/imunologia , Proteína gp160 do Envelope de HIV/imunologia , HIV-1/imunologia , Animais , Cristalografia por Raios X , Técnicas de Introdução de Genes , Células HEK293 , Humanos , Camundongos , Multimerização Proteica/imunologia , Estrutura Terciária de Proteína
8.
Hum Vaccin Immunother ; 13(1): 229-236, 2017 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-27649455

RESUMO

So far, the development of a human immunodeficiency virus (HIV) vaccine has been unsuccessful. However, recent progress in the field of broadly neutralizing antibodies (bNAbs) has reinvigorated the search for an HIV vaccine. bNAbs develop in a minority of HIV infected individuals and passive transfer of these bNAbs to non-human primates provides protection from HIV infection. Studies in a number of HIV infected individuals on bNAb maturation alongside viral evolution and escape have shed light on the features important for bNAb elicitation. Here we review the observations from these studies, and how they influence the rational design of HIV vaccines.


Assuntos
Vacinas contra a AIDS/imunologia , Vacinas contra a AIDS/isolamento & purificação , Anticorpos Neutralizantes/sangue , Descoberta de Drogas/métodos , Anticorpos Anti-HIV/sangue , Infecções por HIV/imunologia , Animais , Humanos , Primatas
9.
Nat Microbiol ; 2: 16199, 2016 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-27841852

RESUMO

The induction by vaccination of broadly neutralizing antibodies (bNAbs) capable of neutralizing various HIV-1 viral strains is challenging, but understanding how a subset of HIV-infected individuals develops bNAbs may guide immunization strategies. Here, we describe the isolation and characterization of the bNAb ACS202 from an elite neutralizer that recognizes a new, trimer-specific and cleavage-dependent epitope at the gp120-gp41 interface of the envelope glycoprotein (Env), involving the glycan N88 and the gp41 fusion peptide. In addition, an Env trimer, AMC011 SOSIP.v4.2, based on early virus isolates from the same elite neutralizer, was constructed, and its structure by cryo-electron microscopy at 6.2 Šresolution reveals a closed, pre-fusion conformation similar to that of the BG505 SOSIP.664 trimer. The availability of a native-like Env trimer and a bNAb from the same elite neutralizer provides the opportunity to design vaccination strategies aimed at generating similar bNAbs against a key functional site on HIV-1.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Anti-HIV/imunologia , Infecções por HIV/imunologia , Sobreviventes de Longo Prazo ao HIV , Anticorpos Neutralizantes/isolamento & purificação , Microscopia Crioeletrônica , Epitopos de Linfócito B/imunologia , Anticorpos Anti-HIV/isolamento & purificação , Proteína gp160 do Envelope de HIV/imunologia , Proteína gp160 do Envelope de HIV/ultraestrutura , Humanos
10.
Retrovirology ; 13(1): 48, 2016 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-27388013

RESUMO

BACKGROUND: Current HIV-1 immunogens are unable to induce antibodies that can neutralize a broad range of HIV-1 (broadly neutralizing antibodies; bNAbs). However, such antibodies are elicited in 10-30 % of HIV-1 infected individuals, and the co-evolution of the virus and the humoral immune responses in these individuals has attracted attention, because they can provide clues for vaccine design. RESULTS: Here we characterized the NAb responses and envelope glycoprotein evolution in an HIV-1 infected "elite neutralizer" of the Amsterdam Cohort Studies on HIV-1 infection and AIDS who developed an unusually potent bNAb response rapidly after infection. The NAb response was dependent on the N332-glycan and viral resistance against the N332-glycan dependent bNAb PGT135 developed over time but viral escape did not occur at or near this glycan. In contrast, the virus likely escaped by increasing V1 length, with up to 21 amino acids, accompanied by the introduction of 1-3 additional glycans, as well as 2-4 additional cysteine residues within V1. CONCLUSIONS: In the individual studied here, HIV-1 escaped from N332-glycan directed NAb responses without changing the epitope itself, but by elongating a variable loop that shields this epitope.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Anti-HIV/imunologia , HIV-1/imunologia , HIV-1/metabolismo , Evasão da Resposta Imune , Produtos do Gene env do Vírus da Imunodeficiência Humana/química , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , Cisteína , Dissulfetos , HIV-1/química , HIV-1/genética , Humanos , Masculino , Polissacarídeos/química , Polissacarídeos/imunologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética , Produtos do Gene env do Vírus da Imunodeficiência Humana/metabolismo
11.
AIDS ; 30(14): 2179-84, 2016 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-27258397

RESUMO

OBJECTIVE(S): The glycan shield of the HIV-1 envelope glycoprotein complex (Env), in particular the glycan at position 332 in gp120, is frequently targeted by broadly neutralizing antibodies (bNAbs) isolated from HIV-1-infected individuals. We investigated the role of the second amino acid position of the N332 glycosylation motif Asn-X-Ser in HIV-1 evolution and neutralization sensitivity. DESIGN AND METHODS: Viral variants harbouring glycosylation motifs with different probabilities of glycan occupancy were tested for their sensitivity to a subset of N332-dependent bNAbs. Furthermore, longitudinal Env sequences of 37 HIV-1 infected individuals were used to analyse the evolution of the N332 glycosylation motif within these individuals. Finally, early Env sequences from 31 historical and 21 contemporaneous seroconverters were compared to analyse this evolution on a population level. RESULTS: Viral variants with a higher probability of N332 occupancy were more sensitive to neutralization by some N332-dependent bNAbs. Furthermore, the longitudinal analyses revealed an increase in probability of glycan occupancy of the N332 site over time, both within patients, and at the population level over the course of 20 years of HIV-1 epidemic. CONCLUSIONS: These observations suggest that modulation of N332 glycan occupancy by the second amino acid position of the canonical glycosylation motif Asn-X-Ser plays a previously unappreciated role in viral escape from immune responses, and should be considered in Env-based vaccine design.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Anti-HIV/imunologia , Proteína gp120 do Envelope de HIV/química , Proteína gp120 do Envelope de HIV/imunologia , Polissacarídeos/análise , Humanos , Evasão da Resposta Imune
12.
AIDS Res Hum Retroviruses ; 32(10-11): 1135-1142, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26910384

RESUMO

The effect of serial HIV-1 infection on the development of the broadly neutralizing antibody (bNAb) response was studied in an individual, H01-10366, with a serial HIV-1 superinfection (SI), hence triple infection, and compared with the bNAb response in three superinfected as well as 11 monoinfected men who have had sex with men (MSM) from Amsterdam, the Netherlands. Neutralization assays measuring heterologous neutralizing antibody (NAb) titers on a panel of six representative viruses from different HIV-1 subtypes were performed on blood serum samples obtained ∼3 years after primary HIV infection (PHI) and longitudinally for H01-10366. A bNAb response was defined as having a geometric mean neutralization titer (the reciprocal serum dilution giving 50% inhibition of virus infection, inhibitory dilution (ID50)) ≥100 and neutralizing >50% of viruses in the panel with an ID50 titer ≥100. H01-10366 quickly developed a potent NAb response against subtype B viruses before subtype B SI, but no broadening of the response occurred after the second subtype B infection or the third infection with CRF01_AE. When comparing H01-10366 with matched monoinfected (N = 11) and superinfected (N = 3) individuals analyzed 3 years after PHI, we found that 5 of the 15 individuals (4/11 monoinfected, 1/4 SI) developed a bNAb response. However, there was no statistically discernible difference between the bNAb response and HIV-1 SI. Thus, HIV-1 SI was not associated with the breadth and potency of the bNAb response in this small group of Dutch MSM with SI that included a triple HIV-1-infected individual.


Assuntos
Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Coinfecção/imunologia , Anticorpos Anti-HIV/sangue , Anticorpos Anti-HIV/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Adulto , Formação de Anticorpos , Coinfecção/virologia , Infecções por HIV/virologia , HIV-1/classificação , Humanos , Estudos Longitudinais , Masculino , Países Baixos , Testes de Neutralização , Adulto Jovem
13.
Cell ; 163(7): 1702-15, 2015 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-26687358

RESUMO

The envelope glycoprotein trimer mediates HIV-1 entry into cells. The trimer is flexible, fluctuating between closed and more open conformations and sometimes sampling the fully open, CD4-bound form. We hypothesized that conformational flexibility and transient exposure of non-neutralizing, immunodominant epitopes could hinder the induction of broadly neutralizing antibodies (bNAbs). We therefore modified soluble Env trimers to stabilize their closed, ground states. The trimer variants were indeed stabilized in the closed conformation, with a reduced ability to undergo receptor-induced conformational changes and a decreased exposure of non-neutralizing V3-directed antibody epitopes. In rabbits, the stabilized trimers induced similar autologous Tier-1B or Tier-2 NAb titers to those elicited by the corresponding wild-type trimers but lower levels of V3-directed Tier-1A NAbs. Stabilized, closed trimers might therefore be useful components of vaccines aimed at inducing bNAbs.


Assuntos
Vacinas contra a AIDS/química , Vacinas contra a AIDS/imunologia , Animais , Anticorpos Neutralizantes , Epitopos/química , Proteína gp41 do Envelope de HIV/química , Proteína gp41 do Envelope de HIV/genética , HIV-1 , Interações Hidrofóbicas e Hidrofílicas , Imunoglobulina G/química , Modelos Moleculares , Mutagênese , Conformação Proteica , Coelhos , Produtos do Gene env do Vírus da Imunodeficiência Humana/química
14.
AIDS ; 28(8): 1237-40, 2014 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-24556870

RESUMO

Broadly reactive neutralizing activity (brNA) against HIV-1 is observed in 10-30% of infected individuals and generally takes 2-4 years to develop. Here, we show that two elite neutralizers, infected through injecting drug use, developed brNA around the first year postseroconversion (post-SC), whereas criteria for elite brNA were fulfilled around 30 months post-SC. These results indicate that brNA does not necessarily require multiple years to develop and they should encourage the search for vaccines that can elicit protective humoral immunity.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Anti-HIV/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Infecções por HIV/complicações , Homossexualidade Masculina , Humanos , Imunidade Humoral , Masculino , Abuso de Substâncias por Via Intravenosa/complicações
15.
Retrovirology ; 10: 102, 2013 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-24059682

RESUMO

BACKGROUND: Current HIV-1 envelope glycoprotein (Env) vaccines are unable to induce cross-reactive neutralizing antibodies. However, such antibodies are elicited in 10-30% of HIV-1 infected individuals, but it is unknown why these antibodies are induced in some individuals and not in others. We hypothesized that the Envs of early HIV-1 variants in individuals who develop cross-reactive neutralizing activity (CrNA) might have unique characteristics that support the induction of CrNA. RESULTS: We retrospectively generated and analyzed env sequences of early HIV-1 clonal variants from 31 individuals with diverse levels of CrNA 2-4 years post-seroconversion. These sequences revealed a number of Env signatures that coincided with CrNA development. These included a statistically shorter variable region 1 and a lower probability of glycosylation as implied by a high ratio of NXS versus NXT glycosylation motifs. Furthermore, lower probability of glycosylation at position 332, which is involved in the epitopes of many broadly reactive neutralizing antibodies, was associated with the induction of CrNA. Finally, Sequence Harmony identified a number of amino acid changes associated with the development of CrNA. These residues mapped to various Env subdomains, but in particular to the first and fourth variable region as well as the underlying α2 helix of the third constant region. CONCLUSIONS: These findings imply that the development of CrNA might depend on specific characteristics of early Env. Env signatures that correlate with the induction of CrNA might be relevant for the design of effective HIV-1 vaccines.


Assuntos
Anticorpos Neutralizantes/imunologia , Glicoproteínas/imunologia , Anticorpos Anti-HIV/imunologia , HIV-1/imunologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , Estudos de Coortes , Reações Cruzadas , Glicoproteínas/genética , HIV-1/genética , Humanos , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética
16.
AIDS ; 26(12): 1517-22, 2012 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-22555160

RESUMO

OBJECTIVE: Recent studies have suggested that the dynamics of HIV-1 evolutionary rate reflect the rate of disease progression. We wished to determine whether viral diversity early in infection is predictive of the subsequent disease course. DESIGN: HIV-1 envelope diversity at seroconversion and 1 year thereafter from 89 homosexual participants of the Amsterdam Cohort Studies on HIV infection and AIDS was correlated with clinical endpoints and markers of disease progression. METHODS: Heteroduplex mobility assay (HMA) and sequencing followed by calculation of pairwise genetic distances were applied to determine HIV-1 envelope diversity. The HMA pattern (presence or absence of heteroduplexes) and sequence diversity were each tested for correlation with the clinical course of infection. RESULTS: HMA pattern at 1-year postseroconversion was significantly associated with progression to AIDS and AIDS-related death, with presence of heteroduplexes associated with accelerated disease progression. Moreover, not only this dichotomous measure of viral diversity (absence or presence of heteroduplexes), but also genetic diversity itself was associated with disease course. HMA pattern was an independent predictor of accelerated disease progression, also when CCR5 genotype, human leukocyte antigen (HLA)-type, viral load, CD4 T-cell counts, and coreceptor use at viral load set point were included in the analysis. CONCLUSION: Viral diversity early in HIV-1 infection is predictive of the subsequent disease progression. It remains to be established whether viral diversity itself plays a causal role in the increased damage to the immune system or whether it is a reflection of immune pressure or other selective forces.


Assuntos
Infecções por HIV/virologia , Soropositividade para HIV/virologia , HIV-1/imunologia , Proteínas do Envelope Viral/genética , Síndrome da Imunodeficiência Adquirida/mortalidade , Síndrome da Imunodeficiência Adquirida/virologia , Biomarcadores/sangue , Linfócitos T CD4-Positivos , Progressão da Doença , Infecções por HIV/genética , Soropositividade para HIV/genética , HIV-1/genética , Antígenos HLA/imunologia , Análise Heteroduplex , Homossexualidade Masculina , Humanos , Masculino , Estudos Prospectivos , RNA Viral/imunologia , Receptores CCR5/imunologia , Fatores de Tempo , Carga Viral
17.
J Virol ; 86(4): 2045-55, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22156522

RESUMO

We previously established that at 3 years postseroconversion, ~30% of HIV-infected individuals have cross-reactive neutralizing activity (CrNA) in their sera. Here we studied the kinetics with which CrNA develops and how these relate to the development of autologous neutralizing activity as well as viral escape and diversification. For this purpose, sera from five individuals with CrNA and one elite neutralizer that were obtained at three monthly intervals in the first year after seroconversion and at multiple intervals over the disease course were tested for neutralizing activity against an established multiclade panel of six viruses. The same serum samples, as well as sera from three individuals who lacked CrNA, were tested for their neutralizing activities against autologous clonal HIV-1 variants from multiple time points covering the disease course from seroconversion onward. The elite neutralizer already had CrNA at 9.8 months postseroconversion, in contrast with the findings for the other five patients, in whom CrNA was first detected at 20 to 35 months postseroconversion and peaked around 35 months postseroconversion. In all patients, CrNA coincided with neutralizing activity against autologous viruses that were isolated <12 months postseroconversion, while viruses from later time points had already escaped autologous neutralizing activity. Also, the peak in gp160 sequence diversity coincided with the peak of CrNA titers. Individuals who lacked CrNA had lower peak autologous neutralizing titers, viral escape, and sequence diversity than individuals with CrNA. A better understanding of the underlying factors that determine the presence of CrNA or even an elite neutralizer phenotype may aid in the design of an HIV-1 vaccine.


Assuntos
Anticorpos Anti-HIV/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Estudos de Coortes , Reações Cruzadas , Infecções por HIV/virologia , HIV-1/classificação , HIV-1/genética , HIV-1/isolamento & purificação , Humanos , Estudos Longitudinais , Masculino , Testes de Neutralização
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...