RESUMO
The magnitude of the HIV-1 epidemic in Nigeria is second only to the subtype C epidemic in South Africa, yet the subtypes prevalent in Nigeria require further characterization. A panel of 50 subtype G and 18 CRF02_AG Nigerian HIV-1 pseudoviruses (PSV) was developed and envelope coreceptor usage, neutralization sensitivity and cross-clade reactivity were characterized. These PSV were neutralized by some antibodies targeting major neutralizing determinants, but potentially important differences were observed in specific sensitivities (eg. to sCD4, MPER and V2/V3 monoclonal antibodies), as well as in properties such as variable loop lengths, number of potential N-linked glycans and charge, demonstrating distinct antigenic characteristics of CRF02_AG and subtype G. There was preferential neutralization of the matched CRF/subtype when PSV from subtype G or CRF02_AG were tested using pooled plasma. These novel Nigerian PSV will be useful to study HIV-1 CRF- or subtype-specific humoral immune responses for subtype G and CRF02_AG.
Assuntos
Anticorpos Neutralizantes , Anticorpos Anti-HIV , Infecções por HIV , HIV-1 , Testes de Neutralização , HIV-1/imunologia , HIV-1/genética , HIV-1/classificação , Nigéria , Anticorpos Neutralizantes/imunologia , Anticorpos Neutralizantes/sangue , Humanos , Anticorpos Anti-HIV/imunologia , Anticorpos Anti-HIV/sangue , Infecções por HIV/imunologia , Infecções por HIV/virologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/genética , Reações Cruzadas/imunologiaRESUMO
The membrane proximal external region (MPER) of HIV-1 gp41 is targeted by several neutralizing antibodies (NAbs) and is of interest for vaccine design. In this study, we identified novel MPER peptide mimotopes and evaluated their reactivity with HIV + plasma antibodies to characterize the diversity of the immune responses to MPER during natural infection. We utilized phage display technology to generate novel mimotopes that fit antigen-binding sites of MPER NAbs 4E10, 2F5 and Z13. Plasma antibodies from 10 HIV + patients were mapped by phage immunoprecipitation, to identify unique patient MPER binding profiles that were distinct from, and overlapping with, those of MPER NAbs. 4E10 mimotope binding profiles correlated with plasma neutralization of HIV-2/HIV-1 MPER chimeric virus, and with overall plasma neutralization breadth and potency. When administered as vaccines, 4E10 mimotopes elicited low titer NAb responses in mice. HIV mimotopes may be useful for detailed analysis of plasma antibody specificity.
Assuntos
Epitopos/química , Anticorpos Anti-HIV/biossíntese , Proteína gp41 do Envelope de HIV/química , Infecções por HIV/prevenção & controle , HIV-1/imunologia , HIV-2/imunologia , Vacinas contra a AIDS/administração & dosagem , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/biossíntese , Anticorpos Neutralizantes/biossíntese , Especificidade de Anticorpos , Antígenos Virais/química , Antígenos Virais/imunologia , Antígenos Virais/metabolismo , Ligação Competitiva , Ensaio de Imunoadsorção Enzimática , Mapeamento de Epitopos , Epitopos/imunologia , Epitopos/metabolismo , Feminino , Proteína gp41 do Envelope de HIV/imunologia , Proteína gp41 do Envelope de HIV/metabolismo , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , HIV-1/genética , HIV-2/efeitos dos fármacos , HIV-2/genética , Humanos , Imunidade Humoral/efeitos dos fármacos , Imunização/métodos , Camundongos , Camundongos Endogâmicos BALB C , Biblioteca de Peptídeos , Peptídeos/química , Peptídeos/imunologia , Peptídeos/metabolismo , Ligação ProteicaRESUMO
Despite anti-retroviral therapy (ART) interventions for HIV+ pregnant mothers, over 43,000 perinatal infections occur yearly. Understanding risk factors that lead to mother-to-child transmission (MTCT) of HIV are critical. We evaluated maternal and infant plasma binding and neutralizing antibody responses in a drug-naïve, CRF01_AE infected MTCT cohort from Thailand to determine associations with transmission risk. Env V3-specific IgG and neutralizing antibody responses were significantly higher in HIV- infants, as compared to HIV+ infants. In fact, infant plasma neutralizing antibodies significantly associated with non-transmission. Conversely, increased maternal Env V3-specific IgG and neutralizing antibody responses were significantly associated with increased transmission risk, after controlling for maternal viral load. Our results highlight the importance of evaluating both maternal and infant humoral immune responses to better understand mechanisms of protection, as selective placental antibody transport may have a role in MTCT. This study further emphasizes the complex role of Env-specific antibodies in MTCT of CRF01_AE HIV.