RESUMO
As the HIV/AIDS pandemic still progresses, understanding the mechanisms governing viral transmission as well as protection from HIV acquisition is fundamental. In this context, cohorts of HIV serodiscordant heterosexual couples (SDC) represent a unique tool. The present study was aimed to evaluate specific parameters of innate, cellular and humoral immune responses in SDC. Specifically, plasma levels of cytokines and chemokines, HIV-specific T-cell responses, gp120-specific IgG and IgA antibodies, and HIV-specific antibody-dependent cellular cytotoxicity (ADCC) activity were assessed in nine HIV-exposed seronegative individuals (ESN) and their corresponding HIV seropositive partners (HIV+-P), in eighteen chronically infected HIV subjects (C), nine chronically infected subjects known to be HIV transmitters (CT) and ten healthy HIV- donors (HD). Very low magnitude HIV-specific cellular responses were found in two out of six ESN. Interestingly, HIV+-P had the highest ADCC magnitude, the lowest IgA levels and the highest IgG/IgA ratio, all compared to CT. Positive correlations between CD4+ T-cell counts and both IgG/IgA ratios and %ADCC killing uniquely distinguished HIV+-P. Additionally, evidence of IgA interference with ADCC responses from HIV+-P and CT is provided. These data suggest for the first time a potential role of ADCC and/or gp120-specific IgG/IgA balance in modulating heterosexual transmission. In sum, this study provides key information to understand the host factors that influence viral transmission, which should be considered in both the development of prophylactic vaccines and novel immunotherapies for HIV-1 infection.
Assuntos
Proteína gp120 do Envelope de HIV/sangue , Infecções por HIV/imunologia , HIV/imunologia , Imunidade Celular , Imunidade Humoral , Adulto , Idoso , Feminino , HIV/patogenicidade , Anticorpos Anti-HIV/sangue , Anticorpos Anti-HIV/imunologia , Proteína gp120 do Envelope de HIV/imunologia , Infecções por HIV/transmissão , Infecções por HIV/virologia , Heterossexualidade , Humanos , Imunoglobulina A/sangue , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Estudos Soroepidemiológicos , Parceiros Sexuais , Linfócitos T/imunologiaRESUMO
BACKGROUND: The first multicenter, international National Institutes of Allergy and Infectious Diseases (NIAID)-sponsored HIV vaccine trial took place in Brazil, Haiti, Peru and Trinidad. This randomized, double-blind, placebo-controlled, phase 2 trial evaluated the safety and immunogenicity of a clade B-derived, live canarypox HIV vaccine, vCP1452. vCP1452 was administered alone or with a heterologous boost of MN rgp120 glycoprotein. The trial was pivotal in deciding whether these vaccines advanced to phase 3 efficacy trials. METHODS: Forty seronegative volunteers per site were randomized to ALVAC alone, ALVAC plus MN rgp120, or placebo in a 0, 1, 3, and 6 month schedule. Immunogenicity was assayed by chromium-release cytotoxic T lymphocyte (CTL) responses; interferon-gamma (IFN-gamma) enzyme-linked immunosorbent spot assays (ELISpot); lymphocyte proliferation assays (LPA); neutralization; and enzyme-linked immunosorbent assays (ELISA). RESULTS: Enrollment and follow-up were excellent. Both vaccines were well tolerated. Neutralizing antibody to the laboratory-adapted MN strain was detected. Cellular immune responses, as measured by CTL, ELISpot, and LPA, did not differ between vaccines and placebos. CONCLUSIONS: The observation of disappointing immunogenicity in this and a parallel domestic study has informed future vaccine development. Equally important, challenges to doing an integrated trial across countries, cultures, languages, and differing at-risk populations were overcome. The identification of specific safety, ethical, logistic, and immunological issues in this trial established the foundation for current larger international studies.
Assuntos
Vacinas contra a AIDS/imunologia , Proteína gp120 do Envelope de HIV/imunologia , Infecções por HIV/imunologia , HIV-1 , Vacinação , Vacinas contra a AIDS/administração & dosagem , Vacinas contra a AIDS/sangue , Adolescente , Adulto , Brasil , Método Duplo-Cego , Feminino , Anticorpos Anti-HIV/sangue , Proteína gp120 do Envelope de HIV/administração & dosagem , Proteína gp120 do Envelope de HIV/sangue , Haiti , Humanos , Esquemas de Imunização , Imunização Secundária , Injeções Intramusculares , Interferon gama/análise , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Testes de Neutralização , Peru , Linfócitos T Citotóxicos/imunologia , Resultado do Tratamento , Trinidad e Tobago , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/sangue , Vacinas Sintéticas/imunologiaRESUMO
We investigated the presence of NK suppressor factors in HIV+ sera. We further investigated if gp120 could be one of the substances responsible for the impairment of NKC regulation found in HIV+ asymptomatic patients. Our results indicate that HIV+ sera inhibit significantly normal NKC in a dose-dependent way, even at concentrations as low as 1%. The inhibitory effect of HIV+ sera decreased, but was not completely removed, by adsorptions of IgG or by treatment with a MoAb against human FcIgG. Pretreatment of normal effector cells with anti-CD16 MoAb slightly reduced their cytotoxic capability, but did not modify the suppressor effect of HIV+ sera. The The preincubation of normal PBMC with recombinant gp120 had also a suppressor effect even at 10 ng/ml. Pretreatment of HIV+ sera with anti-gp120 or anti-FcIgG MoAb reduced, but not completely, their inhibitory effect. In conclusion, HIV+ serum has a dose-dependent inhibitory effect on normal NKC. Most of this inhibition is caused by IgG, but other substances, such as gp120, can also contribute to it. Since the removal of IgG and further treatments of HIV+ sera were not able to abrogate completely the NK suppression, other serum factors still undetermined (TNF-alpha, other cytokines), should be considered.