RESUMEN
The development of an effective vaccine against HIV-1 has proven to be challenging. Broadly neutralizing antibodies (bNAbs), whilst exhibiting neutralization breadth and potency, are elicited only in a small subset of infected individuals and have yet to be induced by vaccination. Case-control studies of RV144 identified an inverse correlation of HIV-1 infection risk with antibodies (Abs) to the V1V2 region of gp120 with high antibody-dependent cellular cytotoxicity (ADCC) activity. The neutralizing activity of Abs was not found to contribute to this protective outcome. Using primary effector and target cells and primary virus isolates, we studied the ADCC profile of different monoclonal Abs targeting the V1V2 loop of gp120 that had low or no neutralizing activity. We compared their ADCC activity to some bNAbs targeting different regions of gp120. We found that mAbs targeting the V1V2 domain induce up to 60% NK cell mediated lysis of HIV-1 infected PBMCs in a physiologically relevant ADCC model, highlighting the interest in inducing such Abs in future HIV vaccine trials. Our data also suggest that in addition to neutralization, lysis of infected cells by Abs can effectively participate in HIV protection, as suggested by the RV144 immune correlate analysis.
Asunto(s)
Anticuerpos Anti-VIH/inmunología , Proteína gp120 de Envoltorio del VIH/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Vacunas contra el SIDA/inmunología , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/uso terapéutico , Citotoxicidad Celular Dependiente de Anticuerpos/inmunología , Reacciones Cruzadas/inmunología , Epítopos/inmunología , Proteína gp120 de Envoltorio del VIH/uso terapéutico , Infecciones por VIH/prevención & control , Infecciones por VIH/virología , VIH-1/patogenicidad , Humanos , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/virología , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/virología , Dominios Proteicos/inmunología , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/virologíaRESUMEN
A subset of characterized HIV-1 broadly neutralizing antibodies (bnAbs) are polyreactive with additional specificities for self-antigens and it has been proposed immunological tolerance may present a barrier to their participation in protective humoral immunity. We address this hypothesis by immunizing autoimmune-prone mice with HIV-1 Envelope (Env) and characterizing the primary antibody response for HIV-1 neutralization. We find autoimmune mice generate neutralizing antibody responses to tier 2 HIV-1 strains with alum treatment alone in the absence of Env. Importantly, experimentally breaching immunological tolerance in wild-type mice also leads to the production of tier 2 HIV-1-neutralizing antibodies, which increase in breadth and potency following Env immunization. In both genetically prone and experimentally induced mouse models of autoimmunity, increased serum levels of IgM anti-histone H2A autoantibodies significantly correlated with tier 2 HIV-1 neutralization, and anti-H2A antibody clones were found to neutralize HIV-1. These data demonstrate that breaching peripheral tolerance permits a cross-reactive HIV-1 autoantibody response able to neutralize HIV-1.
Asunto(s)
Anticuerpos Neutralizantes/inmunología , VIH-1/inmunología , Tolerancia Periférica/inmunología , Animales , Formación de Anticuerpos/inmunología , Autoanticuerpos/inmunología , Reacciones Cruzadas/inmunología , Femenino , Proteína gp120 de Envoltorio del VIH/inmunología , Proteína gp120 de Envoltorio del VIH/uso terapéutico , Inmunoglobulina M/inmunología , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Prophylactic vaccination against HIV-1 sexual transmission will probably require antibody elicitation at genital mucosal surfaces. However, HIV-1 envelope glycoprotein (Env)-based antigens are weakly immunogenic, particularly when applied mucosally. The polyanion PRO 2000 is safe for human vaginal application, and thus may represent a potential formulating agent for vaginal delivery of experimental vaccine immunogens. Based upon its biochemical properties, we hypothesized that PRO 2000 might enhance mucosal immunogenicity of HIV-1 envelope glycoprotein (Env)-based antigens, promoting local and systemic immune responses. Vaginal immunization with Env-PRO 2000 resulted in significantly increased titres of Env-specific mucosal IgA and IgG in mice and rabbits, respectively, compared to Env alone, revealing modest but significant mucosal adjuvant activity for PRO 2000. In vitro, PRO 2000 associated with Env, protecting the glycoprotein from proteolytic degradation in human vaginal lavage. Unexpectedly, PRO 2000 antagonized TLR4 activation, suppressing local production of inflammatory cytokines. Since inflammation-mediated recruitment of viral target cells is a major risk factor in HIV-1 transmission, the immune modulatory and anti-inflammatory activities of PRO 2000 combined with its intravaginal safety profile suggests promise as an HIV-1 mucosal vaccine formulating agent.
Asunto(s)
Vacunas contra el SIDA/química , Anticuerpos Anti-VIH/biosíntesis , Inmunidad Mucosa/efectos de los fármacos , Inflamación/prevención & control , Vacunas contra el SIDA/farmacología , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/farmacología , Adyuvantes Inmunológicos/uso terapéutico , Administración Intravaginal , Animales , Antígenos Virales/uso terapéutico , Combinación de Medicamentos , Anticuerpos Anti-VIH/efectos de los fármacos , Proteína gp120 de Envoltorio del VIH/administración & dosificación , Proteína gp120 de Envoltorio del VIH/inmunología , Proteína gp120 de Envoltorio del VIH/uso terapéutico , Humanos , Inmunidad Mucosa/inmunología , Ratones , Naftalenosulfonatos/administración & dosificación , Naftalenosulfonatos/farmacología , Naftalenosulfonatos/uso terapéutico , Polímeros/administración & dosificación , Polímeros/farmacología , Polímeros/uso terapéutico , ConejosRESUMEN
Painful distal sensory polyneuropathy (DSP) is the most common neurological complication of HIV1 infection. Although infection with the virus itself is associated with an incidence of DSP, patients are more likely to become symptomatic following initiation of nucleoside reverse transcriptase inhibitor (NRTI) treatment. The chemokines monocyte chemoattractant protein-1 (MCP1/CCL2) and stromal derived factor-1 (SDF1/CXCL12) and their respective receptors, CCR2 and CXCR4, have been implicated in HIV1 related neuropathic pain mechanisms including NRTI treatment in rodents. Utilizing a rodent model that incorporates the viral coat protein, gp120, and the NRTI, 2'3'-dideoxycytidine (ddC), we examined the degree to which chemokine receptor signaling via CCR2 and CXCR4 potentially influences the resultant chronic hypernociceptive behavior. We observed that following unilateral gp120 sciatic nerve administration, rats developed profound tactile hypernociception in the hindpaw ipsilateral to gp120 treatment. Behavioral changes were also present in the hindpaw contralateral to the injury, albeit delayed and less robust. Using immunohistochemical studies, we demonstrated that MCP1 and CCR2 were upregulated by primary sensory neurons in lumbar ganglia by post-operative day (POD) 14. The functional nature of these observations was confirmed using calcium imaging in acutely dissociated lumbar dorsal root ganglion (DRG) derived from gp120 injured rats at POD 14. Tactile hypernociception in gp120 treated animals was reversed following treatment with a CCR2 receptor antagonist at POD 14. Some groups of animals were subjected to gp120 sciatic nerve injury in combination with an injection of ddC at POD 14. This injury paradigm produced pronounced bilateral tactile hypernociception from POD 14-48. More importantly, functional MCP1/CCR2 and SDF1/CXCR4 signaling was present in sensory neurons. In contrast to gp120 treatment alone, the hypernociceptive behavior associated with the injury plus drug combination was only effectively reversed using the CXCR4 antagonist AMD3100. These studies indicate that the functional upregulation of CCR2 and CXCR4 signaling systems following a combination of gp120 and an NRTI are likely to be of central importance to associated DSP and may serve as potential therapeutic targets for treatment of this syndrome.
Asunto(s)
Quimiocinas/metabolismo , Infecciones por VIH/complicaciones , Enfermedades del Sistema Nervioso Periférico/metabolismo , Transducción de Señal/fisiología , Animales , Células Cultivadas , Quimiocina CCL2/metabolismo , Modelos Animales de Enfermedad , Femenino , Ganglios Espinales/citología , Proteína gp120 de Envoltorio del VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Inmunohistoquímica , Hibridación in Situ , Enfermedades del Sistema Nervioso Periférico/etiología , Enfermedades del Sistema Nervioso Periférico/patología , Ratas , Receptores CXCR4/metabolismo , Inhibidores de la Transcriptasa Inversa/uso terapéuticoRESUMEN
A large number of multicomponent vaccine candidates are currently in clinical evaluation, many of which also include the HIV-1 Tat protein, an important regulatory protein of the virus. However, whether Tat, a known immune effector molecule with a well-conserved sequence among different HIV subtypes, affects the immune response to a coimmunogen is not well understood. In this study, using a bicistronic vector expressing both gp120 and Tat, we have analyzed the role of Tat in elicitation of the gp120-specific immune response. The T cell responses to gp120 were greatly diminished in mice coimmunized with Tat as compared with mice immunized with gp120 alone. This immunosuppressive activity of Tat was not confined to viral Ag only because it also suppressed the immune response of unrelated Ag. Analysis of the cytokine profile suggests that Tat induces IL-10 and since IL-10 has been demonstrated to have appreciable T cell inhibitory activity, it is plausible that IL-10 could be responsible for Tat-mediated immunosuppression. Finally, the immunosuppressive effect of Tat was not observed in IL-10-deficient mice, confirming the role of IL-10 in Tat-mediated immunosuppression. Thus, our results demonstrate for the first time that the immunosuppressive effect of Tat is mediated through IL-10 and suggests that Tat-induced IL-10-mediated immune suppression seems to cripple immune surveillance during HIV-1 infection.
Asunto(s)
Vacunas contra el SIDA/inmunología , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Tolerancia Inmunológica/genética , Interleucina-10/metabolismo , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/inmunología , Vacunas contra el SIDA/genética , Vacunas contra el SIDA/uso terapéutico , Animales , Linfocitos T CD4-Positivos/inmunología , Clonación Molecular , Vectores Genéticos/genética , Proteína gp120 de Envoltorio del VIH/genética , Proteína gp120 de Envoltorio del VIH/inmunología , Proteína gp120 de Envoltorio del VIH/uso terapéutico , Infecciones por VIH/prevención & control , Interleucina-10/genética , Ratones , Ovalbúmina/inmunología , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/uso terapéuticoRESUMEN
Effects of human immunodeficiency virus type 1 (HIV-1) recombinant envelope glycoprotein vaccines on cell-mediated immune (CMI) responses were assessed in HIV-1-infected patients. Asymptomatic, antiretroviral-treatment-naïve, HIV-1-infected patients with CD4(+) T-cell counts greater than 400/microl received multiple intramuscular injections of HIV-1 IIIB recombinant envelope glycoprotein (rgp160) vaccine or HIV-1 MN recombinant envelope glycoprotein (rgp120) vaccine (eight patients, referred to as the HIV-1 vaccinees) or placebo or hepatitis B vaccine (three patients, referred to as the controls). Lymphocyte proliferation in response to HIV-1 envelope glycoproteins, both homologous and heterologous to the HIV-1 immunogens, was absent prior to study treatment in all patients but increased significantly during the vaccination series and after the final vaccination in HIV-1 vaccinees (P < 0.05) and remained absent in control patients. In flow cytometric analyses of intracellular cytokines, T-cell receptor stimulation with an anti-CD3 antibody induced gamma interferon (IFN-gamma) expression by activated CD4(+) and CD8(+) lymphocytes at greater frequencies than did stimulation with recombinant envelope glycoprotein and p24 of HIV-1 (P < 0.05). Mean frequencies of HIV-1 envelope glycoprotein-stimulated, activated intra-cellular IFN-gamma-producing CD4(+) and CD8(+) lymphocytes and of interleukin-2-producing CD4(+) lymphocytes did not increase after vaccination, but cytokine-producing cells were detectable in some patients. Comparing pre- to post-HIV-1 vaccination time points, changes in frequencies of activated, IFN-gamma-producing CD4(+) cells correlated inversely with changes in lymphocyte proliferation in response to recombinant envelope glycoprotein in HIV-1 vaccinees (P < 0.05). Increased CMI responses to HIV-1 envelope glycoprotein measured by lymphocyte proliferation were associated with HIV-1 recombinant envelope glycoprotein vaccines.
Asunto(s)
Vacunas contra el SIDA/uso terapéutico , Proteína gp120 de Envoltorio del VIH/uso terapéutico , Proteínas gp160 de Envoltorio del VIH/uso terapéutico , Infecciones por VIH/terapia , VIH-1/inmunología , Vacunas Sintéticas/uso terapéutico , Antígenos CD/metabolismo , Antígenos de Diferenciación de Linfocitos T/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Femenino , Infecciones por VIH/inmunología , Humanos , Inmunoterapia Activa/métodos , Interferón gamma/metabolismo , Lectinas Tipo C , Activación de Linfocitos/inmunología , MasculinoRESUMEN
Vaccines against highly variable pathogens should elicite antibodies to a huge number of clinical isolates. For this purpose, new strategies to overcome the variability are needed. We have previously reported a useful method to conjugate multiple antigen peptides (MAPs) to carrier proteins. Also, we have suggested that these conjugates might enhance cross-reactivity in comparison to other synthetic structures. In this work, MAPs were synthesized and their respective conjugates to HBsAg were obtained. Two peptides from the V3 loop of HIV-1 were included in the MAPs as B cell epitopes because of their variability. Groups of mice were immunized and the immunogenicity and the level of cross-reaction to a panel of five heterologous V3 peptides were studied. Our results show that sera from mice immunized with MAPs coupled to HBsAg recognize a higher number of heterologous peptides (P < 0.05). This behavior was related neither to the immunogenicity nor the antigenicity of the synthetic structures. These results have important implications for the choice of better immunogens against variable epitopes.
Asunto(s)
Vacunas contra el SIDA/síntesis química , Reacciones Cruzadas/inmunología , Proteína gp120 de Envoltorio del VIH/inmunología , Antígenos de Superficie de la Hepatitis B/inmunología , Fragmentos de Péptidos/inmunología , Vacunas Sintéticas/inmunología , Vacunas contra el SIDA/inmunología , Vacunas contra el SIDA/uso terapéutico , Animales , Anticuerpos Antivirales/sangre , Formación de Anticuerpos , Antígenos Virales/uso terapéutico , Femenino , Proteína gp120 de Envoltorio del VIH/uso terapéutico , Antígenos de Superficie de la Hepatitis B/uso terapéutico , Inmunización , Ratones , Ratones Endogámicos BALB C , Fragmentos de Péptidos/síntesis química , Fragmentos de Péptidos/uso terapéutico , Ingeniería de Proteínas , Vacunas Sintéticas/uso terapéuticoRESUMEN
Entry of HIV-1 virions into cells is a complex and dynamic process carried out by envelope (Env) glycoproteins on the surface of the virion that promote the thermodynamically unfavorable fusion of highly stable viral and target cell membranes. Insight gained from studies of the mechanism of viral entry allowed insight into the design of novel inhibitors of HIV-1 entry, several of which are now in clinical trials. This review highlights the mechanism by which viral and cellular proteins mediate entry of HIV-1 into permissive cells, with an emphasis on targeting this process in the design of novel therapies that target distinct steps of the entry process, including antagonizing receptor binding events and blocking conformational changes intimately involved in membrane fusion.
Asunto(s)
Fármacos Anti-VIH/farmacología , Antígenos CD4/metabolismo , Infecciones por VIH/prevención & control , VIH-1/efectos de los fármacos , Fusión de Membrana/efectos de los fármacos , Fármacos Anti-VIH/uso terapéutico , Proteína gp120 de Envoltorio del VIH/uso terapéutico , Proteína gp41 de Envoltorio del VIH/uso terapéutico , VIH-1/fisiología , Humanos , Modelos Biológicos , Receptores CCR5/metabolismo , Receptores CCR5/uso terapéutico , Receptores CXCR4/metabolismo , Receptores CXCR4/uso terapéutico , Receptores de Quimiocina/metabolismoRESUMEN
BACKGROUND: It has not been clearly demonstrated whether HIV vaccination can complicate routine HIV testing. In this report, we describe the laboratory data of two prisoners who received rgp120 vaccine in a phase III trial underway in Thailand. These data indicate that previous vaccination may complicate the interpretation of screening HIV diagnostic tests. CASE PRESENTATION: The participants were identified from a cohort study on "Health factors related to HIV-1 and other viral infections among incarcerated people" that was approved by The Ethical Committee for Research in Human Subjects, Ministry of Public Health, Thailand. HIV diagnosis was definitively established with serial specimens using multi-screening tests, Western blot and diagnostic PCR.Anti-HIV screening tests consistently exhibited either weakly reactive or inconclusive results. The band patterns of the Western blot analysis corresponded to those found in individuals who received the rgp120 vaccination. Definite results were established using diagnostic PCR, which exhibited consistently negative results with follow-up specimens. Such problems in HIV testing are not easily resolved in the routine clinical setting in Thailand. CONCLUSIONS: These data demonstrate that HIV-1 vaccination interferes with routine diagnostic tests. Similar cases will not be uncommon in Thailand, where 2,545 people have already participated in a phase III trial.
Asunto(s)
Vacunas contra el SIDA/efectos adversos , Vacunas contra el SIDA/sangre , Serodiagnóstico del SIDA/métodos , Vacunas contra el SIDA/uso terapéutico , Ensayos Clínicos Fase III como Asunto/efectos adversos , Proteína gp120 de Envoltorio del VIH/sangre , Proteína gp120 de Envoltorio del VIH/uso terapéutico , Proteínas gp160 de Envoltorio del VIH/sangre , Infecciones por VIH/epidemiología , VIH-1/inmunología , VIH-1/aislamiento & purificación , Dependencia de Heroína/sangre , Humanos , Masculino , Tamizaje Masivo/métodos , Compartición de Agujas/efectos adversos , Prisioneros , Estudios Retrospectivos , Tailandia/epidemiologíaRESUMEN
We examined HIV-1 specific memory helper T immune responses in chronically HIV-infected subjects who received an immune-based therapy (HIV-1 immunogen, Remune). Subjects in this study exhibited significant increases (p < 0.05) in the frequency of helper T memory cells expressing interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) in response to HIV-1 antigens in vitro. The frequencies of HIV-specific memory T cells increased after successive immunizations and exhibited a correlation with the standard tritiated thymidine incorporation lymphocyte proliferation assay (r = 0.72, p < 0.0008). These results support the notion that HIV-specific memory immune responses can be stimulated in subjects with chronic HIV infection. Further investigations are warranted to determine whether the induction of such responses is associated with virologic control.
Asunto(s)
Vacunas contra el SIDA/uso terapéutico , Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/terapia , VIH-1/inmunología , Linfocitos T CD4-Positivos/metabolismo , Células Cultivadas , Enfermedad Crónica , Citometría de Flujo , Proteína p24 del Núcleo del VIH/uso terapéutico , Proteína gp120 de Envoltorio del VIH/uso terapéutico , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Seropositividad para VIH , Humanos , Inmunidad Celular , Memoria Inmunológica , Interferón gamma/metabolismo , Activación de Linfocitos/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismoAsunto(s)
Síndrome de Inmunodeficiencia Adquirida/terapia , Proteína gp120 de Envoltorio del VIH/uso terapéutico , Vacunas Virales/uso terapéutico , Síndrome de Inmunodeficiencia Adquirida/inmunología , Recuento de Linfocito CD4 , Estudios de Seguimiento , Humanos , Proteínas Recombinantes/uso terapéutico , Factores de Tiempo , Vacunas Sintéticas/uso terapéuticoRESUMEN
A multibranched peptide construct (SPC3) derived from the conserved sequence of the third variable domain (V3) of the human immunodeficiency virus (HIV) envelope (Env) inhibits HIV infectivity. It is being tested in phase II clinical trials (FDA protocol 257A). Because some Env-derived peptides inhibit HIV infectivity through alteration of Env biosynthetic pathway, we studied whether SPC3 displays its activity through interference with Env biosynthesis or with its functions at the membrane. Syncytium formation was impaired when human CD4+ cells expressed recombinant HIV Env in the presence of SPC3. This inhibition was not due to an effect of SPC3 on the amount of Env expressed at the cell membrane. As assessed using antibodies, the conformation of the receptor binding site and of V3 presented on membrane Env was not affected by the presence of SPC3 during biosynthesis. Finally, despite the ability of SPC3 to bind to CD4+ cell membrane, SPC3 did not interfere with Env binding to CD4. These data suggest that SPC3 interferes with the infection process at a post-CD4 binding step, and not with the folding of Env.
Asunto(s)
Vacunas contra el SIDA/química , Proteína gp120 de Envoltorio del VIH/química , Infecciones por VIH/prevención & control , VIH-1/aislamiento & purificación , Fragmentos de Péptidos/química , Vacunas contra el SIDA/uso terapéutico , Sitios de Unión , Células Cultivadas , Ensayos Clínicos Fase II como Asunto , Proteína gp120 de Envoltorio del VIH/farmacología , Proteína gp120 de Envoltorio del VIH/uso terapéutico , VIH-1/química , Humanos , Fragmentos de Péptidos/farmacología , Fragmentos de Péptidos/uso terapéutico , Conformación Proteica , Receptores del VIH/antagonistas & inhibidoresAsunto(s)
Vacunas contra el SIDA , Proteína gp120 de Envoltorio del VIH , Infecciones por VIH/prevención & control , Vacunas contra el SIDA/inmunología , Vacunas contra el SIDA/uso terapéutico , Ensayos Clínicos Fase I como Asunto , Ensayos Clínicos Fase II como Asunto , VIH/inmunología , Anticuerpos Anti-VIH/inmunología , Proteína gp120 de Envoltorio del VIH/inmunología , Proteína gp120 de Envoltorio del VIH/uso terapéutico , Infecciones por VIH/inmunología , Infecciones por VIH/terapia , Humanos , Linfocitos T Citotóxicos/inmunología , Tailandia , Estados Unidos , Vacunas SintéticasRESUMEN
AIDS: Development of a safe and effective AIDS vaccine remains a critical issue, particularly in developing nations where HIV infections will account for 90 percent of all new infections by 2000. The AIDS Vaccine Evaluation Group (AVEG) is conducting phase I and II studies of several candidate HIV-1 vaccines. Technical and ethical issues, including significant problems that need to be addressed in vaccine trials, are discussed. The safety of the current candidate vaccines, their immunogenicity, and the continued spread of HIV-1 in spite of educational efforts indicate that clinical trials are warranted. An extensive bibliography of articles related to vaccine development is included.^ieng
Asunto(s)
Vacunas contra el SIDA/inmunología , Avipoxvirus/inmunología , Ensayos Clínicos como Asunto , Infecciones por VIH/prevención & control , VIH-1 , Vacunas Virales/inmunología , Vacunas contra el SIDA/genética , Vacunas contra el SIDA/uso terapéutico , Animales , Vectores Genéticos , Proteína gp120 de Envoltorio del VIH/uso terapéutico , Proteínas gp160 de Envoltorio del VIH/uso terapéutico , Infecciones por VIH/inmunología , Infecciones por VIH/transmisión , Humanos , Inmunoterapia/métodos , Estados Unidos , Vacunas Sintéticas/inmunología , Vacunas Sintéticas/uso terapéutico , Vacunas Virales/genética , Vacunas Virales/uso terapéuticoRESUMEN
In an attempt to compare the protective effect of vaccination with two forms of envelope antigens, and to define immunological correlates of protection against HIV infection, chimpanzees were vaccinated with either recombinant gp160 or gp120. Homologous HIV challenge was performed 3 weeks after the fourth immunization. The animal with the highest level of serum neutralizing antibodies (gp160 immunogen) was protected against HIV infection. All other chimpanzees became infected, but displayed various levels of infected PBMCs. The postchallenge data gave rise to the following conclusions: (1) protection correlated with the level of the serological immune response, but not with the nature of immunogen (gp120 versus gp160); (2) the virus-neutralizing titre at day of challenge correlated with protection from infection; (3) the relative magnitude of the lymphoproliferative T-cell response at day of challenge did not correlate with any protective effect; (4) the peak numbers of virus-infected PBMCs in vaccinated animals were lower than those observed in control animals, and this effect was correlated with the intensity of the antibody response at day of challenge. This raises the possibility that a beneficial effect of HIV vaccination may be achieved in a situation where sterile immunity is not consistently obtained.
Asunto(s)
Vacunas contra el SIDA/inmunología , Productos del Gen env/inmunología , Anticuerpos Anti-VIH/biosíntesis , Proteína gp120 de Envoltorio del VIH/inmunología , VIH-1/inmunología , Precursores de Proteínas/inmunología , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Clonación Molecular , Modelos Animales de Enfermedad , Estudios de Seguimiento , Productos del Gen env/uso terapéutico , Genes env/genética , Proteína gp120 de Envoltorio del VIH/uso terapéutico , Proteínas gp160 de Envoltorio del VIH , Infecciones por VIH/inmunología , Infecciones por VIH/prevención & control , VIH-1/genética , Inmunidad Celular , Inmunización Secundaria , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Pruebas de Neutralización , Neutrófilos/citología , Neutrófilos/inmunología , Pan troglodytes , Precursores de Proteínas/uso terapéutico , Linfocitos T/citología , Linfocitos T/inmunología , Vacunación , Vacunas Sintéticas/inmunologíaRESUMEN
The V3 loop is an hypervariable region of the HIV-1 surface envelope glycoprotein gp120 that is able to generate neutralizing antibodies. These antibodies are generally type-specific. They inhibit the interaction between the V3 loop and the membrane molecules involved in virus-cell and cell-cell fusion. Synthetic peptides based on the V3 loop sequence have been tentatively used to block the fusion process, but the results were unsuccessful. In this report, we confirm that monomeric V3 peptides are devoid of any anti-HIV activity. However, we found that, when assembled in a synthetic polymeric construction (SPC), these peptides have been able to inhibit the infection of human CD4+ lymphocytes and macrophages as well as CD4- epithelial intestinal cells by distantly related isolates of HIV-1 and HIV-2. V3 SPCs, based on the consensus HIV-1 sequence, may therefore represent a new class of therapeutically useful anti-HIV agents able to neutralize a wide range of viral isolates in both CD4+ and CD4- susceptible cells.
Asunto(s)
Secuencia de Consenso , Proteína gp120 de Envoltorio del VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , VIH-1/química , VIH-2 , Antígenos CD4/análisis , Linfocitos T CD4-Positivos/microbiología , Células Epiteliales , Epitelio/microbiología , Proteína gp120 de Envoltorio del VIH/química , Humanos , Intestinos/citología , Macrófagos/química , Macrófagos/microbiología , PolímerosRESUMEN
Human immunodeficiency virus (HIV) infection has become one of the leading causes of mortality among American women of childbearing age. Many women will experience a pregnancy after they have been infected. Several rationales exist for offering the pregnant infected woman anti-HIV therapy, including interruption of vertical transmission and improvement of her own health and the outcome of her pregnancy. The bases for these rationales are explored, the options (chemotherapy and immunotherapy) are described, and the potential toxicities are examined.