RESUMO
BACKGROUNDBroadly neutralizing monoclonal antibodies (bNAbs) represent a promising strategy for HIV-1 immunoprophylaxis and treatment. 10E8VLS and VRC07-523LS are bNAbs that target the highly conserved membrane-proximal external region (MPER) and the CD4-binding site of the HIV-1 viral envelope glycoprotein, respectively.METHODSIn this phase 1, open-label trial, we evaluated the safety and pharmacokinetics of 5 mg/kg 10E8VLS administered alone, or concurrently with 5 mg/kg VRC07-523LS, via s.c. injection to healthy non-HIV-infected individuals.RESULTSEight participants received either 10E8VLS alone (n = 6) or 10E8VLS and VRC07-523LS in combination (n = 2). Five (n = 5 of 8, 62.5%) participants who received 10E8VLS experienced moderate local reactogenicity, and 1 participant (n = 1/8, 12.5%) experienced severe local reactogenicity. Further trial enrollment was stopped, and no participant received repeat dosing. All local reactogenicity resolved without sequelae. 10E8VLS retained its neutralizing capacity, and no functional anti-drug antibodies were detected; however, a serum t1/2 of 8.1 days was shorter than expected. Therefore, the trial was voluntarily stopped per sponsor decision (Vaccine Research Center, National Institute of Allergy and Infectious Diseases [NIAID], NIH). Mechanistic studies performed to investigate the underlying reason for the reactogenicity suggest that multiple mechanisms may have contributed, including antibody aggregation and upregulation of local inflammatory markers.CONCLUSION10E8VLS resulted in unexpected reactogenicity and a shorter t1/2 in comparison with previously tested bNAbs. These studies may facilitate identification of nonreactogenic second-generation MPER-targeting bNAbs, which could be an effective strategy for HIV-1 immunoprophylaxis and treatment.TRIAL REGISTRATIONClinicaltrials.gov, accession no. NCT03565315.FUNDINGDivision of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH.
Assuntos
Infecções por HIV , Soropositividade para HIV , HIV-1 , Humanos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/prevenção & controle , Anticorpos Anti-HIV , Anticorpos Amplamente Neutralizantes/farmacologia , Anticorpos Monoclonais/farmacologiaRESUMO
BACKGROUND: Atopic dermatitis (AD) is characterized by Staphylococcus aureus (S. aureus) colonization. Longitudinal early life data delineating relationships of S. aureus colonization, barrier function, and AD outcomes are lacking. We define longitudinal S. aureus endotypes and AD pathogenesis in early life. METHODS: We defined longitudinal S. aureus skin colonization phenotypes across two annual visits (non-colonized: V1- V2- , early transient: V1+ V2- , late-onset: V1- V2+ , persistent: V1+ V2+ ) in the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children cohort. We analyzed AD severity, sensitization, and skin barrier function across phenotypes, and performed mediation analyses between colonization and FLG expression. RESULTS: Persistent S. aureus colonization was associated with increased SCORAD at V1 (33.5 vs. 19.0, p = .004) and V2 (40.1 vs.16.9, p < .001), and lower non-lesional (NL) FLG at V2 (1.77 vs. 4.09, p = .029) compared to the non-colonized phenotype, with early transient and late-onset colonization as intermediate phenotypes. Children colonized at V2 demonstrated a decrease in NL-FLG expression from V1 to V2 compared to those non-colonized at V2 (p = .0012), who maintained expression. This effect remained significant even after adjusting for V1 colonization and SCORAD (p = .011). CONCLUSIONS: Our findings are the first to present longitudinal quantitative FLG expression and S. aureus skin colonization in early life and suggest that a decrease in NL-FLG drives later colonization. Hence, therapies to maintain NL-FLG expression may prevent S. aureus colonization. Further, a longitudinal AD endotype of persistent colonization is characterized by increased AD severity, sensitization, and decreasing NL-FLG.
Assuntos
Dermatite Atópica , Proteínas Filagrinas , Staphylococcus aureus , Staphylococcus aureus/fisiologia , Pele/microbiologia , Humanos , Dermatite Atópica/microbiologia , Lactente , Pré-Escolar , Masculino , Feminino , Gravidade do Paciente , Proteínas Filagrinas/genéticaRESUMO
Agents that can simultaneously activate latent HIV, increase immune activation and enhance the killing of latently-infected cells represent promising approaches for HIV cure. Here, we develop and evaluate a trispecific antibody (Ab), N6/αCD3-αCD28, that targets three independent proteins: (1) the HIV envelope via the broadly reactive CD4-binding site Ab, N6; (2) the T cell antigen CD3; and (3) the co-stimulatory molecule CD28. We find that the trispecific significantly increases antigen-specific T-cell activation and cytokine release in both CD4+ and CD8+ T cells. Co-culturing CD4+ with autologous CD8+ T cells from ART-suppressed HIV+ donors with N6/αCD3-αCD28, results in activation of latently-infected cells and their elimination by activated CD8+ T cells. This trispecific antibody mediates CD4+ and CD8+ T-cell activation in non-human primates and is well tolerated in vivo. This HIV-directed antibody therefore merits further development as a potential intervention for the eradication of latent HIV infection.
Assuntos
Infecções por HIV , HIV-1 , Animais , Linfócitos T CD8-Positivos , Linfócitos T CD4-Positivos , Latência Viral , Anticorpos Anti-HIVRESUMO
Broadly neutralizing antibodies (bNAbs) represent an alternative to drug therapy for the treatment of HIV-1 infection. Immunotherapy with single bNAbs often leads to emergence of escape variants, suggesting a potential benefit of combination bNAb therapy. Here, a trispecific bNAb reduces viremia 100- to 1000-fold in viremic SHIV-infected macaques. After treatment discontinuation, viremia rebounds transiently and returns to low levels, through CD8-mediated immune control. These viruses remain sensitive to the trispecific antibody, despite loss of sensitivity to one of the parental bNAbs. Similarly, the trispecific bNAb suppresses the emergence of resistance in viruses derived from HIV-1-infected subjects, in contrast to parental bNAbs. Trispecific HIV-1 neutralizing antibodies, therefore, mediate potent antiviral activity in vivo and may minimize the potential for immune escape.
Assuntos
Anticorpos Amplamente Neutralizantes/imunologia , Anticorpos Amplamente Neutralizantes/uso terapêutico , Anticorpos Anti-HIV/uso terapêutico , Evasão da Resposta Imune/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/terapia , Vírus da Imunodeficiência Símia/imunologia , Animais , Antivirais/uso terapêutico , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Anticorpos Anti-HIV/imunologia , HIV-1/imunologia , Humanos , Imunoterapia/métodos , Macaca mulatta , Células THP-1 , Viremia/prevenção & controle , Viremia/terapiaRESUMO
BACKGROUND: In addition to its involvement in both the innate and adaptive immune systems, vitamin D has been found to affect keratinocyte function and proliferation, suggesting a possible role for vitamin D in cutaneous allergic sensitization. OBJECTIVE: To explore the role of circulating vitamin D levels in allergic sensitization. METHODS: Serum 25-hydroxyvitamin D (25(OH)D) levels were measured in a subset of children (N = 323) enrolled in the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children cohort, a prospective early life cohort of children with atopic dermatitis. Allergic sensitization was determined using skin prick testing, and FLG expression in the keratinocytes was measured by quantitative polymerase chain reaction. Multiple Poisson regression was used to evaluate interaction effects between serum 25(OH)D levels and FLG expression with sensitization load as the outcome. RESULTS: Black participants had significantly lower mean levels of serum 25(OH)D compared with non-Black participants (29.3 vs 32.9 ng/mL; P < .001). FLG expression and sensitization load were negatively correlated in non-Black participants with 25(OH)D levels less than 27.2 ng/mL (Rho = -0.45; P = .02). No association between FLG expression and sensitization load was found in Black participants or participants with 25(OH)D levels greater than or equal to 27.2 ng/mL. Multiple Poisson regression models confirmed that 25(OH)D levels interact with FLG expression to affect sensitization load in non-Black participants. CONCLUSION: Despite lower vitamin D levels in Black participants, sensitization load was associated with nonlesional skin FLG expression in non-Black, but not Black, children with low vitamin D levels. Thus, a complex interplay of factors determines the impact of vitamin D on allergic sensitization.
Assuntos
Dermatite Atópica , Eczema , Proteínas Filagrinas , Vitamina D , População Negra , Criança , Dermatite Atópica/etnologia , Dermatite Atópica/genética , Eczema/etnologia , Eczema/genética , Proteínas Filagrinas/genética , Humanos , Estudos Prospectivos , Vitamina D/sangueRESUMO
Primary HIV-1 infection can be classified into six Fiebig stages based on virological and serological laboratory testing, whereas simian-HIV (SHIV) infection in nonhuman primates (NHPs) is defined in time post-infection, making it difficult to extrapolate NHP experiments to the clinics. We identified and extensively characterized the Fiebig-equivalent stages in NHPs challenged intrarectally or intravenously with SHIVAD8-EO. During the first month post-challenge, intrarectally challenged monkeys were up to 1 week delayed in progression through stages. However, regardless of the challenge route, stages I-II predominated before, and stages V-VI predominated after, peak viremia. Decrease in lymph node (LN) CD4+ T cell frequency and rise in CD8+ T cells occurred at stage V. LN virus-specific CD8+ T cell responses, dominated by degranulation and TNF, were first detected at stage V and increased at stage VI. A similar late elevation in follicular CXCR5+ CD8+ T cells occurred, consistent with higher plasma CXCL13 levels at these stages. LN SHIVAD8-EO RNA+ cells were present at stage II, but appeared to decline at stage VI when virions accumulated in follicles. Fiebig-equivalent staging of SHIVAD8-EO infection revealed concordance of immunological events between intrarectal and intravenous infection despite different infection progressions, and can inform comparisons of NHP studies with clinical data.
Assuntos
Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Vírus da Imunodeficiência Símia/imunologia , Administração Intravenosa , Administração Retal , Animais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/virologia , Progressão da Doença , Feminino , Infecções por HIV/imunologia , Infecções por HIV/virologia , HIV-1 , Humanos , Macaca mulatta , Masculino , Síndrome de Imunodeficiência Adquirida dos Símios/classificação , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/patogenicidade , Fatores de Tempo , Pesquisa Translacional Biomédica , Carga Viral , Viremia/imunologia , Viremia/virologiaRESUMO
Treatment of HIV infection with either antiretroviral (ARV) therapy or neutralizing monoclonal antibodies (NAbs) leads to a reduction in HIV plasma virus. Both ARVs and NAbs prevent new rounds of viral infection, but NAbs may have the additional capacity to accelerate the loss of virus-infected cells through Fc gamma receptor (FcγR)-mediated effector functions, which should affect the kinetics of plasma-virus decline. Here, we formally test the role of effector function in vivo by comparing the rate and timing of plasma-virus clearance in response to a single-dose treatment with either unmodified NAb or those with either reduced or augmented Fc function. When infused into viremic simian HIV (SHIV)-infected rhesus macaques, there was a 21% difference in slope of plasma-virus decline between NAb and NAb with reduced Fc function. NAb engineered to increase FcγRIII binding and improve antibody-dependent cellular cytotoxicity (ADCC) in vitro resulted in arming of effector cells in vivo, yet led to viral-decay kinetics similar to NAbs with reduced Fc function. These studies show that the predominant mechanism of antiviral activity of HIV NAbs is through inhibition of viral entry, but that Fc function can contribute to the overall antiviral activity, making them distinct from standard ARVs.
Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Anti-HIV/imunologia , Infecções por HIV , HIV-1/imunologia , Receptores de IgG/imunologia , Animais , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Células Cultivadas , Modelos Animais de Doenças , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/virologia , Macaca mulatta , Síndrome de Imunodeficiência Adquirida dos Símios , Vírus da Imunodeficiência SímiaRESUMO
Even after more than 30 years since its discovery, there is no cure for HIV-1 infection. Combination antiretroviral therapy (cART) is currently the only HIV-1 infection management option in clinics. Despite its success in suppressing viral replication and converting HIV-1 from a lethal infection to a chronic and manageable disease, cART treatment is life long and long-term use can result in major drawbacks such as high cost, multiple side effects, and an increase in the development of multidrug-resistant escape mutants. Recently, antibody-based anti-HIV-1 treatment has emerged as a potential alternative therapeutic modality for HIV-1 treatment and cure strategies. These antibody-based anti-HIV-1 treatments comprising either receptor-targeting antibodies or broad neutralizing antibodies (bNAbs) are currently being developed and evaluated in clinical trials. These antibodies have demonstrated potent antiviral effects against multiple strains of HIV-1, and shown promise for prevention, maintenance, and prolonged remission of HIV-1 infection. This review gives an update on the current status of these antibody-based treatments for HIV-1, discusses their mechanism of action and the challenges in developing them, providing insight for their development as novel clinical therapies against HIV-1 infection.