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1.
Proc Natl Acad Sci U S A ; 116(49): 24748-24759, 2019 12 03.
Artículo en Inglés | MEDLINE | ID: mdl-31748275

RESUMEN

Peptides generated by proteasome-catalyzed splicing of noncontiguous amino acid sequences have been shown to constitute a source of nontemplated human leukocyte antigen class I (HLA-I) epitopes, but their role in pathogen-specific immunity remains unknown. CD8+ T cells are key mediators of HIV type 1 (HIV-1) control, and identification of novel epitopes to enhance targeting of infected cells is a priority for prophylactic and therapeutic strategies. To explore the contribution of proteasome-catalyzed peptide splicing (PCPS) to HIV-1 epitope generation, we developed a broadly applicable mass spectrometry-based discovery workflow that we employed to identify spliced HLA-I-bound peptides on HIV-infected cells. We demonstrate that HIV-1-derived spliced peptides comprise a relatively minor component of the HLA-I-bound viral immunopeptidome. Although spliced HIV-1 peptides may elicit CD8+ T cell responses relatively infrequently during infection, CD8+ T cells primed by partially overlapping contiguous epitopes in HIV-infected individuals were able to cross-recognize spliced viral peptides, suggesting a potential role for PCPS in restricting HIV-1 escape pathways. Vaccine-mediated priming of responses to spliced HIV-1 epitopes could thus provide a novel means of exploiting epitope targets typically underutilized during natural infection.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Reactividad Cruzada/genética , Infecciones por VIH/inmunología , VIH-1/inmunología , Complejo de la Endopetidasa Proteasomal/metabolismo , Vacunas contra el SIDA/inmunología , Vacunas contra el SIDA/uso terapéutico , Antígenos Virales/genética , Antígenos Virales/inmunología , Antígenos Virales/metabolismo , Linfocitos T CD8-positivos/metabolismo , Línea Celular , Estudios de Cohortes , Reacciones Cruzadas/inmunología , Conjuntos de Datos como Asunto , Epítopos de Linfocito T/genética , Epítopos de Linfocito T/inmunología , Epítopos de Linfocito T/metabolismo , Infecciones por VIH/sangre , Infecciones por VIH/terapia , Infecciones por VIH/virología , VIH-1/genética , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase I/metabolismo , Humanos , Evasión Inmune , Péptidos/genética , Péptidos/inmunología , Péptidos/metabolismo , Complejo de la Endopetidasa Proteasomal/inmunología , Empalme del ARN/inmunología , ARN Viral/sangre , ARN Viral/genética , ARN Viral/aislamiento & purificación , RNA-Seq , Proteínas Virales/genética , Proteínas Virales/inmunología , Proteínas Virales/metabolismo
2.
J Virol ; 92(4)2018 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-29167337

RESUMEN

The well-characterized association between HLA-B*27:05 and protection against HIV disease progression has been linked to immunodominant HLA-B*27:05-restricted CD8+ T-cell responses toward the conserved Gag KK10 (residues 263 to 272) and polymerase (Pol) KY9 (residues 901 to 909) epitopes. We studied the impact of the 3 amino acid differences between HLA-B*27:05 and the closely related HLA-B*27:02 on the HIV-specific CD8+ T-cell response hierarchy and on immune control of HIV. Genetic epidemiological data indicate that both HLA-B*27:02 and HLA-B*27:05 are associated with slower disease progression and lower viral loads. The effect of HLA-B*27:02 appeared to be consistently stronger than that of HLA-B*27:05. In contrast to HLA-B*27:05, the immunodominant HIV-specific HLA-B*27:02-restricted CD8+ T-cell response is to a Nef epitope (residues 142 to 150 [VW9]), with Pol KY9 subdominant and Gag KK10 further subdominant. This selection was driven by structural differences in the F pocket, mediated by a polymorphism between these two HLA alleles at position 81. Analysis of autologous virus sequences showed that in HLA-B*27:02-positive subjects, all three of these CD8+ T-cell responses impose selection pressure on the virus, whereas in HLA-B*27:05-positive subjects, there is no Nef VW9-mediated selection pressure. These studies demonstrate that HLA-B*27:02 mediates protection against HIV disease progression that is at least as strong as or stronger than that mediated by HLA-B*27:05. In combination with the protective Gag KK10 and Pol KY9 CD8+ T-cell responses that dominate HIV-specific CD8+ T-cell activity in HLA-B*27:05-positive subjects, a Nef VW9-specific response is additionally present and immunodominant in HLA-B*27:02-positive subjects, mediated through a polymorphism at residue 81 in the F pocket, that contributes to selection pressure against HIV.IMPORTANCE CD8+ T cells play a central role in successful control of HIV infection and have the potential also to mediate the eradication of viral reservoirs of infection. The principal means by which protective HLA class I molecules, such as HLA-B*27:05 and HLA-B*57:01, slow HIV disease progression is believed to be via the particular HIV-specific CD8+ T cell responses restricted by those alleles. We focus here on HLA-B*27:05, one of the best-characterized protective HLA molecules, and the closely related HLA-B*27:02, which differs by only 3 amino acids and which has not been well studied in relation to control of HIV infection. We show that HLA-B*27:02 is also protective against HIV disease progression, but the CD8+ T-cell immunodominance hierarchy of HLA-B*27:02 differs strikingly from that of HLA-B*27:05. These findings indicate that the immunodominant HLA-B*27:02-restricted Nef response adds to protection mediated by the Gag and Pol specificities that dominate anti-HIV CD8+ T-cell activity in HLA-B*27:05-positive subjects.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Infecciones por VIH/inmunología , Antígeno HLA-B27/genética , Epítopos Inmunodominantes/inmunología , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/genética , Productos del Gen nef del Virus de la Inmunodeficiencia Humana/genética , Genes MHC Clase I , Infecciones por VIH/virología , VIH-1 , Humanos , Carga Viral
3.
Proc Natl Acad Sci U S A ; 111(33): 12187-92, 2014 Aug 19.
Artículo en Inglés | MEDLINE | ID: mdl-25092293

RESUMEN

During HIV type-1 (HIV-1), hepatitis C virus (HCV), and hepatitis B virus (HBV) infections, altered iron balance correlates with morbidity. The liver-produced hormone hepcidin dictates systemic iron homeostasis. We measured hepcidin, iron parameters, cytokines, and inflammatory markers in three cohorts: plasma donors who developed acute HIV-1, HBV, or HCV viremia during the course of donations; HIV-1-positive individuals progressing from early to chronic infection; and chronically HIV-1-infected individuals (receiving antiretroviral therapy or untreated). Hepcidin increased and plasma iron decreased during acute HIV-1 infection, as viremia was initially detected. In patients transitioning from early to chronic HIV-1 infection, hepcidin in the first 60 d of infection positively correlated with the later plasma viral load set-point. Hepcidin remained elevated in individuals with untreated chronic HIV-1 infection and in subjects on ART. In contrast to HIV-1, there was no evidence of hepcidin up-regulation or hypoferremia during the primary viremic phases of HCV or HBV infection; serum iron marginally increased during acute HBV infection. In conclusion, hepcidin induction is part of the pathogenically important systemic inflammatory cascade triggered during HIV-1 infection and may contribute to the establishment and maintenance of viral set-point, which is a strong predictor of progression to AIDS and death. However, distinct patterns of hepcidin and iron regulation occur during different viral infections that have particular tissue tropisms and elicit different systemic inflammatory responses. The hypoferremia of acute infection is therefore a pathogen-specific, not universal, phenomenon.


Asunto(s)
Infecciones por VIH/metabolismo , Hepatitis B/metabolismo , Hepatitis C/metabolismo , Hepcidinas/metabolismo , Hierro/metabolismo , Proteínas de Fase Aguda/metabolismo , Fármacos Anti-VIH/uso terapéutico , Estudios de Cohortes , Citocinas/metabolismo , Infecciones por VIH/tratamiento farmacológico , VIH-1 , Regulación hacia Arriba , Carga Viral
4.
PLoS Comput Biol ; 11(4): e1004179, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25837979

RESUMEN

HIV-1 can disseminate between susceptible cells by two mechanisms: cell-free infection following fluid-phase diffusion of virions and by highly-efficient direct cell-to-cell transmission at immune cell contacts. The contribution of this hybrid spreading mechanism, which is also a characteristic of some important computer worm outbreaks, to HIV-1 progression in vivo remains unknown. Here we present a new mathematical model that explicitly incorporates the ability of HIV-1 to use hybrid spreading mechanisms and evaluate the consequences for HIV-1 pathogenenesis. The model captures the major phases of the HIV-1 infection course of a cohort of treatment naive patients and also accurately predicts the results of the Short Pulse Anti-Retroviral Therapy at Seroconversion (SPARTAC) trial. Using this model we find that hybrid spreading is critical to seed and establish infection, and that cell-to-cell spread and increased CD4+ T cell activation are important for HIV-1 progression. Notably, the model predicts that cell-to-cell spread becomes increasingly effective as infection progresses and thus may present a considerable treatment barrier. Deriving predictions of various treatments' influence on HIV-1 progression highlights the importance of earlier intervention and suggests that treatments effectively targeting cell-to-cell HIV-1 spread can delay progression to AIDS. This study suggests that hybrid spreading is a fundamental feature of HIV infection, and provides the mathematical framework incorporating this feature with which to evaluate future therapeutic strategies.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Interacciones Huésped-Patógeno/inmunología , Modelos Inmunológicos , Biología Computacional , Femenino , Infecciones por VIH/virología , Humanos , Masculino
5.
Eur J Immunol ; 43(11): 2875-85, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23897063

RESUMEN

Interleukin-10 (IL-10) plays a key role in regulating proinflammatory immune responses to infection but can interfere with pathogen clearance. Although IL-10 is upregulated throughout HIV-1 infection in multiple cell subsets, whether this is a viral immune evasion strategy or an appropriate response to immune activation is unresolved. Analysis of IL-10 production at the single cell level in 51 chronically infected subjects (31 antiretroviral (ART) naïve and 20 ART treated) showed that a subset of CD8(+) T cells with a CD25(neg) FoxP3(neg) phenotype contributes substantially to IL-10 production in response to HIV-1 gag stimulation. The frequencies of gag-specific IL-10- and IFN-γ-producing T cells in ART-naïve subjects were strongly correlated and the majority of these IL-10(+) CD8(+) T cells co-produced IFN-γ; however, patients with a predominant IL-10(+) /IFN-γ(neg) profile showed better control of viraemia. Depletion of HIV-specific CD8(+) IL-10(+) cells from PBMCs led to upregulation of CD38 on CD14(+) monocytes together with increased IL-6 production, in response to gag stimulation. Increased CD38 expression was positively correlated with the frequency of the IL-10(+) population and was also induced by exposure of monocytes to HIV-1 in vitro. Production of IL-10 by HIV-specific CD8(+) T cells may represent an adaptive regulatory response to monocyte activation during chronic infection.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Interleucina-10/metabolismo , ADP-Ribosil Ciclasa 1/metabolismo , Adulto , Terapia Antirretroviral Altamente Activa , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/metabolismo , Femenino , Factores de Transcripción Forkhead/metabolismo , Humanos , Interferón gamma/biosíntesis , Interleucina-10/biosíntesis , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Interleucina-6/biosíntesis , Receptores de Lipopolisacáridos/metabolismo , Activación de Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Regulación hacia Arriba , Carga Viral , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/inmunología
6.
Blood ; 119(21): 4928-38, 2012 May 24.
Artículo en Inglés | MEDLINE | ID: mdl-22490682

RESUMEN

CD8 T cells lose the capacity to control HIV infection, but the extent of the impairment of CD8 T-cell functions and the mechanisms that underlie it remain controversial. Here we report an extensive ex vivo analysis of HIV-specific CD8 T cells, covering the expression of 16 different molecules involved in CD8 function or differentiation. This approach gave remarkably homogeneous readouts in different donors and showed that CD8 dysfunction in chronic HIV infection was much more severe than described previously: some Ifng transcription was observed, but most cells lost the expression of all cytolytic molecules and Eomesodermin and T-bet by chronic infection. These results reveal a cellular mechanism explaining the dysfunction of CD8 T cells during chronic HIV infection, as CD8 T cells are known to maintain some functionality when either of these transcription factors is present, but to lose all cytotoxic activity when both are not expressed. Surprisingly, they also show that chronic HIV and lymphocytic choriomeningitis virus infections have a very different impact on fundamental T-cell functions, "exhausted" lymphocytic choriomeningitis virus-specific cells losing the capacity to secrete IFN-γ but maintaining some cytotoxic activity as granzyme B and FasL are overexpressed and, while down-regulating T-bet, up-regulating Eomesodermin expression.


Asunto(s)
Linfocitos T CD8-positivos/fisiología , Diferenciación Celular/genética , Infecciones por VIH/genética , Infecciones por VIH/inmunología , Proteínas de Dominio T Box/genética , Linfocitos T CD8-positivos/metabolismo , Estudios de Casos y Controles , Diferenciación Celular/inmunología , Diferenciación Celular/fisiología , Enfermedad Crónica , Proteína Ligando Fas/genética , Proteína Ligando Fas/metabolismo , Proteína Ligando Fas/fisiología , Regulación de la Expresión Génica/inmunología , Granzimas/genética , Granzimas/metabolismo , Granzimas/fisiología , Infecciones por VIH/patología , Humanos , Interferón gamma/metabolismo , Proteínas de Dominio T Box/metabolismo , Proteínas de Dominio T Box/fisiología , Linfocitos T Colaboradores-Inductores/metabolismo , Linfocitos T Colaboradores-Inductores/fisiología , Factores de Tiempo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/fisiología
7.
Retrovirology ; 10: 146, 2013 Dec 03.
Artículo en Inglés | MEDLINE | ID: mdl-24299076

RESUMEN

BACKGROUND: Following mucosal human immunodeficiency virus type 1 (HIV-1) transmission, type 1 interferons (IFNs) are rapidly induced at sites of initial virus replication in the mucosa and draining lymph nodes. However, the role played by IFN-stimulated antiviral activity in restricting HIV-1 replication during the initial stages of infection is not clear. We hypothesized that if type 1 IFNs exert selective pressure on HIV-1 replication in the earliest stages of infection, the founder viruses that succeed in establishing systemic infection would be more IFN-resistant than viruses replicating during chronic infection, when type 1 IFNs are produced at much lower levels. To address this hypothesis, the relative resistance of virus isolates derived from HIV-1-infected individuals during acute and chronic infection to control by type 1 IFNs was analysed. RESULTS: The replication of plasma virus isolates generated from subjects acutely infected with HIV-1 and molecularly cloned founder HIV-1 strains could be reduced but not fully suppressed by type 1 IFNs in vitro. The mean IC50 value for IFNα2 (22 U/ml) was lower than that for IFNß (346 U/ml), although at maximally-inhibitory concentrations both IFN subtypes inhibited virus replication to similar extents. Individual virus isolates exhibited differential susceptibility to inhibition by IFNα2 and IFNß, likely reflecting variation in resistance to differentially up-regulated IFN-stimulated genes. Virus isolates from subjects acutely infected with HIV-1 were significantly more resistant to in vitro control by IFNα than virus isolates generated from the same individuals during chronic, asymptomatic infection. Viral IFN resistance declined rapidly after the acute phase of infection: in five subjects, viruses derived from six-month consensus molecular clones were significantly more sensitive to the antiviral effects of IFNs than the corresponding founder viruses. CONCLUSIONS: The establishment of systemic HIV-1 infection by relatively IFNα-resistant founder viruses lends strong support to the hypothesis that IFNα plays an important role in the control of HIV-1 replication during the earliest stages of infection, prior to systemic viral spread. These findings suggest that it may be possible to harness the antiviral activity of type 1 IFNs in prophylactic and potentially also therapeutic strategies to combat HIV-1 infection.


Asunto(s)
Farmacorresistencia Viral , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , VIH-1/inmunología , Interferón-alfa/inmunología , Interferón-alfa/farmacología , Replicación Viral/efectos de los fármacos , Infecciones por VIH/inmunología , VIH-1/aislamiento & purificación , Humanos , Concentración 50 Inhibidora , Pruebas de Sensibilidad Microbiana
8.
PLoS Pathog ; 7(2): e1001273, 2011 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-21347345

RESUMEN

In the present study, we analyzed the functional profile of CD8+ T-cell responses directed against autologous transmitted/founder HIV-1 isolates during acute and early infection, and examined whether multifunctionality is required for selection of virus escape mutations. Seven anti-retroviral therapy-naïve subjects were studied in detail between 1 and 87 weeks following onset of symptoms of acute HIV-1 infection. Synthetic peptides representing the autologous transmitted/founder HIV-1 sequences were used in multiparameter flow cytometry assays to determine the functionality of HIV-1-specific CD8+ T memory cells. In all seven patients, the earliest T cell responses were predominantly oligofunctional, although the relative contribution of multifunctional cell responses increased significantly with time from infection. Interestingly, only the magnitude of the total and not of the poly-functional T-cell responses was significantly associated with the selection of escape mutants. However, the high contribution of MIP-1ß-producing CD8+ T-cells to the total response suggests that mechanisms not limited to cytotoxicity could be exerting immune pressure during acute infection. Lastly, we show that epitope entropy, reflecting the capacity of the epitope to tolerate mutational change and defined as the diversity of epitope sequences at the population level, was also correlated with rate of emergence of escape mutants.


Asunto(s)
Variación Antigénica/inmunología , Linfocitos T CD8-positivos/inmunología , Epítopos/inmunología , Infecciones por VIH/inmunología , VIH-1/genética , VIH-1/inmunología , Evasión Inmune/genética , Adulto , Variación Antigénica/genética , Linfocitos T CD8-positivos/metabolismo , Epítopos/genética , Infecciones por VIH/virología , Humanos , Evasión Inmune/inmunología , Memoria Inmunológica/inmunología , Memoria Inmunológica/fisiología , Masculino , Persona de Mediana Edad , Mutación/fisiología , Organismos Modificados Genéticamente , Selección Genética/inmunología , Adulto Joven
9.
Retrovirology ; 8: 16, 2011 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-21401915

RESUMEN

BACKGROUND: Non-neutralising antibodies to the envelope glycoprotein are elicited during acute HIV-1 infection and are abundant throughout the course of disease progression. Although these antibodies appear to have negligible effects on HIV-1 infection when assayed in standard neutralisation assays, they have the potential to exert either inhibitory or enhancing effects through interactions with complement and/or Fc receptors. Here we report that non-neutralising antibodies produced early in response to HIV-1 infection can enhance viral infectivity. RESULTS: We investigated this complement-mediated antibody-dependent enhancement (C'-ADE) of early HIV infection by carrying out longitudinal studies with primary viruses and autologous sera derived sequentially from recently infected individuals, using a T cell line naturally expressing the complement receptor 2 (CR2; CD21). The C'-ADE was consistently observed and in some cases achieved infection-enhancing levels of greater than 350-fold, converting a low-level infection to a highly destructive one. C'-ADE activity declined as a neutralising response to the early virus emerged, but later virus isolates that had escaped the neutralising response demonstrated an increased capacity for enhanced infection by autologous antibodies. Moreover, sera with autologous enhancing activity were capable of C'ADE of heterologous viral isolates, suggesting the targeting of conserved epitopes on the envelope glycoprotein. Ectopic expression of CR2 on cell lines expressing HIV-1 receptors was sufficient to render them sensitive to C'ADE. CONCLUSIONS: Taken together, these results suggest that non-neutralising antibodies to the HIV-1 envelope that arise during acute infection are not 'passive', but in concert with complement and complement receptors may have consequences for HIV-1 dissemination and pathogenesis.


Asunto(s)
Anticuerpos Neutralizantes/sangre , Acrecentamiento Dependiente de Anticuerpo , Proteínas del Sistema Complemento/metabolismo , Anticuerpos Anti-VIH/sangre , Infecciones por VIH/inmunología , VIH-1/patogenicidad , Anticuerpos Neutralizantes/inmunología , Línea Celular , Activación de Complemento , Proteínas del Sistema Complemento/inmunología , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/sangre , Infecciones por VIH/fisiopatología , Infecciones por VIH/virología , VIH-1/inmunología , Humanos , Estudios Longitudinales , Masculino , Pruebas de Neutralización , Receptores de Complemento 3d/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo
10.
Retrovirology ; 8: 41, 2011 Jun 02.
Artículo en Inglés | MEDLINE | ID: mdl-21635736

RESUMEN

BACKGROUND: CD8+ T cells play an important role in control of viral replication during acute and early human immunodeficiency virus type 1 (HIV-1) infection, contributing to containment of the acute viral burst and establishment of the prognostically-important persisting viral load. Understanding mechanisms that impair CD8+ T cell-mediated control of HIV replication in primary infection is thus of importance. This study addressed the relative extent to which HIV-specific T cell responses are impacted by viral mutational escape versus reduction in response avidity during the first year of infection. RESULTS: 18 patients presenting with symptomatic primary HIV-1 infection, most of whom subsequently established moderate-high persisting viral loads, were studied. HIV-specific T cell responses were mapped in each individual and responses to a subset of optimally-defined CD8+ T cell epitopes were followed from acute infection onwards to determine whether they were escaped or declined in avidity over time. During the first year of infection, sequence variation occurred in/around 26/33 epitopes studied (79%). In 82% of cases of intra-epitopic sequence variation, the mutation was confirmed to confer escape, although T cell responses were subsequently expanded to variant sequences in some cases. In contrast, < 10% of responses to index sequence epitopes declined in functional avidity over the same time-frame, and a similar proportion of responses actually exhibited an increase in functional avidity during this period. CONCLUSIONS: Escape appears to constitute a much more important means of viral evasion of CD8+ T cell responses in acute and early HIV infection than decline in functional avidity of epitope-specific T cells. These findings support the design of vaccines to elicit T cell responses that are difficult for the virus to escape.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/inmunología , Evasión Inmune , Mutación Missense , Proteínas Virales/inmunología , Epítopos de Linfocito T/genética , Epítopos de Linfocito T/inmunología , Humanos , Proteínas Virales/genética
11.
J Immunol ; 182(11): 7131-45, 2009 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-19454710

RESUMEN

Multiple lines of evidence support a role for CD8(+) T cells in control of acute/early HIV replication; however, features of the primary HIV-specific CD8(+) T cell response that may impact on the efficiency of containment of early viral replication remain poorly defined. In this study, we performed a novel, comprehensive analysis of the kinetics of expansion of components of the HIV-specific CD8(+) T cell response in 21 acutely infected individuals. Epitope-specific T cell responses expanded asynchronously during primary infection in all subjects. The most rapidly expanded responses peaked as early as 5 days following symptomatic presentation and were typically of very limited epitope breadth. Responses of additional specificities expanded and contracted in subsequent waves, resulting in successive shifts in the epitope immunodominance hierarchy over time. Sequence variation and escape were temporally associated with the decline in magnitude of only a subset of T cell responses, suggesting that other factors such as Ag load and T cell exhaustion may play a role in driving the contraction of HIV-specific T cell responses. These observations document the preferential expansion of CD8(+) T cells recognizing a subset of epitopes during the viral burst in acute HIV-1 infection and suggest that the nature of the initial, very rapidly expanded T cell response may influence the efficiency with which viral replication is contained in acute/early HIV infection.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Infecciones por VIH/inmunología , Epítopos Inmunodominantes/inmunología , Especificidad del Receptor de Antígeno de Linfocitos T/inmunología , Proliferación Celular , Epítopos/inmunología , Seropositividad para VIH , VIH-1/genética , VIH-1/inmunología , Humanos , Cinética , Activación de Linfocitos , Carga Viral
12.
Res Sq ; 2021 Mar 17.
Artículo en Inglés | MEDLINE | ID: mdl-33758833

RESUMEN

There is an urgent need to understand the nature of immune responses against SARS-CoV-2, to inform risk-mitigation strategies for people living with HIV (PLWH). We show that the majority of PLWH, controlled on ART, mount a functional adaptive immune response to SARS-CoV-2. Humoral and SARS-CoV-2-specific T cell responses are comparable between HIV-positive and negative subjects and persist 5-7 months following predominately mild COVID-19 disease. T cell responses against Spike, Membrane and Nucleocapsid are the most prominent, with SARS-CoV-2-specific CD4 T cells outnumbering CD8 T cells. We further show that the overall magnitude of SARS-CoV-2-specific T cell responses relates to the size of the naive CD4 T cell pool and the CD4:CD8 ratio in PLWH, in whom disparate antibody and T cell responses are observed. These findings suggest that inadequate immune reconstitution on ART, could hinder immune responses to SARS-CoV-2 with implications for the individual management and vaccine effectiveness in PLWH.

13.
Nat Commun ; 12(1): 5839, 2021 10 05.
Artículo en Inglés | MEDLINE | ID: mdl-34611163

RESUMEN

There is an urgent need to understand the nature of immune responses against SARS-CoV-2, to inform risk-mitigation strategies for people living with HIV (PLWH). Here we show that the majority of PLWH with ART suppressed HIV viral load, mount a detectable adaptive immune response to SARS-CoV-2. Humoral and SARS-CoV-2-specific T cell responses are comparable between HIV-positive and negative subjects and persist 5-7 months following predominately mild COVID-19 disease. T cell responses against Spike, Membrane and Nucleoprotein are the most prominent, with SARS-CoV-2-specific CD4 T cells outnumbering CD8 T cells. We further show that the overall magnitude of SARS-CoV-2-specific T cell responses relates to the size of the naive CD4 T cell pool and the CD4:CD8 ratio in PLWH. These findings suggest that inadequate immune reconstitution on ART, could hinder immune responses to SARS-CoV-2 with implications for the individual management and vaccine effectiveness in PLWH.


Asunto(s)
Infecciones por VIH/inmunología , Infecciones por VIH/virología , Inmunidad Humoral , SARS-CoV-2/fisiología , Linfocitos T/inmunología , Adulto , Anciano , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Formación de Anticuerpos/inmunología , Antígenos Virales/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , COVID-19/sangre , COVID-19/inmunología , COVID-19/virología , Estudios de Cohortes , Femenino , Genoma Humano , Infecciones por VIH/sangre , Humanos , Interferón gamma/metabolismo , Masculino , Persona de Mediana Edad , Fenotipo , Especificidad de la Especie , Donantes de Tejidos
14.
bioRxiv ; 2021 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-33619489

RESUMEN

There is an urgent need to understand the nature of immune responses generated against SARS-CoV-2, to better inform risk-mitigation strategies for people living with HIV (PLWH). Although not all PLWH are considered immunosuppressed, residual cellular immune deficiency and ongoing inflammation could influence COVID-19 disease severity, the evolution and durability of protective memory responses. Here, we performed an integrated analysis, characterizing the nature, breadth and magnitude of SARS-CoV-2-specific immune responses in PLWH, controlled on ART, and HIV negative subjects. Both groups were in the convalescent phase of predominately mild COVID-19 disease. The majority of PLWH mounted SARS-CoV-2 Spike- and Nucleoprotein-specific antibodies with neutralizing activity and SARS-CoV-2-specific T cell responses, as measured by ELISpot, at levels comparable to HIV negative subjects. T cell responses against Spike, Membrane and Nucleocapsid were the most prominent, with SARS-CoV-2-specific CD4 T cells outnumbering CD8 T cells. Notably, the overall magnitude of SARS-CoV-2-specific T cell responses related to the size of the naive CD4 T cell pool and the CD4:CD8 ratio in PLWH, in whom disparate antibody and T cell responses were observed. Both humoral and cellular responses to SARS-CoV-2 were detected at 5-7 months post-infection, providing evidence of medium-term durability of responses irrespective of HIV serostatus. Incomplete immune reconstitution on ART and a low CD4:CD8 ratio could, however, hamper the development of immunity to SARS-CoV-2 and serve as a useful tool for risk stratification of PLWH. These findings have implications for the individual management and potential effectiveness of vaccination against SARS-CoV-2 in PLWH.

15.
Sci Transl Med ; 13(576)2021 01 13.
Artículo en Inglés | MEDLINE | ID: mdl-33441429

RESUMEN

Type 1 interferons (IFN-I) are potent innate antiviral effectors that constrain HIV-1 transmission. However, harnessing these cytokines for HIV-1 cure strategies has been hampered by an incomplete understanding of their antiviral activities at later stages of infection. Here, we characterized the IFN-I sensitivity of 500 clonally derived HIV-1 isolates from the plasma and CD4+ T cells of 26 individuals sampled longitudinally after transmission or after antiretroviral therapy (ART) and analytical treatment interruption. We determined the concentration of IFNα2 and IFNß that reduced viral replication in vitro by 50% (IC50) and found consistent changes in the sensitivity of HIV-1 to IFN-I inhibition both across individuals and over time. Resistance of HIV-1 isolates to IFN-I was uniformly high during acute infection, decreased in all individuals in the first year after infection, was reacquired concomitant with CD4+ T cell loss, and remained elevated in individuals with accelerated disease. HIV-1 isolates obtained by viral outgrowth during suppressive ART were relatively IFN-I sensitive, resembling viruses circulating just before ART initiation. However, viruses that rebounded after treatment interruption displayed the highest degree of IFNα2 and IFNß resistance observed at any time during the infection course. These findings indicate a dynamic interplay between host innate responses and the evolving HIV-1 quasispecies, with the relative contribution of IFN-I to HIV-1 control affected by both ART and analytical treatment interruption. Although elevated at transmission, host innate pressures are the highest during viral rebound, limiting the viruses that successfully become reactivated from latency to those that are IFN-I resistant.


Asunto(s)
Infecciones por VIH , VIH-1 , Interferón Tipo I , Antivirales/uso terapéutico , Linfocitos T CD4-Positivos , Infecciones por VIH/tratamiento farmacológico , Humanos , Interferón Tipo I/farmacología , Carga Viral , Replicación Viral
16.
Front Immunol ; 11: 596841, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33329587

RESUMEN

Human immunodeficiency virus type 1 (HIV-1) infection triggers rapid induction of multiple innate cytokines including type I interferons, which play important roles in viral control and disease pathogenesis. The transforming growth factor (TGF)-ß superfamily is a pleiotropic innate cytokine family, some members of which (activins and bone morphogenetic proteins (BMPs)) were recently demonstrated to exert antiviral activity against Zika and hepatitis B and C viruses but are poorly studied in HIV-1 infection. Here, we show that TGF-ß1 is systemically induced with very rapid kinetics (as early as 1-4 days after viremic spread begins) in acute HIV-1 infection, likely due to release from platelets, and remains upregulated throughout infection. Contrastingly, no substantial systemic upregulation of activins A and B or BMP-2 was observed during acute infection, although plasma activin levels trended to be elevated during chronic infection. HIV-1 triggered production of type I interferons but not TGF-ß superfamily cytokines from plasmacytoid dendritic cells (DCs) in vitro, putatively explaining their differing in vivo induction; whilst lipopolysaccharide (but not HIV-1) elicited activin A production from myeloid DCs. These findings underscore the need for better definition of the protective and pathogenic capacity of TGF-ß superfamily cytokines, to enable appropriate modulation for therapeutic purposes.


Asunto(s)
Citocinas/metabolismo , Infecciones por VIH/inmunología , Infecciones por VIH/metabolismo , VIH-1/inmunología , Interacciones Huésped-Patógeno/inmunología , Inmunidad Innata , Factor de Crecimiento Transformador beta/metabolismo , Biomarcadores , Citocinas/sangre , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Infecciones por VIH/virología , Humanos , Factor de Crecimiento Transformador beta/sangre
17.
Front Immunol ; 9: 474, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29616021

RESUMEN

Human cytomegalovirus (HCMV) co-infection is highly prevalent within HIV-1 cohorts and is an important cofactor in driving ongoing immune activation, even during effective antiretroviral treatment. HCMV infection has recently been associated with expansion of adaptive-like natural killer (NK) cells, which harbor epigenetic alterations that impact on their cellular function and phenotype. The influence of HCMV co-infection on the considerable heterogeneity among NK cells and their functional responses to different stimuli was assessed in a cohort of HIV-1-infected individuals sampled during different stages of infection, compared with healthy subjects stratified according to HCMV serostatus. Our data demonstrate a reshaping of the NK cell pool in HIV-1 infection of HCMV-seropositive individuals, with an accentuated peripheral transition of CD56dim NK cells toward a mature CD57+ CD85j+ NKG2C+ NKG2A- phenotype. Lack of PLZF further distinguishes adaptive NK cells from other NK cells expressing CD57 or NKG2C. PLZF- NK cells from HIV-infected individuals had high expression of CD2, were Siglec-7 negative and exhibited downregulation of key signaling molecules, SYK and FcεRI-γ, overwhelmingly displaying features of adaptive NK cells that correlated with HCMV serum Ab levels. Notably this adaptive-like signature was detected during early HIV-1 infection and persisted during treatment. Adaptive-like NK cell subsets in HIV-1-infected individuals displayed enhanced IFN-γ production following Fc receptor triggering compared with their conventional NK cell counterparts, and their ability to produce TNF-α and degranulate was preserved. Together, these data suggest that HMCV infection/reactivation, a hallmark of HIV-1 infection, plays a role in driving a relative expansion of NK cells with adaptive features during HIV-1 infection. The identification of selective NK subsets with retained effector activity in HIV-1-infected subjects raises the possibility of developing therapeutic strategies that exploit specific NK subpopulations to achieve better HIV-1 control.


Asunto(s)
Coinfección/inmunología , Infecciones por Citomegalovirus/inmunología , Citomegalovirus/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Células Asesinas Naturales/inmunología , Adulto , Antígenos de Diferenciación/inmunología , Coinfección/patología , Infecciones por Citomegalovirus/patología , Infecciones por VIH/patología , Humanos , Interferón gamma/inmunología , Células Asesinas Naturales/patología , Masculino
18.
Cell Rep ; 25(4): 893-908.e7, 2018 10 23.
Artículo en Inglés | MEDLINE | ID: mdl-30355496

RESUMEN

Densely arranged N-linked glycans shield the HIV-1 envelope (Env) trimer from antibody recognition. Strain-specific breaches in this shield (glycan holes) can be targets of vaccine-induced neutralizing antibodies that lack breadth. To understand the interplay between glycan holes and neutralization breadth in HIV-1 infection, we developed a sequence- and structure-based approach to identify glycan holes for individual Env sequences that are shielded in most M-group viruses. Applying this approach to 12 longitudinally followed individuals, we found that transmitted viruses with more intact glycan shields correlated with development of greater neutralization breadth. Within 2 years, glycan acquisition filled most glycan holes present at transmission, indicating escape from hole-targeting neutralizing antibodies. Glycan hole filling generally preceded the time to first detectable breadth, although time intervals varied across hosts. Thus, completely glycan-shielded viruses were associated with accelerated neutralization breadth development, suggesting that Env immunogens with intact glycan shields may be preferred components of AIDS vaccines.


Asunto(s)
Anticuerpos Neutralizantes/metabolismo , VIH-1/metabolismo , Polisacáridos/metabolismo , Productos del Gen env del Virus de la Inmunodeficiencia Humana/metabolismo , Biología Computacional , Secuencia Conservada , Células HEK293 , Humanos , Cinética , Modelos Moleculares , Pruebas de Neutralización , Polisacáridos/química , Productos del Gen env del Virus de la Inmunodeficiencia Humana/química
19.
Lancet HIV ; 8(6): e317-e318, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-34087093
20.
PLoS One ; 6(8): e23961, 2011.
Artículo en Inglés | MEDLINE | ID: mdl-21887353

RESUMEN

BACKGROUND: The rapid and continual viral escape from neutralizing antibodies is well documented in HIV-1 infection. Here we report in vivo emergence of viruses with heightened sensitivity to neutralizing antibodies, sometimes paralleling the development of neutralization escape. METHODOLOGY/PRINCIPAL FINDINGS: Sequential viral envs were amplified from seven HIV-1 infected men monitored from seroconversion up to 5 years after infection. Env-recombinant infectious molecular clones were generated and tested for coreceptor use, macrophage tropism and neutralization sensitivity to homologous and heterologous serum, soluble CD4 and monoclonal antibodies IgG1b12, 2G12 and 17b. We found that HIV-1 evolves sensitivity to contemporaneous neutralizing antibodies during infection. Neutralization sensitive viruses grow out even when potent autologous neutralizing antibodies are present in patient serum. Increased sensitivity to neutralization was associated with susceptibility of the CD4 binding site or epitopes induced after CD4 binding, and mediated by complex envelope determinants including V3 and V4 residues. The development of neutralization sensitive viruses occurred without clinical progression, coreceptor switch or change in tropism for primary macrophages. CONCLUSIONS: We propose that an interplay of selective forces for greater virus replication efficiency without the need to resist neutralizing antibodies in a compartment protected from immune surveillance may explain the temporal course described here for the in vivo emergence of HIV-1 isolates with high sensitivity to neutralizing antibodies.


Asunto(s)
Anticuerpos Neutralizantes , VIH-1/inmunología , Evasión Inmune/inmunología , Infecciones por VIH/inmunología , Humanos , Replicación Viral
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