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1.
Nature ; 614(7947): 309-317, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36599977

RESUMEN

Human immunodeficiency virus 1 (HIV-1) reservoir cells persist lifelong despite antiretroviral treatment1,2 but may be vulnerable to host immune responses that could be exploited in strategies to cure HIV-1. Here we used a single-cell, next-generation sequencing approach for the direct ex vivo phenotypic profiling of individual HIV-1-infected memory CD4+ T cells from peripheral blood and lymph nodes of people living with HIV-1 and receiving antiretroviral treatment for approximately 10 years. We demonstrate that in peripheral blood, cells harbouring genome-intact proviruses and large clones of virally infected cells frequently express ensemble signatures of surface markers conferring increased resistance to immune-mediated killing by cytotoxic T and natural killer cells, paired with elevated levels of expression of immune checkpoint markers likely to limit proviral gene transcription; this phenotypic profile might reduce HIV-1 reservoir cell exposure to and killing by cellular host immune responses. Viral reservoir cells harbouring intact HIV-1 from lymph nodes exhibited a phenotypic signature primarily characterized by upregulation of surface markers promoting cell survival, including CD44, CD28, CD127 and the IL-21 receptor. Together, these results suggest compartmentalized phenotypic signatures of immune selection in HIV-1 reservoir cells, implying that only small subsets of infected cells with optimal adaptation to their anatomical immune microenvironment are able to survive during long-term antiretroviral treatment. The identification of phenotypic markers distinguishing viral reservoir cells may inform future approaches for strategies to cure and eradicate HIV-1.


Asunto(s)
Linfocitos T CD4-Positivos , Infecciones por VIH , VIH-1 , Fenotipo , Latencia del Virus , Humanos , Antirretrovirales/farmacología , Antirretrovirales/uso terapéutico , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/virología , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , VIH-1/genética , VIH-1/inmunología , VIH-1/aislamiento & purificación , Provirus/efectos de los fármacos , Provirus/genética , Provirus/aislamiento & purificación , Carga Viral , Latencia del Virus/efectos de los fármacos , Memoria Inmunológica , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Supervivencia Celular , Antígenos CD28 , Receptores de Interleucina-21
2.
Curr Opin HIV AIDS ; 19(3): 110-115, 2024 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-38457193

RESUMEN

PURPOSE OF REVIEW: Elite controllers (ECs) and Posttreatment controllers (PTCs) represent a small subset of individuals who are capable of maintaining drug-free control of HIV plasma viral loads despite the persistence of a replication-competent viral reservoir. This review aims to curate recent experimental studies evaluating viral reservoirs that distinguish EC/PTC and may contribute to their ability to maintain undetectable viral loads in the absence of antiretroviral therapy. RECENT FINDINGS: Recent studies on ECs have demonstrated that integration sites of intact proviruses in EC/PTC are markedly biased towards heterochromatin regions; in contrast, intact proviruses in accessible and permissive chromatin were profoundly underrepresented. Of note, no such biases were noted when CD4 + T cells from EC were infected directly ex vivo, suggesting that the viral reservoir profile in EC is not related to altered integration site preferences during acute infection, but instead represents the result of immune-mediated selection mechanisms that can eliminate proviruses in transcriptionally-active euchromatin regions while promoting preferential persistence of intact proviruses in nonpermissive genome regions. Proviral transcription in such "blocked and locked" regions may be restricted through epigenetic mechanisms, protecting them from immune-recognition but presumably limiting their ability to drive viral rebound. While the exact immune mechanisms driving this selection process remain undefined, recent single-cell analytic approaches support the hypothesis that HIV reservoir cells are subject to immune selection pressure by host factors. SUMMARY: A "blocked and locked" viral reservoir profile may constitute a structural virological correlate of a functional cure of HIV-1 infection. Further research into the immunological mechanism promoting HIV-1 reservoir selection and evolution in EC/PTC is warranted and could inform foreseeable cure strategies.


Asunto(s)
Infecciones por VIH , VIH-1 , Humanos , VIH-1/genética , Provirus/genética , Replicación Viral , Linfocitos T CD4-Positivos , Integración Viral , Carga Viral , Latencia del Virus
3.
Nat Rev Microbiol ; 22(6): 328-344, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38337034

RESUMEN

Successful approaches for eradication or cure of HIV-1 infection are likely to include immunological mechanisms, but remarkably little is known about how human immune responses can recognize and interact with the few HIV-1-infected cells that harbour genome-intact viral DNA, persist long term despite antiretroviral therapy and represent the main barrier to a cure. For a long time regarded as being completely shielded from host immune responses due to viral latency, these cells do, on closer examination with single-cell analytic techniques, display discrete footprints of immune selection, implying that human immune responses may be able to effectively engage and target at least some of these cells. The failure to eliminate rebound-competent virally infected cells in the majority of persons likely reflects the evolution of a highly selected pool of reservoir cells that are effectively camouflaged from immune recognition or rely on sophisticated approaches for resisting immune-mediated killing. Understanding the fine-tuned interplay between host immune responses and viral reservoir cells will help to design improved interventions that exploit the immunological vulnerabilities of HIV-1 reservoir cells.


Asunto(s)
Infecciones por VIH , VIH-1 , Latencia del Virus , VIH-1/inmunología , VIH-1/fisiología , Humanos , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Infecciones por VIH/tratamiento farmacológico , Latencia del Virus/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/virología
4.
Med ; 4(5): 285-287, 2023 05 12.
Artículo en Inglés | MEDLINE | ID: mdl-37178680

RESUMEN

A cure of HIV-1 infection has previously been described in two individuals undergoing allogeneic hematopoietic stem cell transplants from homozygous carriers of the CCR5Δ32 gene variant, which confers HIV-1 resistance. Two recent reports corroborate these earlier studies, underscoring that in HIV-1-infected persons with hematologic malignancies, these procedures may provide a realistic perspective for a cure of HIV-1 infection.


Asunto(s)
Infecciones por VIH , Seropositividad para VIH , VIH-1 , Neoplasias Hematológicas , Trasplante de Células Madre Hematopoyéticas , Humanos , VIH-1/genética , Infecciones por VIH/terapia , Infecciones por VIH/genética , Trasplante de Células Madre Hematopoyéticas/métodos
5.
Viruses ; 12(1)2019 12 29.
Artículo en Inglés | MEDLINE | ID: mdl-31905741

RESUMEN

Sindbis virus (SINV) infection induces eIF2α phosphorylation, which leads to stress granule (SG) assembly. SINV infection also stimulates autophagy, which has an important role in controlling the innate immune response. The importance of autophagy to virus-induced translation arrest is not well understood. In this study, we show that the autophagy protein ATG16L1 not only regulates eIF2α phosphorylation and the translation of viral and antiviral proteins, but also controls SG assembly. Early in infection (2hpi), capsids were recruited by host factors Cytotoxic Granule-Associated RNA Binding Protein (TIA1), Y-box binding protein 1 (YBX1), and vasolin-containing protein 1 (VCP), to a single perinuclear body, which co-localized with the viral pattern recognition sensors, double stranded RNA-activated protein-kinase R (PKR) and RIG-I. By 6hpi, there was increased eIF2α phosphorylation and viral protein synthesis. However, in cells lacking the autophagy protein ATG16L1, SG assembly was inhibited and capsid remained in numerous small foci in the cytoplasm containing YBX1, TIA1 with RIG-I, and these persisted for over 8hpi. In the absence of ATG16L1, there was little phosphorylation of eIF2α and low levels of viral protein synthesis. Compared to wild type cells, there was potentiated interferon protein and interferon-stimulated gene (ISG) mRNA expression. These results show that ATG16L1 is required for maximum eIF2α phosphorylation, proper SG assembly into a single perinuclear focus, and for attenuating the innate immune response. Therefore, this study shows that, in the case of SINV, ATG16L1 is pro-viral, required for SG assembly and virus replication.


Asunto(s)
Proteínas Relacionadas con la Autofagia/genética , Gránulos Citoplasmáticos/metabolismo , Factor 2 Eucariótico de Iniciación/genética , Fibroblastos/virología , Interacciones Huésped-Patógeno , Animales , Autofagia , Línea Celular , Factor 2 Eucariótico de Iniciación/metabolismo , Ratones , Fosforilación , Biosíntesis de Proteínas , Virus Sindbis , Proteínas Virales/genética
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