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Nat Commun ; 12(1): 3727, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34140517


Clonal expansion of HIV-infected cells contributes to the long-term persistence of the HIV reservoir in ART-suppressed individuals. However, the contribution from cell clones that harbor inducible proviruses to plasma viremia is poorly understood. Here, we describe a single-cell approach to simultaneously sequence the TCR, integration sites and proviral genomes from translation-competent reservoir cells, called STIP-Seq. By applying this approach to blood samples from eight participants, we show that the translation-competent reservoir mainly consists of proviruses with short deletions at the 5'-end of the genome, often involving the major splice donor site. TCR and integration site sequencing reveal that cell clones with predicted pathogen-specificity can harbor inducible proviruses integrated into cancer-related genes. Furthermore, we find several matches between proviruses retrieved with STIP-Seq and plasma viruses obtained during ART and upon treatment interruption, suggesting that STIP-Seq can capture clones that are responsible for low-level viremia or viral rebound.

Antirretrovirais/uso terapêutico , Infecções por HIV/sangue , Infecções por HIV/tratamento farmacológico , HIV-1/metabolismo , Provírus/genética , Análise de Célula Única/métodos , Viremia/virologia , Linfócitos T CD4-Positivos/virologia , DNA Viral/sangue , Infecções por HIV/virologia , HIV-1/genética , HIV-1/patogenicidade , Humanos , Ionomicina/farmacologia , Masculino , Pessoa de Meia-Idade , Filogenia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Deleção de Sequência , Carga Viral/genética
Genome Biol ; 22(1): 97, 2021 04 06.
Artigo em Inglês | MEDLINE | ID: mdl-33823910


The integration of a viral genome into the host genome has a major impact on the trajectory of the infected cell. Integration location and variation within the associated viral genome can influence both clonal expansion and persistence of infected cells. Methods based on short-read sequencing can identify viral insertion sites, but the sequence of the viral genomes within remains unobserved. We develop PCIP-seq, a method that leverages long reads to identify insertion sites and sequence their associated viral genome. We apply the technique to exogenous retroviruses HTLV-1, BLV, and HIV-1, endogenous retroviruses, and human papillomavirus.

Viruses ; 12(2)2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-32012811


While current antiretroviral therapies are able to halt HIV-1 progression, they are not curative, as an interruption of treatment usually leads to viral rebound. The persistence of this stable HIV-1 latent reservoir forms the major barrier in HIV-1 cure research. The need for a better understanding of the mechanisms behind reservoir persistence resulted in the development of several novel assays allowing to perform an extensive in-depth characterization. The objective of this review is to present an overview of the current state-of-the-art PCR-based technologies to study the replication-competent HIV-1 reservoir. Here, we outline the advantages, limitations, and clinical relevance of different approaches. Future HIV-1 eradication studies would benefit from information-rich, high-throughput assays as they provide a more efficient and standardized way of characterizing the persisting HIV-1 reservoir.

Infecções por HIV/virologia , HIV-1/genética , Reação em Cadeia da Polimerase/métodos , Latência Viral , Animais , Genoma Viral , Soropositividade para HIV , Humanos , Vírus da Imunodeficiência Símia/genética , Carga Viral/métodos , Replicação Viral