RESUMO
HIV-1 is capable of integrating its genome into that of its host cell. We examined the influence of the activation state of CD4+ T cells, the effect of antiretroviral therapy (ART), and the clinical stage of HIV-1 infection on HIV-1 integration site features and selection. HIV-1 integration sites were sequenced from longitudinally sampled resting and activated CD4+ T cells from 12 HIV-1-infected individuals. In total, 589 unique HIV-1 integration sites were analyzed: 147, 391, and 51 during primary, chronic, and late presentation of HIV-1 infection, respectively. As early as during primary HIV-1 infection and independent of the activation state of CD4+ T cells collected on and off ART, HIV-1 integration sites were preferentially detected in recurrent integration genes, genes associated with clonal expansion of latently HIV-1-infected CD4+ T cells, cancer-related genes, and highly expressed genes. The preference for cancer-related genes was more pronounced at late stages of HIV-1 infection. Host genomic features of HIV-1 integration site selection remained stable during HIV-1 infection in both resting and activated CD4+ T cells. In summary, characteristic HIV-1 integration site features are preestablished as early as during primary HIV-1 infection and are found in both resting and activated CD4+ T cells.
Assuntos
Linfócitos T CD4-Positivos/metabolismo , Proliferação de Células/genética , Infecções por HIV/genética , HIV-1/genética , Interações entre Hospedeiro e Microrganismos/genética , Neoplasias/genética , Integração Viral/genética , Latência Viral/genética , Terapia Antirretroviral de Alta Atividade , Progressão da Doença , Infecções por HIV/tratamento farmacológico , Infecções por HIV/metabolismo , HIV-1/metabolismo , Humanos , Ativação Linfocitária , Carga ViralRESUMO
To systematically test whether coinfections spread along the HIV-1 transmission network and whether similarities in HIV-1 genomes predict AIDS-defining illnesses and comorbidities, we analyzed the distribution of these variables on the HIV phylogeny of the densely sampled Swiss HIV Cohort Study. By combining different statistical methods, we could detect, quantify, and explain the clustering of diseases. Infectious conditions such as hepatitis C, but also Kaposi sarcoma, clustered significantly, suggesting transmission of these infections along the HIV-1 transmission network. The clustering of patients with neurocognitive complaints could not be completely explained by the clustering of patients with similar demographic risk factors, which suggests a potential impact of viral genetics. In summary, the consistent and robust signal for coinfections and comorbidities highlights the strong interaction of HIV-1 and other infections and shows the potential of combining phylogenetic methods to identify disease traits that are likely to be related to virus genetic factors.