Human cytomegalovirus (HCMV) can cause significant end-organ diseases such as pneumonia in HIV-exposed infants. Complex viral factors may influence pathogenesis including: a large genome with a sizeable coding capacity, numerous gene regions of hypervariability, multiple-strain infections, and tissue compartmentalization of strains. We used a whole genome sequencing approach to assess the complexity of infection by comparing high-throughput sequencing data obtained from respiratory and blood specimens of HIV-exposed infants with severe HCMV pneumonia with those of lung transplant recipients and patients with hematological disorders. There were significantly more specimens from HIV-exposed infants showing multiple HCMV strain infection. Some genotypes, such as UL73 G4B and UL74 G4, were significantly more prevalent in HIV-exposed infants with severe HCMV pneumonia. Some genotypes were predominant in the respiratory specimens of several patients. However, the predominance was not statistically significant, precluding firm conclusions on anatomical compartmentalization in the lung.

• MeSH
• cytomegalovirové infekce * epidemiologie   MeSH
• Cytomegalovirus genetika   MeSH
• HIV infekce * komplikace   MeSH
• kojenec MeSH
• lidé MeSH
• pneumonie * MeSH
• Check Tag
• kojenec MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Jihoafrická republika MeSH

The genomic characteristics of human cytomegalovirus (HCMV) strains sequenced directly from clinical pathology samples were investigated, focusing on variation, multiple-strain infection, recombination, and gene loss. A total of 207 datasets generated in this and previous studies using target enrichment and high-throughput sequencing were analyzed, in the process enabling the determination of genome sequences for 91 strains. Key findings were that (i) it is important to monitor the quality of sequencing libraries in investigating variation; (ii) many recombinant strains have been transmitted during HCMV evolution, and some have apparently survived for thousands of years without further recombination; (iii) mutants with nonfunctional genes (pseudogenes) have been circulating and recombining for long periods and can cause congenital infection and resulting clinical sequelae; and (iv) intrahost variation in single-strain infections is much less than that in multiple-strain infections. Future population-based studies are likely to continue illuminating the evolution, epidemiology, and pathogenesis of HCMV.

• MeSH
• cytomegalovirové infekce virologie   MeSH
• Cytomegalovirus genetika   MeSH
• databáze nukleových kyselin MeSH
• datové soubory jako téma MeSH
• DNA virů genetika   MeSH
• genetická variace MeSH
• genom virový * genetika   MeSH
• genotyp MeSH
• lidé MeSH
• molekulární evoluce MeSH
• mutace MeSH
• rekombinace genetická * MeSH
• sekvence nukleotidů * MeSH
• sekvenční analýza DNA MeSH
• sekvenování celého genomu MeSH
• virové geny MeSH
• vysoce účinné nukleotidové sekvenování MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Human cytomegalovirus (HCMV) is an important pathogen with multiple immune evasion strategies, including virally facilitated degradation of host antiviral restriction factors. Here, we describe a multiplexed approach to discover proteins with innate immune function on the basis of active degradation by the proteasome or lysosome during early-phase HCMV infection. Using three orthogonal proteomic/transcriptomic screens to quantify protein degradation, with high confidence we identified 35 proteins enriched in antiviral restriction factors. A final screen employed a comprehensive panel of viral mutants to predict viral genes that target >250 human proteins. This approach revealed that helicase-like transcription factor (HLTF), a DNA helicase important in DNA repair, potently inhibits early viral gene expression but is rapidly degraded during infection. The functionally unknown HCMV protein UL145 facilitates HLTF degradation by recruiting the Cullin4 E3 ligase complex. Our approach and data will enable further identifications of innate pathways targeted by HCMV and other viruses.

• MeSH
• cytomegalovirové infekce genetika   imunologie   virologie   MeSH
• Cytomegalovirus genetika   imunologie   fyziologie   MeSH
• DNA vazebné proteiny chemie   genetika   imunologie   MeSH
• imunitní únik MeSH
• lidé MeSH
• proteiny chemie   genetika   imunologie   MeSH
• proteomika MeSH
• stabilita proteinů MeSH
• transkripční faktory chemie   genetika   imunologie   MeSH
• virové proteiny chemie   genetika   imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH