Severity: Warning
Message: file_get_contents(https://...@gmail.com&api_key=61f08fa0b96a73de8c900d749fcb997acc09): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
Filename: helpers/my_audit_helper.php
Line Number: 143
Backtrace:
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 143
Function: file_get_contents
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 209
Function: simplexml_load_file_from_url
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 3098
Function: getPubMedXML
File: /var/www/html/application/controllers/Detail.php
Line: 574
Function: pubMedSearch_Global
File: /var/www/html/application/controllers/Detail.php
Line: 488
Function: pubMedGetRelatedKeyword
File: /var/www/html/index.php
Line: 316
Function: require_once
Severity: Warning
Message: Attempt to read property "Count" on bool
Filename: helpers/my_audit_helper.php
Line Number: 3100
Backtrace:
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 3100
Function: _error_handler
File: /var/www/html/application/controllers/Detail.php
Line: 574
Function: pubMedSearch_Global
File: /var/www/html/application/controllers/Detail.php
Line: 488
Function: pubMedGetRelatedKeyword
File: /var/www/html/index.php
Line: 316
Function: require_once
Objective: The ability of HIV-1 Nef to counteract the host restriction factor SERINC5 and enhance virion infectivity has been well-established. However, the impact of long term within-host Nef evolution on this antagonistic capability remains unclear.
Design: Analysis of longitudinal activity of Nef in antagonizing SERINC5.
Methods: We investigated the downregulation activity of Nef against SERINC5 at different stages of infection by analyzing the cognate transmitted/founder, set point, and/or chronic Nef isolates from a cohort of 19 subjects living with either subtype B or C HIV-1.
Results: The Nef isolates from different stages exhibited varying abilities to antagonize SERINC5. Long-term evolution resulted in mutations accumulated in Nef and a decline of Nef-mediated SERINC5 downregulation function in subtype B, but not in subtype C viruses, leading to a rapid reduction in viral load from peak viremia. Furthermore, we identified four polymorphisms of both subtype B and C Nef that are associated with variations in the SERINC5 antagonistic function and viral infectivity. HIV-1 NL4-3 variants encoding Nef E63G, A83G, R105K, or D108E mutants exhibited reduced replication capacity through a SERINC5-dependent mechanism. However, among different subjects, only a small part of naturally occurring mutations at these sites were selected by host T cell responses, suggesting a limited impact of host T cell responses on influencing Nef's ability to antagonize SERINC5.
Conclusion: These results highlight the potential contribution of functional variation in Nef to differences in HIV-1 pathogenesis and provide significant implications for understanding the evolutionary interaction between Nef and SERINC5 in vivo .
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Source |
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http://dx.doi.org/10.1097/QAD.0000000000004079 | DOI Listing |
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