{"doi":"10.1101/2020.04.21.054007","title":"Structural Basis of CD4 Downregulation by HIV-1 Nef","abstract":"The HIV-1 protein Nef suppresses multiple immune surveillance mechanisms to promote viral pathogenesis 1 . Individuals infected with HIV-1 encoding defective nef genes do not develop AIDS for decades 2,3 . A key target of Nef is the cellular receptor CD4. Although essential for viral entry into host cells, CD4 is problematic for the virus later in its replication cycle: CD4 disrupts processing of the viral glycoprotein, Env, inhibiting infectivity 4 ; it interferes with the release of new virions 5,6 ; and it causes vulnerability to superinfection, causing premature cell death and limiting viral productivity 7 . Furthermore, binding of CD4 to Env exposes otherwise-concealed Env epitopes, rendering infected cells more susceptible to antibody-dependent cellular cytotoxicity and virus particles more susceptible to neutralizing antibodies 8-10 . HIV-1 has evolved strategies to mitigate these problems. Newly synthesized CD4 is targeted in the endoplasmic reticulum by the viral Vpu protein for proteasomal degradation 11 . Surface-expressed CD4, in contrast, is targeted by Nef for endocytosis and lysosomal degradation 12-15 . Nef’s effect on CD4 involves hijacking of clathrin adaptor complex 2 (AP2)-dependent endocytosis 16,17 . Although how Nef associates with a part of the tetrameric AP2 is understood 18 , a complete understanding of the interaction, especially how CD4 is sequestered by Nef into a complex with AP2, has remained elusive. Here, we present a high-resolution crystal structure that describes the underlying mechanism. An intricate combination of conformational changes occurs in both Nef and AP2 to enable CD4 binding and downregulation. Strikingly, a pocket on Nef previously identified as crucial for recruiting class I MHC is also responsible for recruiting CD4, revealing a potential approach to inhibit two of Nef’s activities and sensitize the virus to immune clearance","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2020,"id":123616,"datarank":0.20794415416798362,"base_score":1.3862943611198906,"endowment":1.3862943611198906,"self_citation_contribution":0.20794415416798362,"citation_network_contribution":0.0,"self_endowment_contribution":0.20794415416798362,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9513,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":103631,"name":"Robyn M. Kaake","orcid":"0000-0002-8341-3067","position":1,"is_corresponding":false},{"id":2404,"name":"Ignacia Echeverria","orcid":"0000-0003-4717-1467","position":2,"is_corresponding":false},{"id":315946,"name":"Marissa Suarez","orcid":null,"position":3,"is_corresponding":false},{"id":314249,"name":"Charlotte A. Stoneham","orcid":"0000-0003-3729-6936","position":4,"is_corresponding":false},{"id":314250,"name":"Peter W. Ramirez","orcid":"0000-0003-2388-9140","position":5,"is_corresponding":false},{"id":315947,"name":"Jacob Kress","orcid":null,"position":6,"is_corresponding":false},{"id":245488,"name":"Rajendra Singh","orcid":"0000-0002-8586-3221","position":7,"is_corresponding":false},{"id":91660,"name":"Andrej Săli","orcid":"0000-0003-0435-6197","position":8,"is_corresponding":false},{"id":1363,"name":"Nevan J. Krogan","orcid":"0000-0003-4902-337X","position":9,"is_corresponding":false},{"id":315948,"name":"John Guatelli","orcid":null,"position":10,"is_corresponding":false},{"id":314251,"name":"Xiaofei Jia","orcid":"0000-0002-0972-3884","position":11,"is_corresponding":false},{"id":315945,"name":"Yonghwa Kwon","orcid":null,"position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:15:03.403566Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}