1. Variation in HIV-1 Nef function within and among viral subtypes reveals genetically separable antagonism of SERINC3 and SERINC5
- Author
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Jeffrey N. Martin, Peter W. Hunt, Francis M Mwimanzi, Chanson J. Brumme, Thumbi Ndung'u, Mwebesa Bwana, Steven W. Jin, Mark A. Brockman, Guinevere Q. Lee, Jaclyn K. Mann, Zabrina L. Brumme, David R. Bangsberg, and Desrosiers, Ronald C
- Subjects
RNA viruses ,Viral Diseases ,Viral pathogenesis ,viruses ,HIV Infections ,Pathogenesis ,nef Gene Products ,Pathology and Laboratory Medicine ,Virus Replication ,Virions ,Medical Conditions ,Spectrum Analysis Techniques ,Immunodeficiency Viruses ,HIV Seropositivity ,Medicine and Health Sciences ,Tumor Cells, Cultured ,2.2 Factors relating to the physical environment ,2.1 Biological and endogenous factors ,Aetiology ,Biology (General) ,Internalization ,media_common ,Genetics ,0303 health sciences ,Cultured ,Membrane Glycoproteins ,medicine.diagnostic_test ,030302 biochemistry & molecular biology ,virus diseases ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Flow Cytometry ,3. Good health ,Tumor Cells ,Infectious Diseases ,Spectrophotometry ,Medical Microbiology ,Viral Pathogens ,Viruses ,Host-Pathogen Interactions ,293T cells ,HIV/AIDS ,Cell lines ,Cytophotometry ,Pathogens ,Infection ,Biological cultures ,Human Immunodeficiency Virus ,Research Article ,QH301-705.5 ,media_common.quotation_subject ,Immunology ,Biology ,Viral Structure ,Research and Analysis Methods ,Microbiology ,Flow cytometry ,03 medical and health sciences ,Genetic ,Virology ,Retroviruses ,medicine ,Humans ,nef Gene Products, Human Immunodeficiency Virus ,Polymorphism ,Molecular Biology Techniques ,Molecular Biology ,Microbial Pathogens ,030304 developmental biology ,Cloning ,Polymorphism, Genetic ,HEK 293 cells ,Lentivirus ,Organisms ,Biology and Life Sciences ,HIV ,Membrane Proteins ,RC581-607 ,HIV-1 ,Parasitology ,Immunologic diseases. Allergy ,Antagonism ,Function (biology) - Abstract
HIV Nef counteracts cellular host restriction factors SERINC3 and SERINC5, but our understanding of how naturally occurring global Nef sequence diversity impacts these activities is limited. Here, we quantify SERINC3 and SERINC5 internalization function for 339 Nef clones, representing the major pandemic HIV-1 group M subtypes A, B, C and D. We describe distinct subtype-associated hierarchies for Nef-mediated internalization of SERINC5, for which subtype B clones display the highest activities on average, and of SERINC3, for which subtype B clones display the lowest activities on average. We further identify Nef polymorphisms that modulate its ability to counteract SERINC proteins, including substitutions in the N-terminal domain that selectively impair SERINC3 internalization. Our findings demonstrate that the SERINC antagonism activities of HIV Nef differ markedly among major viral subtypes and between individual isolates within a subtype, suggesting that variation in these functions may contribute to global differences in viral pathogenesis., Author summary Cellular restriction factors dampen viral replication and reduce pathogenesis. In response, HIV has evolved a variety of mechanisms to counteract restriction factors, including the ability of its Nef protein to internalize Serine incorporator (SERINC) proteins 3 and 5 from the infected cell surface, thereby enhancing infectivity of viral particles. Nef displays substantial sequence diversity, but how this impacts SERINC antagonism remains unclear. To examine this, we used cell culture models to measure SERINC internalization function for 339 participant-derived Nef clones, representing four globally relevant HIV-1 group M subtypes. We observed significant variability in Nef function among circulating viral strains and subtypes. We also identified naturally occurring Nef mutations that modulate its ability to counteract SERINC proteins, including some that selectively impair SERINC3 internalization. These findings uncover viral features that may contribute to global differences in HIV pathogenesis and provide new insight into the interactions between Nef and SERINC restriction factors that can inform future mechanistic studies.
- Published
- 2020