Abstract
BackgroundBinding of the viral envelope protein (Env), and particularly of its gp120 subunit, to the cellular CD4 receptor is the first essential step of the HIV-1 entry process. The CD4 binding site (CD4bs) of gp120, and especially a recessed cavity occupied by the CD4 Phe43 residue, are known to be highly conserved among the different circulating subtypes and therefore constitute particularly interesting targets for vaccine and drug design. The miniCD4 proteins are a promising class of CD4bs inhibitors. Studying virus evolution under pressure of CD4bs inhibitors could provide insight on the gp120-CD4 interaction and viral entry.ResultsThe present study reports on the resistance induction of two subtype B HIV-1 against the most active miniCD4, M48U1, and its ancestor, M48, and how these mutated positions affect CD4bs recognition, entry efficiency, and sensitivity to other CD4bs inhibitors. Resistance against M48U1 was always associated with S375R/N substitution in both BaL and SF162; M48 resistance was associated with D474N substitution in SF162 and with H105Y substitution in BaL. In addition, some other mutations at position V255 and G471 were of importance for SF162 resistant viruses. Except for 474, all of these mutated positions are conserved, and introducing them into an SF162 Env expressing infectious molecular clone (pBRNL4.3 SF162) resulted in decreased entry efficiency. Furthermore, resistant mutants showed at least some cross-resistance towards other CD4bs inhibitors, the V3 monoclonal antibody 447-52D and some even against the monoclonal antibody 17b, of which the epitope overlaps the co-receptor binding site.ConclusionsThe mutations H105Y, V255M, S375R/N, G471R/E, and D474N are found to be involved in resistance towards M48 and M48U1. All mutated positions are part of, or in close proximity to, the CD4bs; most are highly conserved, and all have an impact on the entry efficiency, suggesting their importance for optimal virus infectivity.
Highlights
Binding of the viral envelope protein (Env), and of its gp120 subunit, to the cellular CD4 receptor is the first essential step of the Human Immunodeficiency Virus type 1 (HIV-1) entry process
Resistance was rapidly acquired, which reflects the flexible nature of the envelope glycoprotein and confirms the low genetic barrier for development of resistance towards most entry inhibitors
An arginine was found in both M48U1 resistant BaL viruses and in one of the M48U1 resistant SF162 viruses, whereas an asparagine was observed in the second M48U1SF162 resistant virus (Table 1)
Summary
Binding of the viral envelope protein (Env), and of its gp120 subunit, to the cellular CD4 receptor is the first essential step of the HIV-1 entry process. HIV-1 entry is a multi-step process that is mediated by the envelope surface glycoprotein gp120 and the transmembrane glycoprotein gp41 [1,2] These two subunits constitute a functional heterotrimeric. The area of actual contact between gp120 and CD4 is much smaller because of cavities formed at the interface One of these cavities is plugged by the aromatic ring of phenylalanine 43 of the CD4 receptor and, as a consequence, named the Phe43-cavity [11]. This important region, at the interface of the outer and inner domains and the bridging sheet, is well-conserved among the different HIV-1 subtypes and is crucial in the lifecycle of the virus [13]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
