Experimental Estimation of the Effects of All Amino-Acid Mutations to HIV's Envelope Protein on Viral Replication in Cell Culture.


Abstract

HIV is notorious for its capacity to evade immunity and anti-viral drugs through rapid sequence evolution. Knowledge of the functional effects of mutations to HIV is critical for understanding this evolution. HIV's most rapidly evolving protein is its envelope (Env). Here we use deep mutational scanning to experimentally estimate the effects of all amino-acid mutations to Env on viral replication in cell culture. Most mutations are under purifying selection in our experiments, although a few sites experience strong selection for mutations that enhance HIV's replication in cell culture. We compare our experimental measurements of each site's preference for each amino acid to the actual frequencies of these amino acids in naturally occurring HIV sequences. Our measured amino-acid preferences correlate with amino-acid frequencies in natural sequences for most sites. However, our measured preferences are less concordant with natural amino-acid frequencies at surface-exposed sites that are subject to pressures absent from our experiments such as antibody selection. Our data enable us to quantify the inherent mutational tolerance of each site in Env. We show that the epitopes of broadly neutralizing antibodies have a significantly reduced inherent capacity to tolerate mutations, rigorously validating a pervasive idea in the field. Overall, our results help disentangle the role of inherent functional constraints and external selection pressures in shaping Env's evolution.

Submission Details

ID: pBpo2uaw

Submitter: Connie Wang

Submission Date: June 25, 2018, 5:06 p.m.

Version: 1

Publication Details
Haddox HK;Dingens AS;Bloom JD,PLoS Pathog (2016) Experimental Estimation of the Effects of All Amino-Acid Mutations to HIV's Envelope Protein on Viral Replication in Cell Culture. PMID:27959955
Additional Information

Structure view and single mutant data analysis

Study data

No weblogo for data of varying length.
Colors: D E R H K S T N Q A V I L M F Y W C G P
 

Data Distribution

Studies with similar sequences (approximate matches)

Correlation with other assays (exact sequence matches)


Relevant UniProtKB Entries

Percent Identity Matching Chains Protein Accession Entry Name
90.2 B Envelope glycoprotein gp160 P19550 ENV_HV1S1
90.9 B Envelope glycoprotein gp160 P05878 ENV_HV1SC
90.3 B Envelope glycoprotein gp160 P19549 ENV_HV1S3
90.8 B Envelope glycoprotein gp160 P12489 ENV_HV1J3
90.5 B Envelope glycoprotein gp160 P31872 ENV_HV1W1
95.7 E Envelope glycoprotein gp160 B9A064 IGLL5_HUMAN
197.1 E,L Envelope glycoprotein gp160 P0DOY2 IGLC2_HUMAN
197.2 E,L Envelope glycoprotein gp160 P0DOY3 IGLC3_HUMAN
191.4 E,L Envelope glycoprotein gp160 P0CG04 IGLC1_HUMAN
187.7 E,L Envelope glycoprotein gp160 P0CF74 IGLC6_HUMAN
183.9 E,L Envelope glycoprotein gp160 A0M8Q6 IGLC7_HUMAN
198.0 D,H Envelope glycoprotein gp160 P01857 IGHG1_HUMAN
190.2 D,H Envelope glycoprotein gp160 P01860 IGHG3_HUMAN
184.2 D,H Envelope glycoprotein gp160 P01861 IGHG4_HUMAN