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 PDB Entries

Structure ID Release Date Resolution Structure Title
1MEQ 2002-08-08T00:00:00+0000 0 HIV gp120 C5
1LB0 2002-04-01T00:00:00+0000 0 NMR Structure of HIV-1 gp41 659-671 13-mer peptide
1LCX 2002-04-07T00:00:00+0000 0 NMR structure of HIV-1 gp41 659-671 13mer peptide
1ZVO 2005-06-02T00:00:00+0000 0 Semi-extended solution structure of human myeloma immunoglobulin D determined by constrained X-ray scattering
2FB4 1989-04-18T00:00:00+0000 1.9 DIR PRIMAERSTRUKTUR DES KRISTALLISIERBAREN MONOKLONALEN IMMUNOGLOBULINS IGG1 KOL. II. AMINOSAEURESEQUENZ DER L-KETTE, LAMBDA-TYP, SUBGRUPPE I (GERMAN)
2IG2 1989-04-18T00:00:00+0000 3.0 DIR PRIMAERSTRUKTUR DES KRISTALLISIERBAREN MONOKLONALEN IMMUNOGLOBULINS IGG1 KOL. II. AMINOSAEURESEQUENZ DER L-KETTE, LAMBDA-TYP, SUBGRUPPE I (GERMAN)
2M8M 2013-05-23T00:00:00+0000 0 NMR assignment and structure of a peptide derived from the membrane proximal external region of HIV-1 gp41 in the presence of hexafluoroisopropanol
2M8O 2013-05-23T00:00:00+0000 0 NMR assignment and structure of a peptide derived from the membrane proximal external region of HIV-1 gp41 in DPC
3E6F 2008-08-15T00:00:00+0000 2.41 MHC CLASS I H-2Dd Heavy chain complexed with Beta-2 Microglobulin and a variant peptide, PA9, from the Human immunodeficiency virus (BaL) envelope glycoprotein 120
4O5L 2013-12-19T00:00:00+0000 1.5 Crystal structure of broadly neutralizing antibody F045-092

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