title: Intersubtype differences in the effect of a rare p24 gag mutation on HIV-1 replicative fitness.
abstract: Certain immune-driven mutations in HIV-1, such as those arising in p24(Gag), decrease viral replicative capacity. However, the intersubtype differences in the replicative consequences of such mutations have not been explored. In HIV-1 subtype B, the p24(Gag) M250I mutation is a rare variant (0.6%) that is enriched among elite controllers (7.2%) (P = 0.0005) and appears to be a rare escape variant selected by HLA-B58 supertype alleles (P < 0.01). In contrast, in subtype C, it is a relatively common minor polymorphic variant (10 to 15%) whose appearance is not associated with a particular HLA allele. Using site-directed mutant viruses, we demonstrate that M250I reduces in vitro viral replicative capacity in both subtype B and subtype C sequences. However, whereas in subtype C downstream compensatory mutations at p24(Gag) codons 252 and 260 reduce the adverse effects of M250I, fitness costs in subtype B appear difficult to restore. Indeed, patient-derived subtype B sequences harboring M250I exhibited in vitro replicative defects, while those from subtype C did not. The structural implications of M250I were predicted by protein modeling to be greater in subtype B versus C, providing a potential explanation for its lower frequency and enhanced replicative defects in subtype B. In addition to accounting for genetic differences between HIV-1 subtypes, the design of cytotoxic-T-lymphocyte-based vaccines may need to account for differential effects of host-driven viral evolution on viral fitness.
authors.affiliation: Institute of Infectious Disease and Molecular Medicine, and the Division of Medical Virology, University of Cape Town and National Health Laboratory Services, Cape Town, South Africa.
authors.forename: Denis R
authors.initials: DR
authors.lastname: Chopera
authors.forename: Laura A
authors.initials: LA
authors.lastname: Cotton
authors.forename: Alexander
authors.initials: A
authors.lastname: Zawaira
authors.forename: Jaclyn K
authors.initials: JK
authors.lastname: Mann
authors.forename: Nobubelo K
authors.initials: NK
authors.lastname: Ngandu
authors.forename: Roman
authors.initials: R
authors.lastname: Ntale
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Carlson
authors.forename: Koleka
authors.initials: K
authors.lastname: Mlisana
authors.forename: Zenda
authors.initials: Z
authors.lastname: Woodman
authors.forename: Debra
authors.initials: D
authors.lastname: de Assis Rosa
authors.forename: Eric
authors.initials: E
authors.lastname: Martin
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Miura
authors.forename: Florencia
authors.initials: F
authors.lastname: Pereyra
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.forename: Clive M
authors.initials: CM
authors.lastname: Gray
authors.forename: Darren P
authors.initials: DP
authors.lastname: Martin
authors.forename: Thumbi
authors.initials: T
authors.lastname: Ndung'u
authors.forename: Mark A
authors.initials: MA
authors.lastname: Brockman
authors.forename: Salim Abdool
authors.initials: SA
authors.lastname: Karim
authors.forename: Zabrina L
authors.initials: ZL
authors.lastname: Brumme
authors.forename: Carolyn
authors.initials: C
authors.lastname: Williamson
mesh_terms: D000595:Amino Acid Sequence; D015331:Cohort Studies; D015750:Genes, gag; D016655:HIV Core Protein p24 / Q000737:chemistry / Q000235:genetics*; D015658:HIV Infections / Q000821:virology; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D014779:Virus Replication / Q000235:genetics*
chemical_list: D016655:HIV Core Protein p24