Abstract
BackgroundThe Sydney blood bank cohort (SBBC) of long-term survivors consists of multiple individuals infected with nef-deleted, attenuated strains of human immunodeficiency virus type 1 (HIV-1). Although the cohort members have experienced differing clinical courses and now comprise slow progressors (SP) as well as long-term nonprogressors (LTNP), longitudinal analysis of nef/long-terminal repeat (LTR) sequences demonstrated convergent nef/LTR sequence evolution in SBBC SP and LTNP. Thus, the in vivo pathogenicity of attenuated HIV-1 strains harboured by SBBC members is dictated by factors other than nef/LTR. Therefore, to determine whether defects in other viral genes contribute to attenuation of these HIV-1 strains, we characterized dominant HIV-1 rev alleles that persisted in 4 SBBC subjects; C18, C64, C98 and D36.ResultsThe ability of Rev derived from D36 and C64 to bind the Rev responsive element (RRE) in RNA binding assays was reduced by approximately 90% compared to Rev derived from HIV-1NL4-3, C18 or C98. D36 Rev also had a 50–60% reduction in ability to express Rev-dependent reporter constructs in mammalian cells. In contrast, C64 Rev had only marginally decreased Rev function despite attenuated RRE binding. In D36 and C64, attenuated RRE binding was associated with rare amino acid changes at 3 highly conserved residues; Gln to Pro at position 74 immediately N-terminal to the Rev activation domain, and Val to Leu and Ser to Pro at positions 104 and 106 at the Rev C-terminus, respectively. In D36, reduced Rev function was mapped to an unusual 13 amino acid extension at the Rev C-terminus.ConclusionThese findings provide new genetic and mechanistic insights important for Rev function, and suggest that Rev function, not Rev/RRE binding may be rate limiting for HIV-1 replication. In addition, attenuated rev alleles may contribute to viral attenuation and long-term survival of HIV-1 infection in a subset of SBBC members.
Highlights
The Sydney blood bank cohort (SBBC) of long-term survivors consists of multiple individuals infected with nef-deleted, attenuated strains of human immunodeficiency virus type 1 (HIV-1)
Our data suggest that Rev function, not Rev/Rev responsive element (RRE) binding may be rate limiting for HIV-1 replication
We demonstrate reduced capacity of persistent and dominant Rev variants isolated from a subset of SBBC members to bind the RRE, which was associated with unique rev alleles carrying rare amino acid substitutions at 3 highly conserved positions outside the RNA-binding domain (RBD); Gln to Pro at position 74 immediately N-terminal to the Rev activation domain, and Val to Leu and Ser to Pro at positions 104 and 106 at the Rev C-terminus, respectively
Summary
The Sydney blood bank cohort (SBBC) of long-term survivors consists of multiple individuals infected with nef-deleted, attenuated strains of human immunodeficiency virus type 1 (HIV-1). The Sydney blood bank cohort (SBBC) of long-term survivors (LTS) consists of multiple individuals who became infected with attenuated strains of human immunodeficiency type 1 (HIV-1) via contaminated blood products from a common blood donor between 1981 and 1984 [13]. Despite convergent nef/LTR sequence evolution, after 22 to 26 years of infection SBBC members comprise antiretroviral therapy (ART)-naïve long-term nonprogressors (LTNP) as well as slow progressors (SP) who eventually commenced ART, suggesting that other viral and/or host factors may contribute to the in vivo pathogenicity (or lack thereof) of SBBC HIV-1 strains [3,4]. Host genetic factors linked to a delay in the onset of AIDS and prolonged survival include the CCR5 Δ32 mutation, CCR2-V64I polymorphism, and certain HLA haplotypes [14,15,16,17]
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