Abstract
BackgroundImpaired HIV-1 Gag, Pol, and Env function has been described in elite controllers (EC) who spontaneously suppress plasma viremia to < 50 RNA copies/mL; however, activity of the accessory protein Nef remains incompletely characterized. We examined the ability of 91 Nef clones, isolated from plasma of 45 EC and 46 chronic progressors (CP), to down-regulate HLA class I and CD4, up-regulate HLA class II invariant chain (CD74), enhance viral infectivity, and stimulate viral replication in PBMC.ResultsIn general, EC Nef clones were functional; however, all five activities were significantly lower in EC compared to CP. Nef clones from HLA-B*57-expressing EC exhibited poorer CD4 down-regulation function compared to those from non-B*57 EC, and the number of EC-specific B*57-associated Nef polymorphisms correlated inversely with 4 of 5 Nef functions in these individuals.ConclusionResults indicate that decreased HIV-1 Nef function, due in part to host immune selection pressures, may be a hallmark of the EC phenotype.
Highlights
Impaired HIV-1 Gag, Pol, and Env function has been described in elite controllers (EC) who spontaneously suppress plasma viremia to < 50 RNA copies/mL; activity of the accessory protein Nef remains incompletely characterized
Recombinant viruses expressing gag and pol sequences from EC exhibit reduced in vitro replication capacity, due in part to cytotoxic T lymphocyte (CTL) escape mutations selected by certain Human Leukocyte Antigen (HLA) class I (HLA-I) alleles [3,4], while EC-derived viral envelopes exhibit impaired entry [7]
Consistent with previous analyses of bulk plasma HIV RNA sequences from our EC cohort [21], clonal Nef sequences from EC showed no evidence of gross defects or recent shared ancestry (Figure 1, Additional file 1: Table S1)
Summary
Impaired HIV-1 Gag, Pol, and Env function has been described in elite controllers (EC) who spontaneously suppress plasma viremia to < 50 RNA copies/mL; activity of the accessory protein Nef remains incompletely characterized. Nef exhibits a variety of in vitro functions that may modulate pathogenesis, including CD4 down-regulation [11], HLA-I down-regulation [12], HLA class II invariant chain (CD74) up-regulation [13], enhancement of virion infectivity [14], and stimulation of viral replication in PBMC [15] (for reviews see [16,17,18]). Multiple Nef activities may act together to facilitate immune evasion and enhancement of viral spread in vivo [19]; multi-functional assessments of patient-derived Nef clones from HIV elite controllers are lacking. Assessing multiple in vitro Nef functions in EC, a population that is highly enriched for protective HLA-I alleles such as B*57 [1], provides an opportunity to investigate these questions
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