HLA-Associated viral mutations are common in human immunodeficiency virus type 1 elite controllers

Elite controllers (EC) of human immunodeficiency virus type 1 (HTV-1) maintain viremia below the limit of detection without antiretroviral treatment. Virus-specific cytotoxic CD8+ T lymphocytes are believed to play a crucial role in viral containment, but the degree of immune imprinting and compensatory mutations in EC is unclear. We obtained plasma gag, pol, and nef sequences from HLA-diverse subjects and found that 30 to 40% of the predefined HLA-associated polymorphic sites show evidence of immune selection pressure in EC., compared to approximately 50% of the sites in chronic progressors. These data indicate ongoing viral replication and escape from cytotoxic T lymphocytes are present even in strictly controlled HTV-1 infection

P09-11. Reduced replication capacity of NL4-3 chimeric viruses encoding RT-Integrase sequences from HIV-1 elite controllers

Background: Spontaneous control of HIV to 0.05). Viruses derived from HLA-B57+ EC (N = 20) appeared to replicate slower than those from B57+ progressors (N = 8) (p = 0.004). Similar results were observed between B51+ EC (N = 4) and B51+ progressors (N = 10) (p = 0.024), but not between B27+ EC (N = 9) and B27+ progressors (N = 5) (p = 0.437). Conclusion: This study extends previous observations for Gag and demonstrates that Pol variants from EC also display reduced function. The association between fitness and expression of certain HLA that present Pol epitopes suggests that immune-mediated mutations impairing viral fitness may play a key role in spontaneous control of HIV. Results indicate that HLA alleles responsible for such defects in protein function may differ among viral genes. Further identification of HLA-associated changes in HIV may allow design of vaccines targeting the most vulnerable regions of the virus

Visualizing the spin of individual molecules

Low-temperature spin-polarized scanning tunneling microscopy is employed to study spin transport across single Cobalt-Phathalocyanine molecules adsorbed on well characterized magnetic nanoleads. A spin-polarized electronic resonance is identified over the center of the molecule and exploited to spatially resolve stationary spin states. These states reflect two molecular spin orientations and, as established by density functional calculations, originate from a ferromagnetic molecule-lead superexchange interaction mediated by the organic ligands

Viral adaptation to immune selection pressure by HLA class I–restricted CTL responses targeting epitopes in HIV frameshift sequences

CD8+ cytotoxic T lymphocyte (CTL)–mediated immune responses to HIV contribute to viral control in vivo. Epitopes encoded by alternative reading frame (ARF) peptides may be targeted by CTLs as well, but their frequency and in vivo relevance are unknown. Using host genetic (human leukocyte antigen [HLA]) and plasma viral sequence information from 765 HIV-infected subjects, we identified 64 statistically significant (q < 0.2) associations between specific HLA alleles and sequence polymorphisms in alternate reading frames of gag, pol, and nef that did not affect the regular frame protein sequence. Peptides spanning the top 20 HLA-associated imprints were used to test for ex vivo immune responses in 85 HIV-infected subjects and showed responses to 10 of these ARF peptides. The most frequent response recognized an HLA-A*03–restricted +2 frame–encoded epitope containing a unique A*03-associated polymorphism at position 6. Epitope-specific CTLs efficiently inhibited viral replication in vitro when viruses containing the wild-type sequence but not the observed polymorphism were tested. Mutating alternative internal start codons abrogated the CTL-mediated inhibition of viral replication. These data indicate that responses to ARF-encoded HIV epitopes are induced during natural infection, can contribute to viral control in vivo, and drive viral evolution on a population level