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Articles by Marcus Altfeld
Total Records ( 2 ) for Marcus Altfeld
  Zabrina L. Brumme , Chanson J. Brumme , Jonathan Carlson , Hendrik Streeck , Mina John , Quentin Eichbaum , Brian L. Block , Brett Baker , Carl Kadie , Martin Markowitz , Heiko Jessen , Anthony D. Kelleher , Eric Rosenberg , John Kaldor , Yuko Yuki , Mary Carrington , Todd M. Allen , Simon Mallal , Marcus Altfeld , David Heckerman and Bruce D. Walker
  During acute human immunodeficiency virus type 1 (HIV-1) infection, early host cellular immune responses drive viral evolution. The rates and extent of these mutations, however, remain incompletely characterized. In a cohort of 98 individuals newly infected with HIV-1 subtype B, we longitudinally characterized the rates and extent of HLA-mediated escape and reversion in Gag, Pol, and Nef using a rational definition of HLA-attributable mutation based on the analysis of a large independent subtype B data set. We demonstrate rapid and dramatic HIV evolution in response to immune pressures that in general reflect established cytotoxic T-lymphocyte (CTL) response hierarchies in early infection. On a population level, HLA-driven evolution was observed in ~80% of published CTL epitopes. Five of the 10 most rapidly evolving epitopes were restricted by protective HLA alleles (HLA-B*13/B*51/B*57/B*5801; P = 0.01), supporting the importance of a strong early CTL response in HIV control. Consistent with known fitness costs of escape, B*57-associated mutations in Gag were among the most rapidly reverting positions upon transmission to non-B*57-expressing individuals, whereas many other HLA-associated polymorphisms displayed slow or negligible reversion. Overall, an estimated minimum of 30% of observed substitutions in Gag/Pol and 60% in Nef were attributable to HLA-associated escape and reversion events. Results underscore the dominant role of immune pressures in driving early within-host HIV evolution. Dramatic differences in escape and reversion rates across codons, genes, and HLA restrictions are observed, highlighting the complexity of viral adaptation to the host immune response.
  Galit Alter , Suzannah Rihn , Hendrik Streeck , Nickolas Teigen , Alicja Piechocka-Trocha , Kristin Moss , Kristen Cohen , Angela Meier , Florencia Pereyra , Bruce Walker and Marcus Altfeld
  Virus-specific CD8+ T cells play a central role in the control< of viral infections, including human immunodeficiency virus< type 1 (HIV-1) infection. However, despite the presence of strong< and broad HIV-specific CD8+ T-cell responses in chronic HIV-1< infection, these cells progressively lose critical effector< functions and fail to clear the infection. Mounting evidence< suggests that the upregulation of several inhibitory regulatory< receptors on the surface of CD8+ T cells during HIV-1 infection< may contribute directly to the impairment of T-cell function.< Here, we investigated the role of killer immunoglobulin receptors< (KIR), which are expressed on NK cells and on CD8+ T cells,< in regulating CD8+ T-cell function in HIV-1 infection. KIR expression< was progressively upregulated on CD8+ T cells during HIV-1 infection< and correlated with the level of viral replication. Expression< of KIR was associated with a profound inhibition of cytokine< secretion, degranulation, proliferation, and activation by CD8+< T cells following stimulation with T-cell receptor (TCR)-dependent< stimuli. In contrast, KIR+ CD8+ T cells responded potently to< TCR-independent stimulation, demonstrating that these cells< are functionally competent. KIR-associated suppression of CD8+< T-cell function was independent of ligand engagement, suggesting< that these regulatory receptors may constitutively repress TCR< activation. This ligand-independent repression of TCR activation< of KIR+ CD8+ T cells may represent a significant barrier to< therapeutic interventions aimed at improving the quality of< the HIV-specific CD8+ T-cell response in infected individuals.
 
 
 
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