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and 2Section of Integrative Biology, Center for Computational Biology and Bioinformatics, and Institute for Cell and Molecular Biology, University of Texas at Austin, Austin, Texas.
Clinical Infectious Diseases (Impact Factor: 8.89). 05/2010; 50(10):1425-6. DOI: 10.1086/652285
Source: PubMed
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    ABSTRACT: Rare human immunodeficiency virus 1-infected individuals, termed elite suppressors (ES), maintain plasma virus levels of <50 copies/ml and normal CD4 counts without therapy. The major histocompatibility complex class I allele group human histocompatibility leukocyte antigen (HLA)-B*57 is overrepresented in this population. Mutations in HLA-B*57-restricted epitopes have been observed in ES, but their significance has remained unclear. Here we investigate the extent and impact of cytotoxic T lymphocyte (CTL) escape mutations in HLA-B*57+ ES. We provide the first direct evidence that most ES experience chronic low level viremia. Sequencing revealed a striking discordance between the genotypes of plasma virus and archived provirus in resting CD4+ T cells. Mutations in HLA-B*57-restricted Gag epitopes were present in all viruses from plasma but were rare in proviruses, suggesting powerful selective pressure acting at these epitopes. Surprisingly, strong CD8+ T cell interferon-gamma responses were detected against some mutant epitopes found in plasma virus, suggesting the development of de novo responses to viral variants. In some individuals, relative CD8+ T cell interleukin-2 responses showed better correlation with the selection observed in vivo. Thus, analysis of low level viremia reveals an unexpectedly high level of CTL escape mutations reflecting selective pressure acting at HLA-B*57-restricted epitopes in ES. Continued viral suppression probably reflects CTL responses against unmutated epitopes and residual or de novo responses against epitopes with escape mutations.
    Journal of Experimental Medicine 06/2006; 203(5):1357-69. DOI:10.1084/jem.20052319 · 12.52 Impact Factor
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    ABSTRACT: Elite controllers or suppressors are untreated human immunodeficiency virus type 1 (HIV-1)-infected patients who maintain undetectable viral loads. In this study, we show that most elite suppressors do not experience significant changes in T cell counts over a 10-year period. Interestingly, treatment of an elite suppressor with highly active antiretroviral therapy (HAART) led to a marked decrease in immune activation.
    Clinical Infectious Diseases 12/2009; 49(11):1763-6. DOI:10.1086/648081 · 8.89 Impact Factor
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    ABSTRACT: To define predictors of survival time in late human immunodeficiency virus type 1 (HIV-1) disease, long- and short-duration survivors were studied after their CD4+ T cells fell to </=50/mm3. Immune activation of CD4+ and CD8+ T cells, as measured by elevated cell surface expression of CD38 antigen, was strongly associated with shorter subsequent survival (P</=.002). The naive CD45RA+CD62L+ T cell reserve was low in all subjects and did not predict survival (P=.34 for CD4+ and.08 for CD8+ cells). Higher virus burden correlated with CD8+ but not CD4+ cell activation and, after correcting for multiple comparisons, was not associated with shorter survival (P=.02). All of the patients' viruses used CCR5, CXCR4, or both, and coreceptor usage did not predict survival (P=. 27). Through mechanisms apparently unrelated to higher virus burden, immune activation is a major determinant of survival in advanced HIV-1 disease.
    The Journal of Infectious Diseases 04/1999; 179(4):859-70. DOI:10.1086/314660 · 6.00 Impact Factor
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