CD4 and MHC class 1 down-modulation activities of nef alleles from brain- and lymphoid tissue-derived primary HIV-1 isolates

Lachlan Gray, Dana Gabuzda, Daniel Cowley, Anne Ellett, Lisa Chiavaroli, Steven Wesselingh, Melissa Churchill, Paul Gorry

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    26 Citations (Scopus)

    Abstract

    Human immunodeficiency virus type 1 (HIV-1) nef undergoes adaptive evolution in the central nervous system (CNS), reflecting altered requirements for HIV-1 replication in macrophages/microglia and brain-specific immune selection pressures. The role of Nef in HIV-1 neurotropism and pathogenesis of HIV-associated dementia (HAD) is unclear. In this study, we characterized 82 nef alleles cloned from brain, cerebral spinal fluid, spinal cord, and blood/lymphoid tissue-derived HIV-1 isolates from seven subjects with HAD. CNS isolate-derived nef alleles were genetically compartmentalized and had reduced sequence diversity compared to those from lymphoid tissue isolates. Defective nef alleles predominated in a brain-derived isolate from one of the seven subjects (MACS2-br). The ability of Nef to down-modulate CD4 and MHC class 1 (MHC-1) was generally conserved among nefalleles from both CNS and lymphoid tissues. However, the potency of CD4 and MHC-1 down-modulation was variable, which was associated with sequence alterations known to influence these Nef functions. These results suggest that CD4 and MHC-1 down-modulations are highly conserved functions among nef alleles from CNS-and lymphoid tissue-derived HIV-1 isolates that may contribute to viral replication and escape from immune surveillance in the CNS.

    Original languageEnglish
    Pages (from-to)82-91
    Number of pages10
    JournalJournal of Neurovirology
    Volume17
    Issue number1
    DOIs
    Publication statusPublished - Feb 2011

    Keywords

    • CD4MHC-1
    • CNS Lymphoid
    • Dementia
    • HIV-1
    • Nef
    • Neurotropism

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