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

• Published in: Journal of neurovirology Vol. 17; no. 1; pp. 82 - 91
• Main Authors: Gray, Lachlan R., Gabuzda, Dana, Cowley, Daniel, Ellett, Anne, Chiavaroli, Lisa, Wesselingh, Steven L., Churchill, Melissa J., Gorry, Paul R.
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.02.2011
• Subjects: AIDS Dementia Complex - genetics; AIDS Dementia Complex - metabolism; AIDS Dementia Complex - virology; Alleles; Amino Acid Sequence; Biomedical and Life Sciences; Biomedicine; Brain - metabolism; Brain - virology; CD4 Antigens - metabolism; Cell Line; Central Nervous System - metabolism; Central Nervous System - virology; Down-Regulation; Genes, MHC Class I; Genes, nef; HIV Infections - genetics; HIV Infections - metabolism; HIV Infections - virology; HIV-1 - genetics; HIV-1 - pathogenicity; Human immunodeficiency virus 1; Humans; Immunology; Infectious Diseases; Lymphoid Tissue - metabolism; Lymphoid Tissue - virology; Male; Molecular Sequence Data; nef Gene Products, Human Immunodeficiency Virus - genetics; nef Gene Products, Human Immunodeficiency Virus - metabolism; nef Gene Products, Human Immunodeficiency Virus - physiology; Neurology; Neurosciences; Phylogeny; Virology; Virus Replication; HIV-1; CD4; MHC-1; Lymphoid; CNS; Neurotropism; Nef; Dementia
• ISSN: 1355-0284; 1538-2443; 1538-2443
• DOI: 10.1007/s13365-010-0001-6

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 nef alleles 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.