TRIM5alpha and TRIM22 are differentially regulated according to HIV-1 infection phase and compartment
Program in Molecular Medicine; Department of Biochemistry and Molecular Pharmacology
Immunology of Infectious Disease | Immunopathology | Virology | Viruses
The antiviral role of TRIM E3 ligases in vivo is not fully understood. To test the hypothesis that TRIM5alpha and TRIM22 have differential transcriptional regulation and distinct anti-HIV roles according to infection phase and compartment, we measured TRIM5alpha, TRIM22, and type I interferon (IFN-I)-inducible myxovirus resistance protein A (MxA) levels in peripheral blood mononuclear cells (PBMCs) during primary and chronic HIV-1 infection, with chronic infection samples being matched PBMCs and central nervous system (CNS)-derived cells. Associations with biomarkers of disease progression were explored. The impact of IFN-I, select proinflammatory cytokines, and HIV on TRIM E3 ligase-specific expression was investigated. PBMCs from individuals with primary and chronic HIV-1 infection had significantly higher levels of MxA and TRIM22 than did PBMCs from HIV-1-negative individuals (P < 0.05 for all comparisons). PBMCs from chronic infection had lower levels of TRIM5alpha than did PBMCs from primary infection or HIV-1-uninfected PBMCs (P = 0.0001 for both). In matched CNS-derived samples and PBMCs, higher levels of MxA (P = 0.001) and TRIM5alpha (P = 0.0001) in the CNS were noted. There was a negative correlation between TRIM22 levels in PBMCs and plasma viral load (r = -0.40; P = 0.04). In vitro, IFN-I and, rarely, proinflammatory cytokines induced TRIM5alpha and TRIM22 in a cell type-dependent manner, and the knockdown of either protein in CD4(+) lymphocytes resulted in increased HIV-1 infection. These data suggest that there are infection-phase-specific and anatomically compartmentalized differences in TRIM5alpha and TRIM22 regulation involving primarily IFN-I and specific cell types and indicate subtle differences in the antiviral roles and transcriptional regulation of TRIM E3 ligases in vivo.
IMPORTANCE: Type I interferon-inducible TRIM E3 ligases are a family of intracellular proteins with potent antiviral activities mediated through diverse mechanisms. However, little is known about the contribution of these proteins to antiviral immunity in vivo and how their expression is regulated. We show here that TRIM5alpha and TRIM22, two prominent members of the family, have different expression patterns in vivo and that the expression pattern depends on HIV-1 infection status and phase. Furthermore, expression differs in peripheral blood versus central nervous system anatomical sites of infection. Only TRIM22 expression correlated negatively with HIV-1 viral load, but gene silencing of both proteins enhances HIV-1 infection of target cells. We report subtle differences in TRIM5alpha and TRIM22 gene induction by IFN-I and proinflammatory cytokines in CD4(+) lymphocytes, monocytes, and neuronal cells. This study enhances our understanding of antiviral immunity by intrinsic antiviral factors and how their expression is determined.
DOI of Published Version
J Virol. 2014 Apr;88(8):4291-303. doi: 10.1128/JVI.03603-13. Epub 2014 Jan 29. Link to article on publisher's site
Journal of virology
Singh, Ravesh; Patel, Vinod; Mureithi, Marianne W.; Naranbhai, Vivek; Ramsuran, Duran; Tulsi, Sahil; Hiramen, Keshni; Werner, Lise; Mlisana, Koleka; Altfeld, Marcus; Luban, Jeremy; Kasprowicz, Victoria; Dheda, Keertan; Abdool Karim, Salim S.; and Ndung'u, Thumbi, "TRIM5alpha and TRIM22 are differentially regulated according to HIV-1 infection phase and compartment" (2014). Program in Molecular Medicine Publications and Presentations. 70.