HIV-1 clade B Tat, but not clade C Tat, increases X4 HIV-1 entry into resting but not activated CD4+ T cells.
CXCR4-using human immunodeficiency virus, type 1 (HIV-1) variants emerge late in the course of infection in >40% of individuals infected with clade B HIV-1 but are described less commonly with clade C isolates. Tat is secreted by HIV-1-infected cells where it acts on both uninfected bystander cells and infected cells. In this study, we show that clade B Tat, but not clade C Tat, increases CXCR4 surface expression on resting CD4+ T cells through a CCR2b-dependent mechanism that does not involve de novo protein synthesis. The expression of plectin, a cytolinker protein that plays an important role as a scaffolding platform for proteins involved in cellular signaling including CXCR4 signaling and trafficking, was found to be significantly increased following B Tat but not C Tat treatment. Knockdown of plectin using RNA interference showed that plectin is essential for the B Tat-induced translocation of CXCR4 to the surface of resting CD4+ T cells. The increased surface CXCR4 expression following B Tat treatment led to increased function of CXCR4 including increased chemoattraction toward CXCR4-using-gp120. Moreover, increased CXCR4 surface expression rendered resting CD4+ T cells more permissive to X4 but not R5 HIV-1 infection. However, neither B Tat nor C Tat was able to up-regulate surface expression of CXCR4 on activated CD4+ T cells, and both proteins inhibited the infection of activated CD4+ T cells with X4 but not R5 HIV-1. Thus, B Tat, but not C Tat, has the capacity to render resting, but not activated, CD4+ T cells more susceptible to X4 HIV-1 infection.
Campbell
Grant R
GR
Department of Pediatrics, Division of Infectious Diseases, University of California San Diego, La Jolla, California 92093-0672, USA.
Loret
Erwann P
EP
Spector
Stephen A
SA
D000199:Actins / Q000737:chemistry / Q000378:metabolism; D000906:Antibodies / Q000737:chemistry / Q000276:immunology; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism / Q000821:virology*; D002633:Chemotaxis; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015658:HIV Infections / Q000276:immunology / Q000378:metabolism; D015497:HIV-1 / Q000145:classification / Q000502:physiology*; D006801:Humans; D008213:Lymphocyte Activation; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation; D010835:Phytohemagglutinins / Q000276:immunology; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary; D019718:Receptors, CXCR4 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D054380:Receptors, CXCR5 / Q000378:metabolism; D015398:Signal Transduction; D013045:Species Specificity; D015854:Up-Regulation; D053586:Virus Internalization; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
D000199:Actins; D000906:Antibodies; C527276:CXCR4 protein, human; C095085:CXCR5 protein, human; D015699:HIV Envelope Protein gp120; D010835:Phytohemagglutinins; D019718:Receptors, CXCR4; D054380:Receptors, CXCR5; C514793:gp120 protein, Human immunodeficiency virus 1; D054322:tat Gene Products, Human Immunodeficiency Virus; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3