CIITA enhances HIV-1 attachment to CD4+ T cells leading to enhanced infection and cell depletion.
Activated CD4(+) T cells are more susceptible to HIV infection than resting T cells; the reason for this remains unresolved. Induction of CIITA and subsequent expression of the MHC class II isotype HLA-DR are hallmarks of CD4(+) T cell activation; therefore, we investigated the role of CIITA expression in T cells during HIV infection. CIITA-expressing SupT1 cells display enhanced virion attachment in a gp160/CD4-dependent manner, which results in increased HIV infection, virus release, and T cell depletion. Although increased attachment and infection of T cells correlated with HLA-DR surface expression, Ab blocking, transient expression of HLA-DR without CIITA, and short hairpin RNA knockdown demonstrate that HLA-DR does not directly enhance susceptibility of CIITA-expressing cells to HIV infection. Further analysis of the remaining MHC class II isotypes, HLA-DP and HLA-DQ, MHC class I isotypes, HLA-A, HLA-B, and HLA-C, and the class II Ag presentation genes, invariant chain and HLA-DM, demonstrate that these proteins likely do not contribute to CIITA enhancement of HIV infection. Finally, we demonstrate that in activated primary CD4(+) T cells as HLA-DR/CIITA expression increases there is a corresponding increase in virion attachment. Overall, this work suggests that induction of CIITA expression upon CD4(+) T cell activation contributes to enhanced attachment, infection, virus release, and cell death through an undefined CIITA transcription product that may serve as a new antiviral target.
Center for Immunology and Microbial Disease, Albany Medical College, Albany, NY 12208, USA.
Kristen A
KA
Porter
Lauren N
LN
Kelley
Michael D
MD
Nekorchuk
James H
JH
Jones
Amy B
AB
Hahn
Carlos M C
CM
de Noronha
Jonathan A
JA
Harton
Karen M
KM
Duus
D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D002461:Cell Line, Transformed; D002999:Clone Cells; D018390:Gene Targeting; D015658:HIV Infections / Q000276:immunology* / Q000473:pathology; D015497:HIV-1 / Q000276:immunology* / Q000378:metabolism; D006684:HLA-DR Antigens / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D008024:Ligands; D008213:Lymphocyte Activation / Q000235:genetics; D008212:Lymphocyte Depletion; D009687:Nuclear Proteins / Q000502:physiology*; D015534:Trans-Activators / Q000502:physiology*; D014158:Transcription, Genetic / Q000276:immunology; D014771:Virion / Q000276:immunology / Q000378:metabolism; D053585:Virus Attachment
D006684:HLA-DR Antigens; D008024:Ligands; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D015534:Trans-Activators