MHC class II heterodimers follow a similar trafficking route, appearing at both the PM and specialized multivesicular bodies (MVBs) called MHC class II containing compartments (MIICs) [22] . MHC class II is utilized by antigen presenting cells (APCs) to present exogenous processed antigen to CD4+ T cells [22, 23, 24] . MHC Class II genes, including: HLA-DR, -DP and -DQ and the accessory molecules, invariant chain (Ii) and HLA-DM, are transcriptionally activated by the class II transactivator (CIITA), the global regulator of coordinate class II MHC gene expression [25, 26] . As CIITA is induced in CD4+T cells upon activation, these cells express MHC class II [27, 28] . Upon synthesis, HLA-DR heterodimers are assembled in the ER and the immature complex (HLA-DR+ Ii) travels through the secretory pathway to MIICs, where the specialized HLA-DM chaperone loads the HLA-DR heterodimer with peptide [22, 29, 30] . Interestingly, both immature and mature forms of HLA-DR can be found at the PM and can be subsequently internalized to MIICs due to a di-leucine motif in the cytoplasmic tail of Ii (immature HLA-DR) and a dileucine motif and/or ubiquitination of conserved lysine residues within the HLA-DR b chain (mature HLA-DR), respectively [22, 29, 31, 32, 33, 34, 35, 36] . Therefore, a connection between HLA-DR and Gag trafficking would not be surprising as both have an alternative route to intracellular compartments by way of the PM. Indeed, expression of HIV-1 Nef, Vpu and Gag have been shown to alter HLA-DR trafficking [37, 38, 39, 40] . In addition, HLA-DR is preferentially acquired on the viral envelope of budding virions, which enhances virion infectivity and may play a role in bystander apoptosis of T lymphocytes [41, 42, 43] . Therefore, HLA-DR localization at virus assembly sites is not unexpected. Finzi et al. (2006) addressed the contribution of MHC class IIinduced MIIC formation to Pr55Gag trafficking by monitoring virus budding in the presence of transiently expressed HLA-DR heterodimers [8] . In HEK-293T cells expressing HLA-DR, there was a marked redistribution of Gag to intracellular compartments, and reduced virus release at the PM; mature virus budded into HLA-DR containing multivesicular bodies and was retained [8] . We hypothesized that recapitulating endogenous expression of the entire class II antigen presentation pathway in producer cells via expression of CIITA would restore infectious virus release and provide a more physiologically relevant model for HIV-1 assembly studies. As expected, stable or transient expression of CIITA did not induce intracellular retention of Gag. However, HLA-DR induced Gag retention could not be alleviated by transient co-expression with HLA-DM and/or Ii, or CIITA-mediated upregulation of the recycling endosome GTPase, Rab4B [44] . Further, mutating ubiquitinatible lysine residues or complete truncation of the cytoplasmic tails of the HLA-DR a and b chains did not restore virus release. Rather, limiting the amount of HLA-DR DNA transfected into cells restored virus release and alleviated Gag retention. Curiously, CIITA expressing cells produced virus that was significantly more infectious than CIITA deficient cells, and this was independent of the class II antigen presentation pathway. CIITA enhances infectivity of virions from producer cells through a novel function, by improving maturation through an increase in viral protease-dependent Gag processing. Using a panel of CIITA mutants, we demonstrate that cytoplasmic CIITA increases Gag-Pol polyprotein levels. Overall, our work reveals a novel cytoplasmic, post-transcriptional function of CIITA, which is expressed upon T cell activation and is constitutively expressed in macrophages and dendritic cells, all known targets of HIV infection.