Efficient Incorporation of HLA Class II onto Human Immunodeficiency Virus Type 1 Requires Envelope Glycoprotein Packaging

Abstract

HLA class II DR is one of the most abundant cell surface proteins incorporated onto human immunodeficiency virus type 1 (HIV-1) during budding. The mechanism for HLA class II protein incorporation is not known and may involve a viral protein. To determine whether Env affects HLA class II protein incorporation, HIV-1 virions, either with or without Env on their surface, were produced from HLA class II-expressing cells and analyzed by whole-virus immunoprecipitation with antisera against HLA class II proteins. HLA class II proteins were detected on virions only when wild-type Env was incorporated, while similar experiments showed that HLA class I proteins were incorporated independent of Env packaging. Therefore, the packaging of HIV-1 Env protein is required for the efficient incorporation of HLA class II but not class I proteins into the virion. Analysis of two Env mutants revealed that the presence of a 43-amino-acid sequence between amino acids 708 and 750 in the gp41 TM cytoplasmic tail was required for efficient incorporation of HLA class II proteins. These data show that HIV-1 actively incorporates HLA class II proteins in a process that, either directly or indirectly, requires Env.Human immunodeficiency virus type 1 (HIV-1) acquires surface glycoproteins, including Env, by budding through the plasma membrane (reviewed in reference 35). Env is a complex made up of the surface glycoprotein gp120 SU noncovalently bound to the gp41 TM transmembrane (TM) protein. This complex binds to CD4 and various coreceptors and allows for viral entry by mediating virus-cell membrane fusion (reviewed in reference 19). Unlike type C retroviral TM proteins, gp41TM has a relatively long cytoplasmic C terminus (tail) that has been shown to induce cytopathic effects and affect the packaging of Env into the virion (9,12,21,36,37).In addition to Env, many different cellular proteins have been detected on the surface of HIV-1 (reviewed in reference 24). Human leukocyte antigen (HLA) class II DR is the most commonly detected and the most abundant host protein on HIV-1 propagated in cell culture and on virus isolated from patient plasma (24,33). Based on biochemical analysis, HLA class II DR may be present at approximately 1.5 to 2 times the level of gp120 SU on the surface of HIV-1 produced from the H9 human T-cell line (2). Although the mechanism by which HIV-1 acquires HLA class II DR is not known, one possibility is that it is merely incorporated by its proximity to the budding virion. However, many host proteins appear to be excluded from enveloped viruses in general (38). Interestingly, only HLA class II DR is appreciably incorporated into virions, even when the other isotypes of HLA class II (DP and DQ) are present on the surface of cells (2,8,14,34). While these results imply that HLA class II DR is specifically incorporated into the virion, this possibility has not been demonstrated. Expression of Env and HLA class II protein incorporation.One possible mechanism for HLA class II protein incorporation is that the packaging of...

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“…MHC molecules are present in virions at levels exceeding gp120/ gp41 (Henderson et al, 1987;Arthur et al, 1992) and are incorporated non-randomly (Hoxie et al, 1987;Poon et al, 2000;Nguyen & Hildreth, 2000). Furthermore, it has been shown that incorporation of HLA-DR by clinical isolates of HIV-1 expanded in primary human cells depends on the producing cell and the donor source (Cantin et al, 2001).…”

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“…But like many processes in biology, the incorporation of cellular proteins into the external lipid bilayer of a lentivirus likely occurs through several different mechanisms, as it seems to be cell type and virus strain dependent, at least under in vitro conditions (23,24,67,82). One study reported a direct interaction between virion-incorporated HLA-DR and a 43-amino-acid domain located in the cytoplasmic tail of HIV-1 transmembrane envelope glycoprotein gp41 (84). In contrast, incorporation of ICAM-1 was found to be independent of HIV-1 envelope glycoproteins (7).…”