Signal peptide of HIV envelope protein impacts glycosylation and antigenicity of gp120.

The HIV-1 envelope protein (Env) of early-replicating viruses encodes several distinct transmission signatures. One such signature involves a reduced number of potential N-linked glycosylation sites (PNGs). This transmission signature underscores the importance of posttranslational modifications in the fitness of early-replicating isolates. An additional signature in Env involves the overrepresentation of basic amino acid residues at a specific position in the Env signal peptide (SP). In this report, we investigated the potential impact of this SP signature on gp120 glycosylation and antigenicity. Two recombinant gp120s were constructed, one derived from an isolate that lacks this signature and a second from an early-replicating isolate that includes this signature. Chimeric gp120s were also constructed in which the two SPs were swapped between the isolates. All four gp120s were probed with glycan-, structure- and receptor- specific probes in a surface plasmon resonance binding assay. We found that the SP of Env influences qualitative aspects of Env glycosylation that in turn affect the antigenicity of Env in a major way. The SP impacts the affinity of Env for DC-SIGN, a lectin receptor expressed on dendritic cells that is believed to play a role in mucosal transmission. Additionally, affinity for the monoclonal antibodies 17b and A32, which recognize a CD4-induced, open conformation of Env is also altered. These results demonstrate that natural variation in the SP of HIV Env can significantly impact the antigenicity of mature gp120. Thus, the SP is likely subject to antibody-mediated immune pressure.

Long-term results of a porous tantalum monoblock tibia component: clinical and radiographic results at follow-up of 10 years.

BACKGROUND: The purpose of this study is to assess the long-term follow-up of cementless total knee arthroplasty with the trabecular metal (TM) monoblock tibial component at an average 10-year follow-up. This report is an extension of our previously reported series of 108 TM tibias reported in 2011 (Unger and Duggan, 2011). METHODS: Fifty-eight of the original 108 knees were available for review. Each follow-up patient was evaluated by radiologic and clinical Knee Society Scores. The average follow-up was 10.2 years. RESULTS: Our results indicate excellent long-term survivorship (96.5%) with 2 confirmed tibia revisions, and 1 femoral revision for periprosthetic fracture and 1 patella open reduction internal fixation. X-ray evaluation demonstrated one patient with 1 mm medial polyethylene wear and a nonprogressive 1 mm of radiolucency on the medial side. All the other tibial components showed full bone apposition and incorporation. Knee Society Scores were excellent in all the patients seen on follow-up. CONCLUSIONS: Long-term follow-up of TM monoblock tibia components confirm excellent survivorship and biologic implant fixation, with excellent outcomes and knee scores.

The HIV-1 envelope protein gp120 impairs B cell proliferation by inducing TGF-ß1 production and FcRL4 expression.

The humoral immune response after acute infection with HIV-1 is delayed and ineffective. The HIV-1 envelope protein gp120 binds to and signals through integrin α4ß7 on T cells. We found that gp120 also bound to and signaled through α4ß7 on naive B cells, which resulted in an abortive proliferative response. In primary B cells, signaling by gp120 through α4ß7 resulted in increased expression of the immunosuppressive cytokine TGF-ß1 and FcRL4, an inhibitory receptor expressed on B cells. Coculture of B cells with HIV-1-infected autologous CD4(+) T cells also increased the expression of FcRL4 by B cells. Our findings indicated that in addition to mediating chronic activation of the immune system, viral proteins contributed directly to HIV-1-associated B cell dysfunction. Our studies identify a mechanism whereby the virus may subvert the early HIV-1-specific humoral immune response.