The viral spike of HIV-1 is composed of three gp120 envelope glycoproteins attached non-covalently to three gp41 transmembrane molecules. Virus entry is initiated by binding of this complex to the CD4 receptor on the cell surface of T-cells and dendritic cells. Enfuvirtide is a synthetic peptide which binds gp41 and blocks the fusion of the virus to the host cell through the CD4 receptor. Enfuvirtide was approved by the FDA in March 2003 for use in adults, and in children aged 6 and older with advanced HIV infection, and is marketed under the brand name Fuzeon©. The drug is administered by subcutaneous injections, and has been associated with a variety of skin reactions occurring in more than 80 % of patients [13, 14]. In rare cases, it has also been associated with subcutaneous localized amyloidosis [4, 5, 12]. Recently, mass spectrometry-based proteomics studies showed that these amyloid deposits were composed of the synthetic peptide of enfuvirtide [12], and enfuvirtide-induced amyloidosis (AEnf) was recognized as a novel type of iatrogenic amyloidosis by the Nomenclature Committee of the International Society of Amyloidosis [15].

AEnf amyloidosis presents as hemorrhagic nodules at the site of injections, which may persist after discontinuation of the drug. A biopsy with histological examination is required for diagnosis. The histology shows marked subcutaneous amyloid deposition replacing normal structures. As expected, the deposits are strongly Congophilic and show the appropriate optical qualities of amyloid (Fig. 35.2). If the clinical context is known, the diagnosis is straightforward. If typing is required, mass spectrometry-based proteomics is the only method available, as the peptide is synthetic and no antibody-based immunohistochemical assays are available [12] (Fig. 35.2).