The majority of viral infections can be self-limited in normal populations, with no requirement for medical intervention. However, the same viruses can cause severe diseases in patients with compromised immunity due to single-gene diseases, AIDS, hematologic malignancies, or in those receiving immunosuppressive drugs following organ transplant. Occasionally, these immunocompromised patients harbor more than one infectious agent, making it necessary to perform several concomitant diagnostic

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... . The prototype of such conditions is the group of diseases associated with human papillomaviruses (HPV), a family of over 400 genetically distinct types. We have developed a novel whole-transcriptome sequencing (RNA-Seq) based pipeline that allows virome profiling, quantitation, and expression pattern analysis of 926 distinct viruses by sequencing of RNA isolated from a single lesional skin biopsy. We applied this pipeline to six patients with skin lesions associated with immune deficiency secondary to HIV, HTLV1, chronic lymphocytic leukemia, and postrenal transplant immunosuppression. In five cases, definitive HPV infections were identified, in some cases caused by multiple viral types. In addition to HPV, co-infection with other viruses (MCP, CMV, and EBV) was detected in some lesions. In one case, identification of HTLV1 in the skin lesions was diagnostic for adult T-cell leukemia/lymphoma. These findings attest to the power of RNA-Seq in profiling the cutaneous virome in viral skin diseases in the context of compromised immunity.