HIV drug resistance can be an obstacle to successful antiretroviral therapy (ART), but the vast majority of studies on drug resistance have focused on studying blood. Here, we present evidence of drug resistance across multiple tissues in two persons with HIV.
Last Gift study participant 3 (LG03) was a 72-year-old man with HIV and metastatic pancreatic cancer with no previous history of drug resistance. LG05 was a 57-year old man with HIV and amyotrophic lateral sclerosis with pre-existing resistance to nucleoside reverse transcriptase inhibitors (NRTI) and protease inhibitors (PI) identified by the GenoSure Archive NGS-based assay. Both had suppressed HIV RNA in blood plasma collected within 7 hours from death. Tissues were isolated via a rapid autopsy and HIV DNA was extracted from gut (ileum and duodenum), lymph nodes (axillary and aortic), kidney and spleen. 72 3.5-kb pol single genome amplicons were prepared in a single library and sequenced (Illumina MiSeq). Reads were mapped to HIV HXB2, and consensus sequences generated. Mutations at sites of drug resistance were determined (Stanford HIV Drug Resistance Database) and analyzed for each variant.
Despite no previous diagnosis of ART failure with drug resistance, in tissues LG03 had mutations associated to (NRTI) including D67N, K70R, T215F, and K219Q/E in 9 kidney, 3 aortic lymph node, and 3 axillary lymph nodes SGA variants, but not in his duodenum or ileum (Table 1). In tissues, LG05 had NRTI resistance associated mutations (D67N, K70R, T215F, and K219Q/E) in 1 duodenum, 1 ileum, and 3 spleen SGA variants. Nonpolymorphic mutations associated with PI included M46I, I54V, V82T, I84V, and L90M. These mutations matched those identified in the GenoSure Archive assay.
This study found high rates of resistance associated mutations in proviruses across tissues in persons with HIV who were fully suppressed on ART. The pattern of HIV drug resistance associated mutations across PBMC and tissues was not consistent for either LG03 or LG05 (table 1). These discrepancies were pronounced between PBMC DNA (based on the GenoSure Archive assay) and non-circulating tissues. These findings highlight that HIV drug resistance might be present in various tissue reservoirs without prior diagnosis, and that just sampling in one compartment, like PBMC, is likely to miss the full repertoire of HIV drug resistance that is present.