Challenges in Detecting HIV Persistence during Potentially Curative Interventions: A Study of the Berlin Patient

Steven A. Yukl, Eli Boritz, Michael Busch, Christopher Bentsen, Tae-Wook Chun, Daniel Douek, Evelyn Eisele, Ashley Haase, Ya-Chi Ho, Gero Hütter, J. Shawn Justement, Sheila Keating, Tzong-Hae Lee, Peilin Li, Danielle Murray, Sarah Palmer, Christopher Pilcher, Satish Pillai, Richard W. Price, Meghan Rothenberger, Timothy Schacker, Janet Siliciano, Robert Siliciano, Elizabeth Sinclair, Matt Strain, Joseph Wong, Douglas Richman, Steven G. Deeks

There is intense interest in developing curative interventions for HIV. How such a cure will be quantified and defined is not known. We applied a series of measurements of HIV persistence to the study of an HIV-infected adult who has exhibited evidence of cure after allogeneic hematopoietic stem cell transplant from a homozygous CCR5Δ32 donor. Samples from blood, spinal fluid, lymph node, and gut were analyzed in multiple laboratories using different approaches. No HIV DNA or RNA was detected in peripheral blood mononuclear cells (PBMC), spinal fluid, lymph node, or terminal ileum, and no replication-competent virus could be cultured from PBMCs. However, HIV RNA was detected in plasma (2 laboratories) and HIV DNA was detected in the rectum (1 laboratory) at levels considerably lower than those expected in ART-suppressed patients. It was not possible to obtain sequence data from plasma or gut, while an X4 sequence from PBMC did not match the pre-transplant sequence. HIV antibody levels were readily detectable but declined over time; T cell responses were largely absent. The occasional, low-level PCR signals raise the possibility that some HIV nucleic acid might persist, although they could also be false positives. Since HIV levels in well-treated individuals are near the limits of detection of current assays, more sensitive assays need to be developed and validated. The absence of recrudescent HIV replication and waning HIV-specific immune responses five years after withdrawal of treatment provide proof of a clinical cure.