Last year Steven Yukl from UCSF presented the results of an exhaustive search for HIV genetic material in Timothy Brown (aka the Berlin Patient)—the one adult individual considered cured of the infection. The study engendered controversy, because a few of the multiple independent laboratories that participated did obtain positive readings for trace amounts of HIV RNA and DNA in some blood and tissue samples (the vast majority of the tests, including those looking for replication-competent virus in large volumes of cells, were negative). One scientist in particular, who was not involved in the research, made wild-eyed claims—via press release, no less—that the findings meant that Brown was either not really cured or potentially had been re-infected. The results of the study were published yesterday in the open access journal PLoS Pathogens, and the authors offer a sober discussion of their implications. In particular, they highlight the difficulty of formally proving a cure using current virologic assays that are operating at the limits of their sensitivity. Rather, they suggest, the waning of immune responses to HIV in Timothy Brown (both antibodies and T cells) may represent the clearest confirmation that he is indeed cured.
In the staid language of the methods section, the published paper also offers insight into the extent of Timothy Brown’s selfless commitment to contributing to HIV cure research:
“The subject was enrolled in the UCSF-based SCOPE cohort and had multiple study visits over two years. Plasma, serum, and PBMC were obtained at each visit. The subject also consented to separate procedures at UCSF, including leukapheresis, lumbar puncture, and flexible sigmoidoscopy with rectal biopsies. He was also seen at the University of Minnesota, where he underwent a lymph node biopsy and a colonoscopy with ileal and rectal biopsies.”
Any one of these procedures might well prompt trepidation in most people even if they were medically indicated; to volunteer to undergo them for the purposes of research is extraordinarily laudable.
PLoS Pathog 9(5): e1003347. doi:10.1371/journal.ppat.1003347
Yukl SA, Boritz E, Busch M, Bentsen C, Chun T-W, et al.
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.