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.
Abstract
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.
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