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

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.

Predicting the outcomes of treatment to eradicate the latent reservoir for HIV-1

“…(25), assuming, as recently reported, rebound after 27 mo], and a case of hematopoietic stem cell transplant with Δ32 CCR5 donor cells [the Berlin patient (Be.) (22,37)]. For the Chun patient, the annotations represent the maximum likelihood estimate for LR reduction (diamond), as well as 95% confidence intervals (vertical bar).…”

HIV-associated non-Hodgkin lymphoma: viral origins and therapeutic options

“…ART was suspended early after HCT, and the patient remains with undetectable HIV-1 RNA in blood and undetectable HIV-1 DNA in tissues using single-copy sensitive PCR methods for more than 7 years after treatment. 34,35 Despite the success of this single case, widespread use is limited by the rarity of both the homozygous CCR5⌬32/⌬32 mutation and HLA-compatibility, not to mention the morbidity of allogeneic HCT. Alternately, genetic modification of autologous hematopoietic cells circumvents the issues of identifying donors and, given the far lower morbidity of autologous HCT, allows a more viable approach to hematopoietic cell therapy for HIV-1.…”

CRISPRs encounter Cocktail: a dawn for curing HIV/AIDS

“…Then the HAART was stopped after transplantation and there was no any viral rebound for 8-year follow-up. All trials show that "Berlin patient" has been given a sterilizing cure [7].…”