Antiretroviral-Free HIV-1 Remission and Viral Rebound After Allogeneic Stem Cell Transplantation

Abstract

Background It is unknown if the reduction in HIV-1 reservoirs observed following allogeneic hematopoietic stem cell transplantation (HSCT) with susceptible donor cells is sufficient to achieve sustained HIV-1 remission. Objective To characterize HIV-1 reservoirs in blood and tissues, and to perform analytical antiretroviral treatment interruptions to determine the potential for allogeneic HSCT to lead to sustained antiretroviral-free HIV-1 remission. Design Characterization of HIV-1 reservoirs and immunity before and after antiretroviral interruption. Setting Tertiary care center. Patients Two HIV-infected men with undetectable HIV-1 following allogeneic HSCT for hematologic malignancies. Measurements Quantification of HIV-1 in various tissues after HSCT and the duration of antiretroviral-free HIV-1 remission after treatment interruption. Results No HIV-1 was detected from peripheral blood or rectal mucosa prior to analytical treatment interruption. Plasma HIV-1 RNA and cell-associated HIV-1 DNA remained undetectable until 12 to 32 weeks after antiretroviral cessation. Both patients experienced rebound viremia with the development of acute retroviral syndrome within one to two weeks of the most recent negative viral load measurement. One patient developed new efavirenz resistance after re-initiation of antiretroviral therapy. Re-initiation of active therapy led to viral decay and resolution of symptoms in both patients. Limitations The study was limited to 2 patients. Conclusions Allogeneic HSCT may lead to loss of detectable HIV-1 from blood and gut tissue and variable periods of antiretroviral-free HIV-1 remission, but viral rebound can occur despite a minimum 3-log10 reduction in reservoir size. Long-lived tissue reservoirs may have contributed to viral persistence. Defining the nature and half-life of such reservoirs is essential in order to achieve durable antiretroviral-free HIV-1 remission.

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

“…We predict that much higher efficacy will be required for eradication, which may be achieved by multiple rounds of LRA therapy, a combination of therapies, or development of therapies to which a greater fraction of the LR is susceptible. Though we have focused on LRA therapy, our findings also serve to interpret infection eradication or delays in rebound caused by early treatment (24,25,57) or stem cell transplantation (22,23), both of which also reduce the LR. In both of these cases, however, additional immunological dynamics likely play a major role and will need to be incorporated into future models.…”

“…The feasibility of reservoir reduction as a method of HIV-1 cure is supported by case studies of stem cell transplantation (22,23) and, more recently, early treatment initiation (24,25), which have allowed patients to interrupt treatment for months or years without viral rebound. The dramatic reductions in reservoir size accompanying these strategies stands in stark contrast to the actions of current LRAs, which induce only a fraction of latent virus in vitro (26,27) and have not produced a measurable decrease in LR size in vivo (12,13,28).…”

Engineering HIV-Specific Immunity with Chimeric Antigen Receptors

“…The left figure depicts the CD4f CAR, which comprised the entire natural extracellular domain [domains (D) [1][2][3][4] and transmembrane domain of the CD4 molecule fused to the CD3f signaling domain. The right figure depicts a broadly neutralizing antibody (BMAb)-derived CAR, which contains an HIV-recognizing extracellular single-chain variable fragment (scFv).…”

“…Further, attempts to treat individuals with myeloablation and allogeneic stem cells have resulted in short-term suppressed viral replication, followed by reemergence of the virus in the absence of ART. 1 In addition, while most transmitted strains of HIV utilize the CCR5 molecule as a coreceptor for infection, it is also well known that HIV can mutate and evolve in the host to utilize other coreceptors other than CCR5, including the CXCR4 molecule, thus limiting the protective effects of the lack of CCR5 expression on the cell. Thus, recapitulating the parameters that allowed Timothy Brown to clear HIV has proven difficult and the lack of successful ART to clear the virus reiterates a need for a therapeutic strategy to cure HIV infection.…”

Stakeholder Engagement in HIV Cure Research: Lessons Learned from Other HIV Interventions and the Way Forward

“…The preconditioning treatment for cancer reduced the frequencies of HIV-infected cells and prolonged the time to plasma viral load rebound. 5 The VIS-CONTI cohort includes 14 patients in France who were treated during acute HIV infection and subsequently maintained viral suppression in the absence of ART for more than 5 years. 6 Ongoing research is dominated primarily by concerns regarding the conduct and progress of the current trials aiming at durable drug-free viral suppression (functional cure) or true eradication of HIV (sterilizing cure).…”