Lessons Learned From Failures and Success Stories of HIV Breakthroughs: Are We Getting Closer to an HIV Cure?

Abstract

There is a continuous search for an HIV cure as the success of ART in blocking HIV replication and the role of CD4 + T cells in HIV pathogenesis and immunity do not entirely eradicate HIV. The Berlin patient, who is virus-free, serves as the best model for a 'sterilizing cure' and many experts are trying to mimic this approach in other patients. Although failures were reported among Boston and Essen patients, the setbacks have provided valuable lessons to strengthen cure strategies. Following the Berlin patient, two more patients known as London and Düsseldorf patients might be the second and third person to be cured of HIV. In all the cases, the patients underwent chemotherapy regimen due to malignancy and hematopoietic stem cell transplantation (HSCT) which required matching donors for CCR5 32 mutation-an approach that may not always be feasible. The emergence of newer technologies, such as long-acting slow-effective release ART (LASER ART) and CRISPR/Cas9 could potentially overcome the barriers due to HIV latency and persistency and eliminate the need for CCR5 32 mutation donor. Appreciating the failure and success stories learned from these HIV breakthroughs would provide some insight for future HIV eradication and cure strategies.

Preclinical Evaluation of a Novel TALEN Targeting CCR5 Confirms Efficacy and Safety in Conferring Resistance to HIV‐1 Infection

“…On the other hand, the knowledge that a naturally occurring 32 nucleotide deletion (∆32) mutation in the CCR5 locus leads to resistance to CCR5‐tropic (R5‐tropic) HIV‐1 strains, [ 2,3 ] has spurred some encouraging approaches. [ 4 ] People with a homozygous Δ32 mutation are rare, clinically unremarkable, and conduct a normal life. [ 5 ] In 2007, an HIV‐positive patient, later referred to as the “Berlin Patient,” was transplanted with an allogeneic stem cell graft of an human leukocyte antigen (HLA)‐matched donor homozygous for the CCR5 Δ32 mutation after diagnosis of acute myeloid leukemia.…”

CCR5Δ32 in Brazil: Impacts of a European Genetic Variant on a Highly Admixed Population

“…After receiving cell transplantations from CCR5D32 homozygous donors, both showed sustained remission of HIV infection. Other cases like Berlin and London patients are being followed up, such as the 'Düsseldorf patient' (87). The success of this strategy, although involving few cases, shows that sustained remission of HIV is possible to be achieved and subsequently maintained free of antiretroviral therapy.…”

Perspectives on Non-BLT Humanized Mouse Models for Studying HIV Pathogenesis and Therapy

“…It is well known that the major obstacle to curing HIV-1 is the presence of persistently infected latent reservoirs. Several strategies, such as “kick-and-kill”, “block-and-lock”, and genome editing, combined with the augmentation of anti-HIV immunity, have been used for eliminating latently HIV-1-infected cells [ 158 ]. Since it is possible to mimic the in vivo situation of HIV-1 latency with oral ART in mice [ 159 , 160 , 161 , 162 , 163 ], such strategies have been evaluated by employing humanized mouse models.…”

“…A sterilizing cure in HIV-1 infection would be possible if all the hematopoietic cells were replaced with uninfected or infection-resistant cells, as in the case of the “Berlin patient”, who received BM stem-cell transplantations from a genetically CCR5-defective donor [ 158 ]. Stem cell-based gene therapy to introduce anti-HIV T-cell receptor expression or chimeric antigen receptor (CAR)-T cells was employed using BLT mice and has been reviewed elsewhere [ 175 ].…”