Barriers and strategies to achieve a cure for HIV

Abstract

9 years since the report of a cure for HIV after C-C chemokine receptor type 5 Δ32 stem cell transplantation, no other case of HIV cure has been reported, despite much research. However, substantial progress has been made in understanding the biology of the latent HIV reservoir, and in measuring the amount of virus that persists after antiretroviral therapy (ART) with increasingly sophisticated approaches. This knowledge is being translated into a long pipeline of clinical trials seeking to reduce viral persistence in participants on suppressive treatment and ultimately to allow safe cessation of ART. In this Review, we discuss the main barriers preventing the development of an HIV cure, methods used to measure HIV persistence in individuals on ART, clinical strategies that aim to cure HIV, and future directions for studies in the field of HIV cure research.

Figure 1. Mechanisms of HIV persistence in cells and tissue.

(a) Latency is established in long-lived CD4+ T cells through mechanisms such as epigenetic modifications that reduce HIV transcription, including reduced acetylation and enhanced methylation, a lack of HIV transcription factors, inhibition of RNA export and inhibition of protein translation by microRNAs. (b) Integrated latent HIV is replicated upon cellular division. (c) Residual viral replication despite antiretroviral therapy may contribute to HIV persistence on ART. (d) B cell follicles of lymph nodes and other lymphoid tissue provide an immune sanctuary for HIV both within CD4+ T cells (T follicular helper cells) and on the follicular dendritic cell network by excluding cytotoxic CD8+ T lymphocytes. (e) Th17 cells in the gastrointestinal tract are infected and depleted leading to loss of gut barrier integrity, microbial translocation and immune activation. Subsequent chronic inflammation may promote HIV persistence on ART through cellular proliferation, CD8+ T cell exhaustion and possible residual viral replication. Integrated viral DNA is shown in green for latently infected cells and in red for productively infected cells; genomic DNA is blue.

Figure 2. HIV cure clinical trial design.

Interventions are usually administered to HIV infected individuals whilst on suppressive antiretroviral therapy (ART). These interventions may also be continued into the analytical treatment interruption (ATI) period. Several potential plasma viral outcomes are depicted. Yellow line: lack of response to the intervention with rapid viral rebound to a high level and high subsequent viral set point. Red line: rapid but low level viral rebound followed by viraemic control to between 50 and 1000 copies/ml. Green line: viral rebound delayed but virus rebounds to a high level. Blue line: No viral rebound to end of monitoring period. The primary endpoint may be defined as the time to viral rebound, the viral set-point reached following rebound or the area under the plasma virus curve which integrates both of these.

Figure 3. Strategies for HIV cure.

(a) Strategies that target the viral replication cycle. (b) HIV specific immune enhancement. (c) Immune modulation that is not specifically targeted at HIV. DARTs = Dual-Affinity Re-Targeting molecules. CAR = Chimeric Antigen Receptor. Integrated latent viral DNA is shown in green and genomic DNA is blue.