Cell and gene therapy strategies to eradicate HIV reservoirs

Abstract

Purpose of review Highly active antiretroviral treatment has dramatically improved prognosis for people living with HIV by preventing AIDS-related morbidity and mortality through profound suppression of viral replication. However, a long-lived viral reservoir persists in latently infected cells that harbor replication-competent HIV genomes. If therapy is discontinued, latently infected memory cells inevitably reactivate and produce infectious virus, resulting in viral rebound. The reservoir is the biggest obstacle to a cure of HIV. Recent findings This review summarizes significant advances of the past year in the development of cellular and gene therapies for HIV cure. In particular, we highlight work done on suppression or disruption of HIV co-receptors, vectored delivery of antibodies and antibody-like molecules, T cell therapies, and HIV genome disruption. Summary A number of recent advancements in cellular and gene therapies have emerged at the forefront of HIV cure research, potentially having broad implications for the future of HIV treatment.

Concepts for the Production of Viruses and Viral Vectors in Cell Cultures

“…Stable vectors are required because of the long residence times in vivo. These treatments typically involve doses of 100-1000 mL with a virus density of at least Gene therapy is currently used in ongoing clinical trials for the treatment of cancer [8], hereditary diseases [9], infectious diseases such as HIV infection [10,11] and tissue engineering [12]. The replication of the virus particle must be inactivated to ensure that the vector itself does not cause a disease.…”

“…Another strategy is the insertion of a tumor-specific promoter, which restricts viral expression to tumor cells [29]. Viral tropism can be engineered by displaying ligands that bind to cell surface receptors unique to cancer cells [10,[30][31][32]. Several genetically modified viruses have been adapted as potent oncolytic agents for clinical trials, including herpesvirus [33], adenovirus [34], poxvirus [35], coxsackievirus [36], polyovirus [37], Newcastle disease virus [38] and reovirus [39].…”

“…The scope for therapeutic strategies has broadened and now encompasses vectors for replacement protein expression, gene therapy and the treatment of cancer [2,3]. Viruses for in vivo applications show a limited affinity for their target cells, they are generally unstable and large doses of infective virus particles (up to 10 12 active virus particles per dose) are needed to achieve a therapeutic effect. Effective upstream production must therefore be combined with optimized downstream processing.…”

Mechanisms for Controlling HIV-1 Infection: A Gene Therapy Approach

“…Rather, investigators have now turned to potent broadly neutralising antibodies, which have been screened and cloned from various HIV positive patients and target HIV envelope. In this setting, several pre-clinical studies are underway in non-human primates in the laboratories of Kiem and Jerome, where resistance afforded by C46 and shRNA is complexed with one of several CAR modules that incorporates the single variable change of well characterised broadly neutralising antibodies [99].…”

Disruption or Excision of Provirus as an Approach to HIV Cure

“…Hematopoietic cell transplantation can clearly induce a large reduction in the HIV reservoir, 6 and it has been responsible for extended HIV remissions and the single well-documented case of durable cure. 7 Other cell and gene therapy approaches have been suggested to reduce the HIV reservoir, possibly as the effector component of ''shock and kill'' strategies, 8,9 which seek to reactivate latent virus to allow recognition and destruction of latently infected cells. Perhaps the most direct use of gene therapy, however, would be to directly target the integrated HIV for disruption or excision.…”