Genetic Strategies for HIV Treatment and Prevention

Abstract

Conventional HIV gene therapy approaches are based on engineering HIV target cells that are non-permissive to viral replication. However, expansion of gene-modified HIV target cells has been limited in patients. Alternative genetic strategies focus on generating gene-modified producer cells that secrete antiviral proteins (AVPs). The secreted AVPs interfere with HIV entry, and, therefore, they extend the protection against infection to unmodified HIV target cells. Since any cell type can potentially secrete AVPs, hematopoietic and non-hematopoietic cell lineages can function as producer cells. Secretion of AVPs from non-hematopoietic cells opens the possibility of using a genetic approach for HIV prevention. Another strategy aims at modifying cytotoxic T cells to selectively target and eliminate infected cells. This review provides an overview of the different genetic approaches for HIV treatment and prevention.

Keywords: HIV; antiviral proteins; genetic therapies.

Figure 1

Conventional HIV Gene Therapy (A) Ex vivo gene delivery. Autologous CD4⁺ T cells or CD34⁺ HSPCs are genetically modified ex vivo using a suitable vector. The gene-modified cells are infused back into the patient. (B) Positive selection of gene-modified HIV target cells. HIV replicates in susceptible HIV target cells (red). Gene-modified cells (green) are resistant to infection and accumulate to therapeutically relevant levels. (C) The HIV replication cycle and examples of gene therapeutics. RT, HIV reverse transcriptase; IN, HIV integrase.

Figure 2

Genetic Strategies Based on Secreted AVPs (A) Genes encoding secreted AVPs can be delivered by ex vivo gene therapy. Alternatively, suitable vectors can be injected directly into the target tissue, such as muscle. (B) Gene-modified producer cells secrete the AVPs into their surrounding. The secreted AVPs inhibit HIV entry by binding to HIV Env present on virus particles and infected cells or by binding to cellular receptors, such as CCR5. (C) HIV entry and examples of protein-based entry inhibitors.

Figure 3

Gene Therapy Using Engineered CD8⁺ T Cells (A) CD8⁺ T cells are modified to express HIV-specific TCRs or CARs. Upon recognition of an infected cell, gene-modified CD8⁺ T cells mediate the destruction of the infected cell. (B) Examples of HIV-specific CARs. The structure of the TCR/CD3 complex with co-stimulatory receptors CD28 and 4-1BB is shown in the left panel. The structure of HIV-specific CARs is depicted in the right panel.