Novel Vaccine Strategies for Controlling HIV Infection

Early HIV vaccine research focused on generating a neutralizing antibody response (humoral immunity) to the virus; however, some experts suggest that cellular immunity, a strong and consistent response from cytotoxic T-lymphocytes (also known as CTLs or CD8+  T-cells)—perhaps in combination with humoral immunity—is essential to the success of an immunization strategy.1 In the case of HIV, infected memory cells (specialized immune cells) serve as a source for "latent infection" and typically enter into memory compartments, where they lay dormant, expressing minimal amounts of virus. Eventually (years after infection), they become active, circulating HIV infected T-cells, providing a continual source of infection. Since killer T-cells work by identifying and destroying cells infected with a specific antigen, immunization to elicit only an HIV1-specific T-cell response cannot prevent infection.1 Rather, it can control the virus's spread to other cells, keeping viral load low and hopefully delaying progression to AIDS.1 Some vaccines in development are designed to serve this function, while others still aim to prevent infection altogether.

Several strategies for gene-based immunization are under investigation, including virus-based vaccines that use other, less dangerous viruses to deliver genetic material to cells to elicit a T-cell response to control HIV infection. Vaccine developers use a form of virus as a delivery vehicle (vector) to carry immunogenic genetic material to the cell nucleus by infecting the cell. When the immunogenic material is expressed on the cell surface and combined with major histocompatibility complex molecules, it binds to the T-cell receptor of CD8+ cells, and killer T-cells are activated.

AGS-004 (Argos Therapeutics, Inc., Durham, NC, USA) is an autologous personalized therapeutic vaccine composed of dendritic cells (DCs) loaded with RNA antigens relevant to the HIV-1 strains circulating within each patient.2 AGS-004 uses Argos's proprietary Arcelis process, which takes a small plasma sample from patients infected with HIV, before antiretroviral therapy (ART) therapy (higher viral load for amplification), to amplify sufficient quantities of mRNA that encode the viral antigens gag, vpr, rev, and nef and to capture patient-specific protein mutations.3 By using patient-specific HIV-1 strains for AGS-004, the vaccine may have a greater probability of success in controlling residual virus or preventing viral rebound following the cessation of therapy.2

Use of DCs is part of the therapy because they are the most potent antigen- presenting cells in the immune system. To generate the vaccine, in vitro-differentiated (treated with IFN-gamma, TNF-alpha, and PGE2) mature DCs are electroporated with RNA encoding the viral antigens in conjunction with RNA for CD40L, a costimulatory molecule that is purported to greatly enhance the production of IL-12, a proinflammatory cytokine believed to be crucial for the induction of T-cell effector function, lytic activity, memory, and the vaccine's overall potency.4,5 During the natural course of infection, HIV-1 suppresses IL-12 production.6 These antigen-expressing DCs are cryopreserved and readministered to the patient via subcutaneous injection during therapy.5 In a phase IIa trial, patients were administered AGS-004 four times during ART treatment and two times during interruption of ART therapy.7 In addition to better viral load control, results from a small phase IIa study demonstrated...