**7. The 'receptor decoy' strategy**

Hence, the success of this strategy depends on the identification of suitable cellular co-factors of HIV infection which can be down regulated without altering the normal cellular physiology. In the search for such targets, genome wide profiling studies have revealed numerous previously unknown cellular factors that participate in HIV infection. Subsequent knock down studies have validated the effectiveness of silencing these factors for limiting HIV replication [160-162]. Further studies are needed to reveal the adverse effects following the knock down

The technique related pitfalls are the same as the ones mentioned earlier, which include the problems faced with delivery of inhibitory RNAs into specific target cells, off-target effects of the inhibitory RNAs and cytotoxicity to the administered cell. As of date, only one RNAi technique has entered clinical trial. The technique was designed to inhibit both viral (tat protein and TAR RNA) and cellular factors (CCR5). However, the trial was terminated in phase-0 and the results were not disclosed [163]. Table-5 broadly summarizes all the nucleic acid based

**Type Cells targeted Phase acted on Mechanism Technique employed**

kill)

Modification of normal cellular components

Expression of novel protective proteins

in viral replication

Modification of normal cellular components

Direct excision of integrated proviral DNA Genome editing systems -

Activation of viral replication (Shock and

Cell surface modifications

Intracellular modifications

Cell surface expression

Intracellular expression

Cell surface modifications Intracellular modifications

Inhibition of host cellular factors involved

Inhibition of viral mRNA Agents of RNA interference

CRISPR/Cas9, ZFN and

Gene therapy - Vectors based delivery of genes coding for viral proteins of

Genome editing systems - CRISPR/Cas9, ZFN and TALEN to knock out cellular co-factors that support HIV replication

Gene therapy - Vector based delivery of cDNA of novel peptides followed by their recombination and

(siRNA and shRNA) and to a lesser extent other RNA based techniques

(Antisense oligonucleotides, ribozymes and aptamers) delivered in viral / nonviral vectors to the desired target cells by active

TALEN

replication

expression

targeting

of these novel cellular factors.

DNA based techniques

RNA based techniques

therapeutics that are currently being tried against HIV.

232 Trends in Basic and Therapeutic Options in HIV Infection - Towards a Functional Cure

Elimination of latent reservoirs

Diversion of natural course of infection to make the target cells resilient

Inhibition of active viral replication

Diversion of natural course of infection to make the target cells resilient

Infected reservoirs (In vivo)

Uninfected susceptible cells (In vivo / In vitro)

Actively infected

**Table 5.** Nucleic acid based therapeutics for HIV infection

cells (In vivo)

Uninfected susceptible cells (*In vivo* / *In vitro*) The receptor decoy strategy is a novel concept which helps to salvage the natural target cells of HIV by diverting the virus to infect decoy particles, thereby altering the natural course of HIV infection. This involves the usage of decoy cells termed 'cancellers', which possess HIV entry receptors on their surface and do not contain the machinery required for retro-viral replication. The cancellers (Figure-2) intend to function as decoys and get infected by the free HIV virions thereby preventing the infection of the natural target cells. Apart from protection of the natural target cells, the cancellers also serve to limit viremia as the trapped virions cannot replicate inside the cancellers due to the absence of replication machinery. Optionally, the trapped virions could be destroyed by packing anti-viral agents within the cancellers [164].

**Figure 2.** Schematic representation of a canceller particle. RBC particle reconstituted with receptors on the membrane surface and loaded with various molecules. CD4 (red) and CCR5 (green) receptors are involved in the active targeting of HIV virions. Accessory surface molecules (orange) may be added to enhance the fusion process and/or to prevent elimination of the canceller by reticulo-endothelial system. Molecules capable of viral destruction (blue spheres and yellow stars) such as protein and RNA damaging agents are packed within the canceller.

The superiority of the receptor decoy strategy over the conventional anti-retroviral drugs is that it mimics natural conditions and is thereby devoid of the 'adverse factor' effect in selecting out resistance. This attractive strategy is in the concept phase and more discussions and comments could be made only after its implementation. Similar strategies employing modified erythrocytes or nanoparticles as viral traps are being studied for their use against HIV [164].
