**4.2. Targeted drug delivery to infected cells**

To achieve viremic control by anti-retroviral drugs, the patient should also face a plethora of untoward effects. Drug interactions, synergistic toxicity of combination, frequent dosing and pill burden are the various adverse effects of the HAART causing a poor compliance. Novel techniques based on nanotechnology are being developed to overcome the shortcomings of conventional anti-retroviral drug therapy.

Targeted drug delivery is the technique that is extensively being applied to accentuate the beneficial effects and to simultaneously reduce the adverse effects of anti-retroviral drugs. In the course of infection, HIV gains entry into its target cells by membrane fusion, leaving behind its envelope and surface glycoproteins on the surface of the infected cells. During active replication of HIV within the target cells, the infected cells also express these viral glycopro‐ teins synthesized de novo. Active targeting exploits these viral components on the cell surface to selectively identify the infected cells from the uninfected ones [13]. Active replication of HIV *in vivo*, from the point of infection of a CD4 T-cell to release of viral progeny takes an average of 52 hours for completion [14]. This long generation time of HIV could be effectively utilized to specifically deliver the anti-retroviral drugs to the infected cells by nanotechnology methods. This would prevent the dissemination of the viral progeny and reduce the viral load more effectively than systemically administered anti-retroviral drugs.

The scope of the HAART to achieve a 'functional cure' is being studied extensively. Functional cure is said to be achieved when the infected individual treated aggressively with HAART early in the course of infection, does not develop rebound viremia on cessation of therapy for several months [7]. This concept had stemmed from the story of the Mississippi baby, where a mother seropositive for HIV-1 gave birth to an infant who was also found to be infected. Anti-retroviral therapy was initiated to the baby at 30 hours of birth and was continued till 18 months of age after which the therapy was discontinued. Surprisingly at 30 months of age, the child was tested negative for plasma HIV-1 RNA, proviral DNA in peripheral-blood mono‐

In an attempt to replicate the observations of the Mississippi baby, the VISCONTI study conducted in France has effectively achieved a functional cure in a cohort of 14 adults who currently are free of viremia even after several years of interruption of anti-retroviral therapy [9]. Likewise, functional cure has been reported in an elderly German patient who had deliberately interrupted treatment after five years and has controlled rebound viremia for nine

The reason hypothesized behind functional cure is that, early aggressive treatment prevents the build-up of large latent reservoirs and also reduces the viral load low enough that the immune system clears off the residual infection without continued use of antiretroviral drugs [11]. The drawback of this concept is that it necessitates the stoppage of the anti-retroviral drugs that have helped in the control of viremia. It is not known whether this might result in a functional cure or cause a rebound viremia. As it would be unethical to stop treatment in an individual with good viremic control without knowing the correlates of protection, well designed clinical trials must be conducted prior to implementation of this concept, to obtain answers to questions of uncertainty such as; what is the time period within which the treatment should be initiated following infection to favour functional cure? How long should the treatment be given? When is the ideal time for the interruption of treatment? What are the host

By the time the functional cure concept offered some hope, the occurrence of rebound viremia in the Mississippi baby smashed all the excitement [12]. It might only be a matter of time before we know whether the other patients claimed to be functionally cured, progress to viremia or remain "cured". Nevertheless, the Mississippi baby and the other studies have hinted that control of viremia is possible on treatment cessation. Further studies are required to find how

To achieve viremic control by anti-retroviral drugs, the patient should also face a plethora of untoward effects. Drug interactions, synergistic toxicity of combination, frequent dosing and pill burden are the various adverse effects of the HAART causing a poor compliance. Novel techniques based on nanotechnology are being developed to overcome the shortcomings of

nuclear cells and serum HIV-1 antibodies [8].

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

years after the cessation of treatment [10].

factors involved in protection?

to prolong this drug-free control of viremia.

**4.2. Targeted drug delivery to infected cells**

conventional anti-retroviral drug therapy.

The nanoparticles used for targeted drug delivery contain a carrier vessel straddled with a targeting moiety. The carrier nanoparticles are tiny containers which could be loaded with the drug of interest and are capable of delivering their cargo into cells upon fusion. Various types of nanocarriers such as; liposomes, micelles, dendrimers, nanocapsules, nanoemulsions, solid lipid nanoparticles, polymeric nanoparticles, gold nanoparticles and nanocrystals have been successfully loaded with one or more known anti-retroviral agents. The active targeting moiety tagged to the surface of these carriers guides them specifically to the target cells. Recombinant CD4 molecules or Fab fragments of monoclonal anti-gp120 antibodies which possess high affinity to HIV envelope glycoproteins are used to actively target the envelope glycoproteins of HIV present on the surface of the infected CD4 cells [15].

Targeted drug delivery possesses significant advantages over conventional chemotherapy of which, the most important is the reduction of the adverse effect profile of the anti-retroviral agents. This is because, the technique concentrates the drug only to the necessary sites and hence not only it reduces the administered dose, but also avoids the accumulation of drug at unwanted sites. Besides this, some of the nanoparticles have inherent antiretroviral property and function synergistically when loaded. This promising technique however, is not devoid of pitfalls. Nanoparticles face the major problem of opsonization and phagocytic clearance which occurs almost rapidly following their administration. The process of pegylation which involves in coating of the nanoparticles with polyethylene glycol overcomes this disadvantage by making the nanoparticles invisible to immune clearance. However, the fusion kinetics of these 'stealth' nanoparticles is diminished when compared to the non-pegylated ones [16]. Nanocarriers packed with a single drug are more stable and addition of more drugs within the same nanocarrier makes it more unstable. As monotherapy can accelerate viral resistance, stable models of multidrug nanocarriers are now being developed [17]. Poor oral bioavaila‐ bility, causation of target cell membrane instability and cytotoxicity, complications in renal clearance and high production cost are some of the problems that have to be solved before nanotherapeutics come into effective use [13].
