Given the success of HAART in blocking active viral replication, the inability of existing therapies to purge reservoirs of latently infected cells has become the greatest barrier to a cure. To overcome this, strategies are being considered that would induce viral replication in latently infected cells in combination with measures to enhance immune clearance of virus and infected cells. Examples of ways to activate latent virus include the administration of cytokines that activate viral transcription and replication (for example, IL2, IL6, and TNFα), or the use of agents that target epigenetic modifiers, such as histone deacetylase (HDAC) inhibitors, that can activate latent provirus. To date, however, no clinical trial using agents that target latent viral reservoirs has shown a significant reduction in viral load over that gained from HAART alone. Indeed, it was recently discovered that the activation of viral replication in latently infected cells is intrinsically stochastic, so that many immune cells harboring latent provirus will fail to activate viral replication in any given cycle of cellular activation. This adaptation of HIV to avoid elimination of latently infected cells could represent a formidable barrier to strategies aimed at ‘flushing out’ latent virus so that it can be eliminated.
Viral entry inhibitors Viral integrase inhibitors Virus assembly Protease inhibitors Reverse transcriptase inhibitors. Nucleoside analogs and non-nucleoside analogs interrupt transcription of viral RNA into viral cDNA
Fig. 3.39 Possible targets for interference with the HIV life and budding of infectious virions. as yet, only drugs that inhibit cycle. in principle, HiV could be attacked by therapeutic drugs at reverse transcriptase and protease action have been developed. multiple points in its life cycle: virus entry, reverse transcription of viral Combination therapy using different kinds of drugs is more effective Rna, insertion of viral cDna into cellular Dna by the viral integrase, than using a single drug. cleavage of viral polyproteins by the viral protease, and assembly
An alternative strategy for cure has been highlighted in a single HIV patient who underwent hematopoietic stemcell transplantation (HSCT) for treatment of leukemia in Berlin (hence referred to as the Berlin patient). By using a stemcell donor who was homozygous for the CCR5Δ32 coreceptor mutation, the patient was reconstituted with immune cells resistant to viral propagation. The patient’s CD4 Tcell counts rebounded and he was found to be free of any evidence of HIV infection (or leukemia) following cessation of antiretroviral therapy posttransplant. He has remained so for more than 5 years, suggesting that he has been cured of infection. In view of the large number of infected individuals worldwide, the risk of complications with HSCT, and rarity of HLAmatched CCR5deletant donors, this will never be a practical approach for cure at the population level. Moreover, there is a risk of progression or reinfection posttransplant by CXCR4tropic viral variants. This outcome does, however, dramatically establish that eradication of a latency reservoir (in this case by inductive chemoirradiation therapy for leukemia) combined with blockade of viral replication—whether by genetic or therapymediated interventions— might achieve a permanent cure.
13-36 In the course of infection HIV accumulates many mutations, which can result in the outgrowth of drug-resistant variants.