Why haven’t we found a cure for HIV?

     In 1983 the human immunodeficiency virus (HIV) was first isolated and suggested as the root cause of acquired immune deficiency syndrome (AIDS), a universally fatal condition thanks to various opportunistic diseases that take advantage of the sufferers weakened immune system (1). Today HIV is one of the most intensely researched viruses in the world and new drugs are constantly being developed to minimize its effects in HIV+ patients. Yet despite sophisticated cocktails of these drugs that are administered during the most popular treatment for HIV infection, highly active antiretroviral therapy (HAART), we still have not managed to develop a therapeutic strategy to fully eradicate the virus from those infected with it.

     The reason a cure for HIV has been so difficult to obtain has to do with the virus’s latent reservoir. Most cells that become infected with HIV start producing infectious viruses within a few days. And they do this at a high enough rate that the cell eventually dies, either directly due to the viral replication itself or indirectly due to the host’s immune system. These cells die off and are no longer a threat for producing more viruses. A cell involved in the HIV latent reservoir, however, only produces viruses at a low rate or not at all. It can remain dormant, evading the host’s immune system while still containing the HIV genome and, therefore, the ability to produce infective HIV viruses. Recent research has suggested that memory T cells, which are involved in the mechanism that allows the immune system to remember pathogens after infection has cleared, make up the largest proportion of the HIV latent reservoir (P,2). The long-lived nature of this cell type means that it would take an exceedingly long time to wait for each of these proviral cells to die. Recent modeling suggests it could take up to 70 years (3).

     Because so many successful antiretrovirals have been developed, patients adhering to HAART can delay the onset of AIDS indefinitely (P). These drugs are very good at preventing any HIV viruses that persist in the patients bloodstream from infecting new CD4+ T-cells, the viruses target cell type. However, once taken off HAART, these patients start shedding new viruses and progress rapidly to AIDS. Therefore, HAART must be a lifelong treatment, one that is very expensive and very difficult to keep up with. The reason HAART does not fully eradicate HIV is because the cells of the latent reservoir still contain the HIV genome, which enables those cells to manufacture infectious viruses, which are detected in the individuals blood. If the patient is fully adhering to HAART these viruses simply degrade and do not infect new cells. But if the patient is taken off HAART these viruses can infect new cells, which can then go on to shed more viruses.

     If a cure for HIV is to be developed, the latent reservoir must be dealt with (4). One of the most recent ideas is to use histone deacytelase inhibitors (HDACis), commonly used drugs that could theoretically unpack the HIV genome of latently infected cells, allowing for the rapid production of new viruses and subsequent clearance of that cell either directly by HIV replication or indirectly by the host’s immune system (2). If HAART is intensified during this treatment the newly produced viruses would not be able to infect new cells and would eventually die off. At that point the individual would no longer contain any infective HIV viruses or any of the cells that contain its proviral genome.

     Now the question is which HDACi to use. There have been a number of potential candidates but the results of studies involving them have been weak and sometimes contradictory. Bartholomeeusen et al. decided to focus on better understanding the mechanism by which HDACis contribute to the activation of HIV replication in cells of the latent reservoir (P). One of the reasons resting T cells are thought to be involved in the latent reservoir is the combination of their ability to become infected with the HIV genome and their very low levels of the activated form of a protein called Positive Transcription Elongation Factor b (P-TEFb), which is responsible for the initiation of HIV replication.

     In order to determine whether this protein plays a role in the HDACi-mediated reactivation of latently infected cells, Bertholomeeusen et al. infected human T cells with the HIV genome (P). While these cells are not memory T cells they provide a suitable cell line to study HIV latency. After this proviral infection was established the cells were treated with four different HDACis: vorinostat, ST-80, entinostat, and tubastatin A. These cells were then monitored both for the production of new HIV viruses and for their levels of P-TEFb. The HDACi vorinostat successfully reactivated these latently infected cells, leading to the production of new viruses. ST-80 had a similar effect but entinostat showed a weakened effect and tubastatin A had no effect at all.

     The difference in the efficacies of these drugs can be explained by their ability to activate P-TEFb. Treatment with both vorinostat and ST-80 was shown to increase levels of active P-TEFb, an effect not observed with entinostat or tubastatin A. This finding suggests that the unpacking of the HIV genome, which all of the HDACis should be capable of doing, is not sufficient for reactivation of HIV replication in latently infected cells. It is also necessary for there to be activated P-TEFb to initiate HIV replication. This finding was further supported when Bertholomeeusen et al. attempted reactivation of latently infected resting T cells, which were provided by human donors (P). These cells only underwent significant reactivation following treatment with both vorinostat and another drug, bryostatin 1, which increases the levels of active P-TEFb in resting T cells.

     This research provides significant insights into the mechanism of HIV reactivation and can help inform future decisions about which drugs should be investigated during preclinical trials. The major discovery of this study is that the use of an HDACi might not be sufficient without the assistance of an additional drug that can increase the intracellular levels of P-TEFb. It is also important to note that the patient would need to maintain adherence to HAART during treatment. Nonetheless, this study provides new insights into the mechanism of HIV reactivation in the latent reservoir.

     The next step is to identify which HDACi/P-TEFb drug combinations work the best and to get them approved for clinical trials. Unfortunately these trials can take up to 10 years before the treatment reaches consumers. A good HDACi to look into for future studies is valproic acid, which has been shown to target the specific proteins that pack the HIV genome and has already been approved by the FDA for use in humans, which would speed up the approval process for use as a treatment for HIV infection. This study shows that it might be possible that treatment with an HDACi in combination with a drug that upregulates P-TEFb during intensified HAART could facilitate the clearance of the HIV latent reservoir and lead to the complete eradication of the HIV virus from any infected individual. This would allow HIV+ patients to stop receiving complicated and expensive HAART and go on to live normal lives. Even more, on an epidemiological scale, an effective cure for HIV would lead to the decrease and possible elimination of HIV/AIDS from the human population.

Primary Source

Bartholomeeusen, Koen, Koh Fujinaga, Yanhui Xiang, and Matija Peterlin. "HDAC

            Inhibitors That Release Positive Transcription Elongation Factor B (P-TEFb)

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            Biological Chemistry (in press).

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