Combined Immunotherapy as a means of stopping prolonged treatment with ART?

The HIV-1 virus has evolved to exploit the human immune system and counteract all immune defenses mounted against it.  Many different vaccination approaches and therapy treatments have been attempted to control, eliminate, or prevent HIV-1 infection, however, these attempts have not proved successful for virus elimination from the body. 

One approach that has been used to combat HIV-1 infection is the use of ART, or antiretroviral therapy, and this approach has proven to be effective at reducing viral levels in the blood.  ART suppresses HIV-1 viremia to undetectable levels within 12-48 weeks in a majority of patients.  This therapy is a “cocktail” or combination therapy of three or more drugs, including 2  nucleoside-based reverse transcriptase inhibitors (prevents production of the virus genome by inhibiting RNAàDNA transcription), and one or more of the following drugs: non-nucleoside reverse transcriptase inhibitors, membrane fusion inhibitors, viral protease inhibitors, or integrase inhibitors.  Each of these drugs targets a specific part of the viral lifecycle, making it unable to replicate and infect other cells.  Because each drug is mutually exclusive and targets a different area of the lifecycle, it is unlikely that a virus will develop resistance to all three drugs.  Therefore, because the virus does not produce escape mutants from the therapy, this approach is effective at reducing viral levels in the blood (ART information) (more on ART) However, by the time ART is put into effect, the virus has already established residence in T cells in the body, and can continue to infect other cells undetected by the drug by avoiding exposure in the blood via direct cell-to-cell infection.  Another problem with the use of ART for HIV-1 treatment is that it must be administered indefinitely, and if it is discontinued, there is a rapid rebound of viremia, or viral infection of the blood.  Taking ART indefinitely is undesired due to negative side effects (common ART side effects) and resistance to the drugs that develops overtime due to mutation.

Another approach to combat HIV-1 infection has been the use of monoclonal neutralizing anti-HIV-1 antibodies, however, in the past, these antibodies have proven to be ineffective at controlling infection of humanized mice (hu-mice) (Hu-mice as the murine model for the analysis of human hematolymphoid differentiation and function).  However, as of late, more potent antibodies have been uncovered that have decreased viremia in hu-mice and have longer half lives.  Antibodies that target gp120 glycoprotein in the HIV viral envelope have been studied as a potential means of neutralizing HIV infection.  Gp120 binds to CD4 on T cells, enabling initial viral-cell contact before membrane fusion and insertion of the viral genome (more on gp120). 

In a recent study conducted by Horwitz et al (2013) (published in the Proceedings of the National Academy of Sciences of the USA: HIV-1 Suppression and durable control by combining single broadling neutralizing antibodies (bNAbs) and antiretroviral drugs in humanized mice), three antibodies targeting different epitopes of gp120 were used in combination with ART and the effects were analyzed.  The three antibdies were 3BNC117 (a potent CD4 binding site antibody with a long half life), PG16 (which recognizes the V1/V2 loop region), and 10-1074 (which targets the base of the V3 stem). 

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.