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.

STAT3β: Not Such A Downer

STAT3 is a transcription factor that has been of particular interest to oncologists lately for its promotion of oncogenesis through constitutive activation. STAT3 has two key residues that must both by phosphorylated by a kinase in order for the protein to dimerize into a homodimer or heterodimer and thus be active. The two residues, tyrosine 705 and serine 727, are both found on exon 23. STAT3 is activated by several interferons, cytokines, and growth factors.

An article published in the October 25, 2011 edition of PNAS explored the study of Dr. Francesa Zammarchi et al on the alternative splicing that leads to two isoforms of STAT3: STAT3α and STAT3β. Exon 23, which includes the two amino acid residues necessary for activation of the STAT3 TF, can be fully or partially included in the final product. If the entire exon is included, STAT3α is formed and the protein is fully functional. If the 55 amino acids at the end of exon 23 are excluded from the final product, then STAT3β is made. The premature termination of the protein causes serine 727, a necessary residue for phosphorylation and activation of the STAT3 protein, to be truncated. This renders STAT3β able to maintain its DNA binding function, but not able to be fully active as a transcription factor.

Previously, it has been thought that STAT3β was a dominant-negative regulator based on its ability to bind DNA and thus competitively inhibit the activity of STAT3α. However, the findings of Zammarchi et al are questioning that designation, and have made a strong case for STAT3β as an antitumorigenic factor with its own specific set of regulated genes and proteins.

In a series of experiments that tested STAT3β regulation of both RNA and protein products, Zammarchi et al found that IL-8, LEGDF, and PCAF were all regulated specifically by STAT3β rather than total STAT3 knockdown. The transcription factor was demonstrated to downregulate both LEDGF and PCAF transcription and translation. IL-8 is involved in inflammation and in the chemotaxis of neutrophils, which are innate immune cells that phagocytose pathogens. LEDGF is a chromatin-binding protein and a transcriptional coactivator, as well as a pro-survival growth factor. PCAF is a histone acetyl transferase and transcriptional coactivator that promotes growth, invasion, and drug resistance. Clearly these genes are all of great interest to oncologists as potential cancer treatment targets, and thus STAT3β is coming into focus as a gene and protein of interest for all those involved in fighting cancer.

It has been previously demonstrated by Yue and Turkson1 that overexpression of STAT3β can induce apoptosis and inhibit tumor growth, and now the next step investigating the reasons for these effects has begun. Zammarchi et al showed that the STAT3β regulation occurs in several different types of cancer cell lines, including breast cancer, prostate cancer, and lung cancer, demonstrating the potential widespread nature of this factor as a cancer treatment target. There is still a long list of topics to be further investigated before STAT3β can be implicated as a prospective treatment target in humans including determining side effects, testing in animal models, and the development of drug delivery systems that are compatible with this substance, but nonetheless STAT3β appears to be a promising target for future oncological studies.

Reference:

Zammarchi, F. et al. (2011) Antitumorigenic potential of STAT3 alternative splicing modulation. PNAS 108(43):17779-84.

Additional Citation:

1) Yue, P., Turkson, J. (2009) Targeting STAT3 in cancer: How successful are we? Expert Opin Investig Drugs 18:45-56.

Men: Beware the ETS Family of Transcription Factors-It May Control Immunity Genes Involved in Prostate Cancer

Cancer is a state of abnormal and uncontrolled cell growth that can potentially spread throughout the body. Cancerous cells have adverse effects, which the body has many defenses against in order to prevent tumor growth and cancer development. The immune system is thought to aid in the suppression or promotion of tumor growth by exerting multiple cellular controls over the death or proliferation of certain cells (Lin and Karin, 2007). With vast numbers of people being affected by cancer on a daily basis, it is important to identify cellular differences between cancerous and healthy states. Identifying changes that might be associated with the onset of cancer proliferation can potentially lead to better understanding of the onsets of cancer.

The prostate, a gland found in males that stores liquid that carries sperm, is highly susceptible to inflammation and cancer (Eisenburg Center, 2005). Prostate cancer is becoming increasingly common in adult males: In fact, in 1990 prostate cancer became the most frequently diagnosed cancer in men, constituting 29% of all cancers found in men (American Cancer Society, 2011). With such alarming numbers of incidence, prostate cancer has become a great health concern of epidemic proportions. However, the theory behind the recent drastic increases may not be solely attributable to an increase in the prevalence of the disease, but instead to new tests, such as the PSA (prostate-specific antigen) test. The PSA test allows for more accurate and determinate prostate cancer detection (Levy, 1995). Even though the higher number of reported cases appears daunting, the PSA test has had the positive effect of detecting the cancer earlier for effective treatment, resulting in decreasing mortality rates. Therefore, PSA tests may allow for prostate cancer to be detected at younger ages, resulting in more healthy, robust men being diagnosed with greater chances of survival with treatment (Hsing, Tsao, and Devesa, 2000).