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.

An Emerging Influenza Vaccine

            Throughout history, the influenza virus has proven to be highly problematic for human beings.  Various epidemics have spread across the globe and taken many lives, including the recent avian flu (H5N1) and swine flu (H1N1).  While the virus itself does cause a lot of harm, it is often pneumonia caused by Staphylococcus aureus (S. aureus), which results from the influenza infection, that often proves to be fatal (1).  Virologists have been looking for a vaccine that would help not only to prevent influenza infection, but also to deter S. aureus infection.  In their journal article, Dai et al. explain how they found a conserved section of the protein HA which can be made into a vaccine and coupled with the bacterial antigen Ag85A to do just that.

            The HA protein in Influenza A Virus (IAV) holds domains necessary for viral attachment to host cells.  To activate this protein, the virus cleaves it into two domains: HA1 and HA2.  The host often deploys an immune response that targets antibodies to the HA protein, which prevents IAV virions from attaching to the host cells (2).  While this is temporarily affective, IAV tends to evolve very rapidly, so vaccines geared towards the HA protein become outdated very quickly (3).  However, the HA2 domain has been seen to remain highly conserved over virus generations, and the majority of the mutations can be attributed to the HA1 region.  Therefore, it seems reasonable that if antibodies were made to target the HA2 region specifically, then they would be able to be effective for longer periods of time (4).

            Ag85A is an antigen secreted by the bacteria Mycobacterium tuberculosis (M. tuberculosis).  As a vaccine, Ag85A was known to increase the production of T helper 1 (TH1) cytokine responses to M. tuberculosis (5), which in turn lead to an increase in the expression of toll-like receptor 2 (TLR2).  TLR2 recognizes molecules specific to Staphylococcus species and activates immune responses to them (6).  Therefore, Ag85A could act as a vaccine for S. aureus.  Dai et al. hypothesized that combining the HA2 domain of the HA protein and Ag85A into a single vaccine would create both an effective antibody response to IAV and antibacterial response to S. aureus, preventing both influenza and the potentially lethal pneumonia that tends to follow.

Who's responsible?

Did you know that termites are actually incapable of consuming plant material on their own? It's true: they rely on a host of bacterial helpers that reside in their gut to break down their food for them. In turn, the bacteria depend on the host for this supply of raw energy (3). This is a classic example of mutualistic symbiosis, where two organisms benefit from each others' presence (in nature, this can be in the form of chemical aid as mentioned above, or may come in some other form, like protection/shelter).

Why should we care? Well, to better understand cause and effect relationships in nature, we need to be aware of all the components that are playing a role. For example, imagine if there was such a scenario where the flu virus actually infected and resided within helpful bacteria that lived in our lungs, and not us directly (and the cause of sickness were due to the death of these bacteria). If this imaginary flu-carrying bacterium turned out to be unable to survive on skin and other common surfaces but ultra-resilient as an airborne pathogen, then our whole idea of flu transmission would be wrong, and health policy would need be reformed; people would be far less concerned with washing their hands and sanitizing surfaces, and would start wearing masks. To take full advantage of our surroundings, we need to fully understand our surroundings.

Such may be the case with the Tomato yellow leaf curl virus (TYLCV). As its name might suggest, the acquisition of this disease by tomatoes causes a curling/shriveling of the leaf, a yellow discoloration, stunting of plant growth, and more (2), and can result in complete loss of tomato crop; this, consequently, leads to disastrous economical impacts. In a study by Su et al., it was found that the incidence of TYLCV infection correlated strongly with the presence of a bacterial symbiont of whitefly Bemisia tabaci. B. tabaci is known to transmit this virus, but what we did not know previously is that symbiont Hamiltonella is likely responsible for its intense transmission.

Identifying a deadly foodborne bacteria: What’s virus got to do with it?

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--A recent study uses a new approach to investigate the shiga toxin producing bacteria responsible for a serious disease outbreak in Germany in 2011. The real culprits behind the outbreak are the viruses that carry the gene for shiga toxin and transfer it to otherwise harmless bacteria  --

            What’s harder than finding a needle in a haystack? Finding the bacterial genome you’re looking for in a diarrhea sample. A recent study published on April 10, 2013 in the Journal of the American Medical Associaton (JAMA) made this task seem relatively easy. The bacteria being searched for was a  rare shiga toxin producing bacteria that causes bloody diarrhea and other severe complications in humans upon infection. This study was done by an international team of researchers coordinated by Mark J. Pallen who recently became the head of Warwick Medical School’s new Division of Microbiology and Infection. The bacterial strain that caused an outbreak in Germany was especially rare making it hard to identify. Because of this, researchers employed a new method to identify the genome sequence of this highly pathogenic bacteria. Their method of detection was to sequence all the genetic material present in fecal samples from patients with diarrhea during the outbreak and sort through this genetic information to find the sequence of the disease causing strain.

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            The source of the outbreak in Germany during the summer of 2011 is believed to be from the consumpton of raw sprouts contaminated with the dangerous bacteria strain (2). This outbreak affected thousands of people in a wealthy, modern, industrialized society, causing more than 50 deaths (4). In times like this, quick identification of the causative pathogen (in this case a shiga toxin producing bacterial strain) is critical for the management of the outbreak. Traditionally, the standard for identifying pathogens in clinical samples is to isolate the disease causing bacteria from other microbiota in the samples and then sequence it once it is in pure culture. This study's approach is different becuase they directly sequenced the mixed communities of bacteria and anything else present within the feces sample and then analyzed the sequence data to find the disease causing bacteria. The sequencing of mixed microbial communities is called metagenomics and allows identification independent of laboratory isolation and culture of the causative bacteria.

Nipah Virus: a real life Contagion?

A newly emergent, deadly virus

            Throughout the last fifteen years, a highly fatal virus has emerged.  Since its first discovery in 1998, Nipah virus has infected nearly 500 people throughout Asia, and produced a mortality rate greater than 50% (1).  Nipah virus can be spread from either human-animal or human-human contact.  During the first outbreak of Nipah, transmission occurred primarily via respiratory droplets from infected pigs in Malaysia (2).  On the other hand, some of the outbreaks in India and Bangladesh were most likely due to contact with fruit bat saliva or urine (1).  In addition, some of the more recent cases of Nipah were transmitted directly from person to person, with many of the infections occurring in a hospital setting (1).  At first, Nipah virus symptoms resemble those of the flu, as many patients report headaches, muscle pains, vomiting, and a sore throat (1).  However, as the disease progresses, people experience encephalitis, and possible respiratory illness (1).  In serious cases, Nipah can lead to coma and death (1). There currently are no vaccines or treatment options for Nipah.

            Nipah virus is a member of the Paramyxoviridae family (2).  It is closely related to the Hendra virus, which causes similar respiratory and neurological symptoms (3).  Nipah virus is a (-) sense, single-stranded RNA virus that contains a nonsegmented genome (2).  Because Nipah is such a fatal virus, and there are no vaccines or treatment options available, there is little known about it.  All research involving Nipah must be completed at BSL-4 facilities containing the highest possible levels of security and safety.  Recently, researchers at the Institute of Virology, Philipps University of Marburg, Germany investigated how Nipah virus enters and exits an infected epithelial cell.   Although researchers have clinically proven that Nipah infects epithelial cells in the respiratory and urinal tracts, the mechanisms behind this are largely unknown.

Researching the unknown Nipah virus

            The first major objective of this study was to observe the mechanisms of Nipah virus (NiV) entry into a polarized epithelial cell.  To start, the researchers observed the distribution of the NiV entry receptors on the cells.  Specifically, they looked at the ephrin receptor expressions on polarized kidney epithelial cells (MDCK).  The researchers found an even distribution of ephrin throughout the apical and basolateral surfaces of the cell.  Then, MDCK cells were selectively infected to either the apical or basal filter chamber; and immunostained for presence of NiV in the cell.  As expected, NiV was able to infect the MDCK cells regardless of the surface domain.  Thus, NiV entry was found to be bipolar.

Bacterial Infection? ...Have a dose of virus.

            When you go to a hospital, you typically expect it to make you better, not get you sicker. Unfortunately, hospitals are filled with bacteria, many of which ‘prey’ on patients with weakened immune systems and preexisting health issues. One such bacterium is klebsiella, a genus of Enterobacteriaceae. This bacteria is estimated to cause nearly 8% of all nosocomial (hospital-acquired) infections each year (Podschun, 1998). Klebsiella pneumoniae is normally found growing in places such as the mouth and on skin, but it can create health issues if it enters the lungs, causing inflammation, hemorrhaging, and necrosis of lung tissue. It is especially dangerous if bacteria have developed antibiotic resistance, as an increasing number of hospital-acquired infections have done.

            This resistance is coded for in plasmids (small, circular, transferrable bits of DNA) that the bacteria pick up. A common protein that causes antibiotic resistance is beta-lactamase. This enzyme, breaks open the beta-lactam ring in antibiotic molecules containing this structure, thereby deactivating them. Penicillin is one such beta-lactam-based antibiotic. It is widely used to treat bacterial infections, and resistant bacterial strains are a large reason for concern. While there are other antibiotics that can be used, some of these bacteria have extended-spectrum beta-lactamase genes, which makes them even more efficient at denaturing a wider range of beta-lactam antibiotics. In poorer areas, where less common antibiotics are harder to come by, this is even more of an issue. In 2003, over half of the antibiotics in use were beta-lactam compounds (Elander, 2003).

            These infections add time to hospital stays. Not only is this an inconvenience, but it is also an economic drain on the hospitalized individual. These types of infection are also prominent in intensive care units, where patients are already suffering from depressed immune systems, and an added infection without the help of antibiotics can kill a patient.

            For this reason, the search for alternate antimicrobials is a high priority. Bacteriophages (viruses that only infect bacteria) hold great promise in this area, but to be effective, they must be able to infect a wide host of bacteria. There are four types of host resistance mechanisms to bacteriophage infection: adsorption inhibition, blocking of DNA injection, restriction-modification, and abortive infection (Weinbauer, 2004). The host restriction system is one of the best-studied parts of this system. In “Characterizing the biology of novel lytic bacteriophages infecting multidrug resistant Klebsiella pneumoniae,” Kesik-Szeloch et al. culture and screen a number of bacteriophages for the pathogenicity in Klebsiella, and their abilities to resist host restriction-modification mechanisms.