HIV

=__Disease/Drug of interest: __= = HIV/Enfuvirtide =

Motivation and Background:
The human immunodeficiency virus or HIV has been notorious for infecting large populations around the world. It has been determined that the disease originated from chimpanzees of Central Africa. The most common type of this virus is HIV Type 1 and is responsible for infecting people across the globe. If left untreated, the disease can turn into the acquired immunodeficiency syndrome or AIDS. Today, about 36.7 million people live with HIV/AIDS. Of this infected population, 1.8 million are children. In 2015 alone, 2.1 million individuals were infected with this immunocompromising disease. The problem with this disease is that once the virus has begun infecting the body’s cells, there is no way to get rid of it; once a person has HIV, they have it for life. This is a major reason why research be focused towards studying the ailment. HIV is a disease that can severely compromise the health and wellness of everyone in the global population if research is not done to prevent its spread.

HIV attacks the CD4 cells (T cell), a type of white blood cell that play an essential role in fighting diseases, of the human body. HIV targets these cells and destroys them, causing a deficiency over time that could then allow for opportunistic infections to take advantage of the body. This weakened state usually signals the onset of AIDS, the final stage of HIV. Symptoms of HIV include fever, chills, rash, night sweats, muscle aches, sore throat, fatigue, swollen lymph nodes, and mouth ulcers. The best way to tell if the HIV virus is present within an individual is to get an HIV test. The most common way HIV is spread is through sexual behaviors and needle/syringe use. Only certain bodily fluids transmit HIV. These fluids include blood, semen, pre-seminal fluid, vaginal fluids, and breast milk. Transmission occurs when these infected fluids encounter damaged tissue, mucous membranes, or the blood stream. A property of HIV that makes it difficult to cure is mutation. HIV is constantly mutating and because of this it is nearly impossible to find a drug that can cure it. If more research is done, maybe its mutating nature can be controlled, allowing for the creation of a cure.

 Figure 1. Human CD4 cell (blue) under attack by HIV (yellow)


 * References: **
 * 1) Buzon, V.; Natrajan, G.; Schibli, D.; Campelo, F.; Kozlov, M. M.; Weissenhorn, W., Crystal structure of HIV-1 gp41 including both fusion peptide and membrane proximal external regions. //PLoS Pathog// **2010**, 6 (5), e1000880.
 * 2) Dai, Z.; Tao, Y.; Liu, N.; Brenowitz, M. D.; Girvin, M. E.; Lai, J. R., Conditional trimerization and lytic activity of HIV-1 gp41 variants containing the membrane-associated segments. //Biochemistry// **2015**, 54 (8), 1589-99
 * 3) Hardy, H.; Skolnik, P. R., Enfuvirtide, a new fusion inhibitor for therapy of human immunodeficiency virus infection. //Pharmacotherapy// **2004**, 24 (2), 198-211.
 * 4) Matthews, T.; Salgo, M.; Greenberg, M.; Chung, J.; DeMasi, R.; Bolognesi, D., Enfuvirtide: the first therapy to inhibit the entry of HIV-1 into host CD4 lymphocytes. //Nat Rev Drug Discov// **2004**, 3 (3), 215-25.

External links:

 * 1) What is HIV/AIDS? https://www.aids.gov/hiv-aids-basics/hiv-aids-101/what-is-hiv-aids/ (accessed 1/28/17).
 * 2) Symptoms of HIV. https://www.aids.gov/hiv-aids-basics/hiv-aids-101/signs-and-symptoms/ (accessed 1/28/2017).
 * 3) How Do You Get HIV or AIDS? https://www.aids.gov/hiv-aids-basics/hiv-aids-101/how-you-get-hiv-aids/ (accessed 1/28/17).
 * 4) Human Immunodeficiency Virus (HIV). https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0025049/ (accessed 1/28/2017).
 * 5) Enfuvirtide. https://pubchem.ncbi.nlm.nih.gov/compound/16130199#section=Top (accessed 1/28/2017).
 * 6) Enfuvirtide. https://aidsinfo.nih.gov/drugs/306/enfuvirtide/0/patient (accessed 2/1/2017).
 * 7) Maraviroc. https://aidsinfo.nih.gov/drugs/408/maraviroc--hiv-treatment/0/patient (accessed 2/1/2017).

=__Target Information: __= The gp41 protein is an important part of the HIV-1 envelope glycoprotein complex that is responsible for catalyzing virus entry into a host cell. After gp120, another protein subunit of this complex, interacts with the cellular surface of the CD4 cell, it triggers a conformational change that forms a trimeric six-helix bundle. This bundle provides an energy driving force that allows the gp41 subunit to become energetically stable, causing an increase in potential energy that facilitates the fusion of the viral and host cell membranes. Without this protein, the glycoprotein complex that facilitates invasion of the host would be impossible.

Size:
Since the virus is constantly mutating there is not just one strain of this protein. Because of this, the protein has many variants of variable masses and lengths.

Location:
The gp41 protein is an important part of the HIV-1 envelope glycoprotein complex that is responsible for catalyzing virus entry into a host cell.

Function in a normal cell:
The gp41 protein is not regularly found in the body because it is specifically a part of viruses such as HIV; however, other viruses do have proteins like the gp41. These other proteins are important parts of their glycoprotein complexes and are responsible for allowing the virus to infect host cells. In HIV, gp41 is responsible for a conformational change that then provides energy for the virus to bind to the host cell.

[[image:gp41.png width="289" height="405"]]
Figure 2. Crystal structure of gp41528–683 reveals a 90 Å long rod-like structure =__Drug Information: __= Enfuvirtide is one of the only fusion inhibitor drugs that is approved by the Food and Drug Administration for treatment of HIV. The drug mimics the activity of the HR2 sequence and competitively binds to gp41, not allowing for the interaction between HR1 and HR2. This inhibition prevents the conformational change in the gp41 from occurring, and stops the fusion of the host cell and the virus. When successful, enfuvirtide can treat the symptoms associated with the virus and can stop it from cloning. The drug, however, can be ineffective in some strains of the virus as mutations are very common with HIV.

Schematic figure of drug:
Figure 3. Schematic figure of enfuvirtide

<span style="font-family: Arial,Helvetica,sans-serif;">Formula:
C204H301N51O64

<span style="font-family: Arial,Helvetica,sans-serif;">Molecular weight:
4491.945 g/mol

<span style="font-family: Arial,Helvetica,sans-serif;">CAS Number:
<span style="font-family: Arial,Helvetica,sans-serif; font-size: 11pt;">159519-65-0

<span style="font-family: Arial,Helvetica,sans-serif;">Delivery method:
<span style="font-family: Arial,Helvetica,sans-serif; font-size: 11pt;">The delivery method of enfuvirtide is via injection.

<span style="font-family: Arial,Helvetica,sans-serif;">Side effects:
Side effects of the drug include diarrhea, nausea, headache, and dizziness.

<span style="font-family: Arial,Helvetica,sans-serif;">Other names:
Fuzeon

<span style="font-family: Arial,Helvetica,sans-serif;">Maker or company:
<span style="font-family: Arial,Helvetica,sans-serif; font-size: 11pt;">The drug was invented at Duke University; however, it is manufactured by Hoffman-La Roche

<span style="font-family: Arial,Helvetica,sans-serif;">Is it patented?
<span style="font-family: Arial,Helvetica,sans-serif; font-size: 11pt;">Yes, the Duke University holds the patent for the drug.

<span style="font-family: Arial,Helvetica,sans-serif;">Clinical Trials Info:
<span style="font-family: Arial,Helvetica,sans-serif; font-size: 11pt;">The drug has been involved with 65 clinical trials that have been completed, ongoing, or terminated. In some clinical trials, it has been found that the mutations HIV goes through can sometimes render the drug useless as resistance develops.

<span style="font-family: Arial,Helvetica,sans-serif;">__Origin__:
<span style="font-family: Arial,Helvetica,sans-serif; font-size: 11pt;">The drug is derived from a naturally occurring amino acid sequence called heptad repeat 2 (HR2) found in the gp41 protein.

Currently, the alternatives for enfuvirtide are limited. This drug is one of few drugs that has been approved by the FDA to block the entry of HIV. The only other drug that is licensed and approved to block the entrance of HIV is maraviroc. It works by attaching proteins called CCR5 proteins to certain immune system cells. When this happens, certain strains of HIV are inhibited from attaching to host cells.
 * Alternatives to this drug ** :

There are no other uses for enfuvirtide. If in the future other viruses hold the gp41 protein, enfuvirtide may be able to inhibit them as well.
 * Other uses ** : can this drug be used to treat other diseases/conditions?