Human Immunodeficiency Virus : Development Of The C B Chemokine Receptor 5

When the HIV virus was identified in the 1980’s, many companies began to search for an antiviral drug but Burroughs Wellcome led the research effort. There were three drugs being tested by other companies as well including, AZT by Burroughs Wellcome, DDI by Bristol Myers and DDC by Hoffman-LaRoche. These drugs inhibit reproduction of HIV and slow the damage it causes.

Human immunodeficiency virus (HIV) is serious public health problem worldwide. HIV weakens a person’s immune system by infecting the body’s T cells. ("About HIV/AIDS | HIV Basics | HIV/AIDS | CDC", 2016) HIV also attacks and kills CD4 white blood cells, which play an important role in protecting the body from infections. ("Immune System 101", 2016)

HIV is a quite detrimental virus that has caused much disruption during the 1980’s when it came to life. HIV is “one of the fastest evolving of all organisms” (Rambaut A. ET. Al. 2004) HIV has found ways in which to resist drugs and shows evolutionary mechanisms. The HIV virus has also

The ability of the virus to choose its co-receptor is called viral tropism and determines its virulence and disease progression rate. If the virus binds with the co-receptor CCR5 it is called macrophage-tropic (M-tropic) and characterizes most HIV infections. The M-tropic variant is regarded as less virulent because it is nonsyncytial. Some mutations of the CCR5 gene lead to a partial immunity to the virus and can slow the disease and in some cases prevent infection of the M-tropic HIV varient. Also patients with high levels of CCR5 soluble chemokines are more resistant to the virus.

Discovery of a natural mutation in the CCR5 protein that reduces HIV-1 infection, and the tendency for HIV-1 to select CCR5 co receptors for attachment and fusion promoted the development of CCR5 antagonists. A 32bp deletion in the CCR5 gene which creates a truncated receptor was discovered in Caucasian populations in 1996. After assessing DNA from individuals given through various families and by anonymous donors through the genetics department at the Erasme hospital in Brussels, scientist concluded roughly ~10% of people in the population contained this mutant allele. This 32bp deletion, creates a frameshift mutation that produces a non-functional CCR5 protein. The truncated non-functional CCR5 receptor is missing the third intracellular

The entry inhibitors were first approved by FDA in 2003 and their mechanism was to prevent the viruses from entering the target T cells. They are acting on the human CCR5 chemokine receptors to prevent viruses from attaching to the T cell, thus, avoiding entry. (Chereshenev et al., 2013). Fusion inhibitors such as enfuvirtide, are oligopeptides that prevents HIVs from entering host cells by blocking the cell fusion process (Chereshenev et al.) Nucleoside reverse transcriptase inhibitors are (NRTI) the first medication available to treat HIVs. When the viruses replicate, they have to use nucleosides to build their DNAs. Since the NRTIs chemically resemble the naturally occurring nucleosides, so when the viruses use

Resistant viruses can recognize, bind to and utilize the maraviroc/CCR5 complex for entry. Amino acid mutations in gp120 alters the way the protein interacts with CCR5. These modifications cause resistant viruses to be heavily reliant on the CCR5 N-terminus for entry (Roche et al 2015). There are two mutations on maraviroc resistant R5 HIV. These mutations replace Ala316 and Ile323 with Thr316 and Val323 on the V3 loop of the wild type HIV-1 CCR5 tropic strain. The Val323 mutation in the V3 loop of gp120 changes the secondary structure of the V3 loop making the loop less rigid and permits altered interactions with the N-terminus that allows for HIV-1 entry. A loss of beta sheets in the stem of the V3 loop occurs with the presence of the Val323 mutation. In addition, the smaller valine side chain may reduce steric interference and permit closer interaction with the residues on the N-terminus of CCR5. Thus, the Val323 mutation makes the V3 loop more fluid, allowing for closer interactions with the N-terminal of CCR5. In the presence of Maraviroc, HIV-1 resistant strains become considerably dependent on the interaction with N-terminal residues Try3, Tyr10, Tyr13, Tyr14, Tyr15, Glu 18, and Asp11.

HIV is a retrovirus that will constantly attack human’s immune system once an individual is infected and will eventually develop to AIDS, often a deadly sexually transmitted disease. Currently, there are different kinds of antiretroviral treatments available for patients who are tested to be HIV positive as well as patients with AIDS. HIV can easily develop resistance to its treatment through mutation each generation, which leads to ineffectiveness in treatment. The only way to continue to fight off HIV is to change treatment that is still available. Patients have to cooperate with experienced doctors by adhering to their professional recommendations, while doctors are responsible

HIV, a virus only discovered in the late 1970s, has now become the most lethal virus around the world (UNAIDS, 2008). Scientifically HIV is a kind of virus which can destroy human’s immune system. Then, without defense of the body, other virus can easily infect body and ultimately results in death (WHO, 2013). Till the end of 2012, 35.3 millions of people live with HIV (WHO, 2013) and large quantities of family members suffer from the pain. Yet such a lethal disease only has three simple transmissions, through unprotected sex, blood, and maternal-neonatal pregnancy. However, the high mortality rate suggests that there is an urgent need to investigate deeper causes of HIV

AIDS is an extraordinarily serious disease and scientists have failed, thus far, to find a cure. AIDS, or acquired immune deficiency syndrome, develops from the human immunodeficiency virus, HIV (“What is AIDS” par 3). HIV is not the same thing as AIDS; HIV merely turns in to AIDS after a certain amount of time (“What is AIDS” par 4). HIV is also not a curable disease. HIV is a special type of pathogen, known as a retrovirus. This virus has to attach to a host cell in order to live and spread. What makes AIDS so deadly is that it targets the body’s lymphocytes, the cells that normally fight off infection (Nolen 4). Lymphocytes have CCR5 and CD4 molecules on their surface, when HIV enters the body, it attaches itself to these molecules. (Nolen 4). Once the virus has attached to the

Despite of the irrevocable efficacy of cART, therapy is not a cure for HIV-AIDS, as interruption of treatment inevitably lead to viral rebound in most individuals (Davey et al., 1999). HIV/SIV persistence in the form of latently infected cells that decayed very slowly was demonstrated using the PBMCs isolated from patients (Finzi et al., 1997, Finzi et al., 1999, Siliciano et al., 2003). Subsequent characterization of HIV-1 latent infection and testing of latency reversing agents utilize both molecular and cellular methods (Spina et al., 2013, Mbonye and Karn, 2014). Molecular biology is also instrumental in discovering clonal expansion of infected cell as another mechanism for HIV-1 persistence (Maldarelli et al., 2014, Wagner et al.,

Also, due to the widespread infection of HIV there has been a determination for the discovery and use of medicinal agents that can inhibit the virus. HIV type-1 (HIV-1) displays extraordinary genetic variation and can be phylogenetically classified into three

Introduction. Human immunodeficiency virus type 1 (HIV-1) has infected over 33.2 million people world-wide to date [9]. There is a plethora of new and upcoming drugs that are being used to combat against human immunodeficiency virus. Although effective, the drugs that are being used to combat against HIV-1 have also been known to cause resistance, adverse effects and toxicity to the mitochondria [3]. HIV-1 is a retrovirus that belongs to a subfamily of retroviruses called lentiviruses [8]. HIV-1 causes a slow depletion of the immune system and is considered a slow degenerative disease. New drugs that combat against HIV-1 entering into different cells has raised interest due to the fact that these new drugs are able to work against drug resistant viruses that can infect the cell.

According to WHO there are 35 million people globally who are affected with HIV and one in seven people are unaware of being infected. Therefore it becomes an increasingly important concern to target and cure this epidemic on a global scale. That is not the end of the story though; immunocompromised individuals are even more susceptible to opportunistic HIV infections. These pathogens, which come in different varieties such as bacteria, viruses, protozoans and fungi slowly, deteriorate the host by mounting an immense attack causing HIV induced malignancies.

These drugs are effective against a wide range of wild-type and drug resistance HIV, including the strains that use CCR5 or CXCR4 coreceptors for entry into the host cell.