CCR1 Case Study

Enhance the affinity of the recognition site for GABA by inducing conformational changes that make GABA binding more efficacious.

The HIV life cycle occurs in six stages namely; Fusion, Reverse transcription, Integration, transcription, assembly, and budding. Inorder for the virus to proceed to each stage and continue to replicate into new viral cells, it requires catalytic enzymes such as reverse transcriptase (RT), Intergrase (IG), and protease (PT). These replicating enzymes and cycle phases have been identified as potential therapeutic drug targets for HIV-therapy (Fig 2), therefore leading to the development of novel anti-retroviral drugs as stated below;

C- Reactive protein (CRP) is a protein found in the plasma that is released when tissue damage, infection or inflammation occurs within the body.1 C-Reactive Protein, a member of the pentraxin family of proteins is comprised of 206 amino acids folded into two antiparallel beta sheets with a flattened jellyroll topology. Within the interior portion of the protomer, there is a cleft that is formed which at one end contains the C1q and FcR binding sites and at the other end are Ca2+ ion and PCh (Phospocholine) responsible for the binding ligands. This structural orientation of sites and ions allows the protomer to have two faces, the recognition face with the PCh binding sites and an effector face with the C1q and FcR binding sites. (Volankavis)2

Our chosen article is titled “HIV and AIDS News and Updates: New Strain of HIV Found in Cuba Which Can Develop Into a Full-Blown AIDS in a Span of Only 3 Years” written by Steff Lyn Smetham. It was published on November 5th, 2015 on the Crossmap online website. The article was written to inform the readers on a newly discovered strain of HIV, which develops faster than the average known types of HIV. This article mentioned many recently studied concepts including, the rate of disease progression, CRF19’s involvement in the AID’s rapid progression (AID’s-RP), the adverse effects of RANTES defense molecules, and proper HIV treatment. The general consensus is that the average rate of disease progression takes approximately 5 to 10 years to progress into AIDS, however, it is quite complicated to pinpoint the rate due to many factors. Based on many clinical studies done with a diverse group of patients in Cuba, CRF19 has shown to be one of the main recombinant subtype responsible for AIDs-RP. In addition, CCL5 and CCL2 of the RANTES family, have proven to be two specific chemokines that display the adverse effects . Finally, regardless of CD4+ count, treatment should be started immediately preferably with the common therapies Isoniazid preventive therapy (IPT) and Co-trimoxazole preventive therapy (CPT). The authors have used information through studies being done at the University of Leuven located in Belgium, and Professor Anne-Mieke Vandamme and a team

Namely, in TRAV4*01 type II TCR complex, the TCR interacted predominately through the non-germline encoded CDR3 loop region, with both the α- and β-chain contributing equally to the BSA of TCR/CD1d interface, whereas the interaction in type I NKT TCR-mCD1d-Ag is largely germline-mediated and primarily driven by the CDR loops encoded within the α-chain.(Rossjohn et al., 2012). However, the TRAV4*01 TCR-mCD1d framework was found to be much similar to that of type II TCR-CD1d complexes determined to date. It, therefore, remained an interesting question as to why TRAV4*01 type II TCR required a type I NKT TCR-like recognition mode to establish type II NKT TCR footprint? It may be possible that TRAV4*01 type II TCR prerequisite type I like docking mode for its positive selection in the thymus. Interestingly, the tyrosine motif (Tyr49β & Tyr51β) of CDR2β which is regarded as a “key recognition codon” central in the binding orientation of the majority of type I NKT TCR population (Wun et al., 2008) is well-preserved in TRAV4*01 type II TCR. Notably, the tyrosine

Since its discovery in 1981, the scientific community has put up with the struggle of finding a vaccine for the human immunodeficiency virus, or HIV, the root cause of AIDS or acquired immune deficiency syndrome. Although numerous advancements in combating the virus have helped to reverse the epidemic, there is still no known cure. However, recent studies have shown some results that may possibly be the precursors to eradicate the disease. One example would be the trials of a possible vaccine conducted on primates at both Paris-Descartes University and at the University of Chinese Medicine in Guangzhou. Along with finding a vaccine, an alternative method has been proposed in Time Magazine with altering the CCR5 gene in cells, which is

HIV infects cells from the immune system by binding to CD4 receptors on the host cells’ surface. CD4 positive cells release cytokines to activate the production of antibodies and cytotoxic T cells [1]. After CD4 cells enter the host cell, HIV-infected and non-infected cells can die in a number of ways [6]. If CD4 cells die, then the

The ubiquitous nature of the NDV receptor allows for utilization of the virus against a wide variety of cancers. The specificity of the virus for cancer cells due to their defects in antiviral and apoptotic pathways ensures viral safety and may obviate the need for specific tumor targeting. NDV has been shown to replicate in cancer cells possessing various defects in antiviral and apoptotic signaling pathways.

G Protein Coupled Receptors (GPCR) is one of the largest known class of membrane protein receptors which constitute more than 1% of the human genome (Xavier et al., 2007). GPCRs are widely expressed in human body and have an important role in various cell signaling events. Their functions are diverse in peripheral organs and brain, being such an important receptor in signaling has made it an attractive target for various disease pathology. Therefore, obtaining ligands of novel scaffolds by high through put screening on certain receptor families of GPCRs could be a viable strategy to get a new lead molecule with a better potency and selectivity. GPCRs share a common structural architecture of seven transmembrane helix with an extracellular

The HIV-1 diploid RNA genome is encapsulated in a lipid bilayer studded on the exterior surface with glycoproteins (reviewed by Weiss, 2013). These glycoproteins are composed a trimeric structure of three transmembrane proteins (gp41) bound to a trimeric surface glycoprotein (gp120), which together are called the envelope protein (ENV). GP120 is highly glycosylated and forms a protective glycan shield around the viral envelope. Both gp120 and gp41 can participate in binding to the CD4 epitope on the surface of T-helper cells and macrophages, thereby initiating HIV-1 infection of critical immune cells. However, progression to the point of fusing the viral lipid bilayer with the cytoplasmic membrane of CD4+ cells requires the added

First of all, we need to define what is “The human immunodeficiency virus (HIV)”. HIV is a virus and it is considered a lentivirus (family of Retroviridae). This virus causes acquired immunodeficiency syndrome (AIDS). HIV was discovered and considered the agent of the emerging AIDS epidemic by the team of the scientific Luc Montagnier in France in 1983. The virus is spherical, equipped with a jacket and with a capsid protein. Virus’s genome is a single-stranded RNA strand DNA and must be copied temporarily to multiply and integrate into the genome of the cell it infects. Protein antigens of the outer casing are coupled specifically with membrane proteins of the infectable cells, especially CD4 T lymphocytes.

Aside from getting HIV from chimpanzees, HIV can also be obtained through unprotected sex, using an unsterilized needle, childbirth, breastfeeding, or blood to blood contact. Once inside the bloodstream the HIV virus will infect certain white blood cells, primarily the CD4 T cells. The HIV’s outer envelope consist of glycoproteins that mutates frequently, causing the CD4 T cells to not recognize the virus as a threat (_). The CD4 T cells will then allow the virus to bind its GP120 onto the Help T cell receptor/coreceptor, also known as CCR5. After binding to its host cell the virus transmembrane (GP41) will then pull the virus closer to the host cell, ultimately allowing the virus to fuse into the host cell. Once fused, the virus nucleocapsid will then enter into the cell and release two viral RNA strands and three replication enzymes: reverse transcriptase, integrase, and protease. The virus will then replicate and migrate to other white blood cells, infecting and killing the cells. HIV infection will advance through three stages

HIV uses the coreceptors, CCR5 and C-X-C chemokine receptor type 4 (CXCR4), on the CD4+ helper T-cell to infect the cell. (19) After the virus has infected the cell it integrates its own DNA with long terminal repeats into the host genome. Researchers are currently studying zinc finger nucleases (ZFNs) to create this ∆ 32 mutation in the CCR5 and CXCR4 gene as way of preventing further infection. Along with use of ZFNs to remove long terminal repeats of the provirus HIV from the host genome. This review will discuss the molecule techniques used for diagnoses and possible treatment for HIV-1 using ZFNs.

There has been countless number of efforts to develop an effective gene transfer approach to treat HIV-1 infections globally. Many transgenes have been identified to inhibit in vitro HIV-1 infections. As drug resistant HIV-1 is increasingly common even with patients receiving HAART, designing drug treatment methods have been challenging. Therefore, investigation into new therapeutic approaches should continue. Gene delivery plays an important supporting role developing potential therapies directed towards HIV-1 infections. The goals of the anti-HIV-1 gene therapy are to deliver transgenes to directly susceptible cells, Immunize against HIV-1 antigens, inhibit HIV-1 proliferation in target organs, and deliver to Hematopoietic Progenitor Cells. Delivering transgenes to susceptible cells will make them resistant to HIV-1 infections and inhibit viral replication. When CCR5 a major coreceptor for HIV was disrupted in the “Berlin Patient” led to the revival of gene therapy. The naturally occurring CCR5-Δ32 mutation that results in a frameshift mutation dislocates the CCR5 expression on the cell surface. The “Berlin patient” who was HIV+ patient with lymphoma was transplanted with bone marrow from a donor with CCR5-Δ32 mutation and became ‘cured’ of HIV. But as only a small general population with CCR5-Δ32 mutation can be identified alternative methods must be identified for gene therapy.

Human chromosome 3p21–22 harbors a cluster of chemokine receptor genes, several of which serve as major or minor co-receptors of HIV-1 [1]. The genetic associations of CCR5 and CCR2 gene polymorphisms with HIV-1 pathogenesis are well known [2-5], but any potential role of variation in other regions of the cluster is largely unknown. An intergenic SNP (rs1015164 A/G) downstream of the CCRL2 gene was shown to associate with HIV viral load control [6] and progression to AIDS [7] in two independent cohorts of HIV-infected patients. Importantly, the SNP showed genome-wide significant association with HIV outcomes in meta-analyses that collectively examined genotyping data from 6,315 HIV-infected patients [8]. The SNP is in close genomic proximity to a non-coding RNA gene RP-11-24F11.2 (Fig. S1). We were able to detect and quantify the polyadenylated lncRNA transcript in the total RNA from peripheral blood lymphocytes (PBLs) using quantitative PCR (qPCR). Specificity of the primers was confirmed by sequencing of the amplicons. We designated this lncRNA as Lnc11.2. The rs1015164A allele, which associated with higher viral loads (OR=1.4, p=3.3 ×10-5) [6] and more rapid disease progression (HR=1.4, p=8.6 ×10-6) [7] correlated with higher expression levels of Lnc11.2 in PBLs (Fig. 1).