HIV tropism

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Cells from rhesus macaques, clustered by cell type. Red cells are from monkeys infected with simian-human immunodeficiency virus, while blue cells are from uninfected ones. Mapping SHIV infection in the body, 2018 - Wellcome Photography Prize 2019 (bottom right, cropped).jpg
Cells from rhesus macaques, clustered by cell type. Red cells are from monkeys infected with simian-human immunodeficiency virus, while blue cells are from uninfected ones.

HIV tropism refers to the cell type in which the human immunodeficiency virus (HIV) infects and replicates. HIV tropism of a patient's virus is measured by the Trofile assay.

Contents

HIV can infect a variety of cells such as CD4+ helper T-cells and macrophages that express the CD4 molecule on their surface. HIV-1 entry to macrophages and T helper cells is mediated not only through interaction of the virion envelope glycoproteins (gp120) with the CD4 molecule on the target cells but also with its chemokine coreceptors.

Macrophage (M-tropic) strains of HIV-1, or non-syncitia-inducing strains (NSI) use the beta-chemokine receptor CCR5 for entry and are thus able to replicate in macrophages and CD4+ T-cells. [1] These strains are now called R5 viruses. [2] The normal ligands for this receptor—RANTES, macrophage inflammatory protein (MIP)-1β and MIP-1α—are able to suppress HIV-1 infection in vitro. This CCR5 coreceptor is used by almost all primary HIV-1 isolates regardless of viral genetic subtype.

T-tropic isolates, or syncitia-inducing (SI) strains replicate in primary CD4+ T-cells as well as in macrophages and use the alpha-chemokine receptor, CXCR4, for entry. [1] These strains are now called X4 viruses. [2] The alpha-chemokine SDF-1, a ligand for CXCR4, suppresses replication of T-tropic HIV-1 isolates. It does this by downregulating the expression of CXCR4 on the surface of these cells.

Viruses that use only the CCR5 receptor are termed R5, those that only use CXCR4 are termed X4, and those that use both, X4R5. However, the use of a coreceptor alone does not explain viral tropism, as not all R5 viruses are able to use CCR5 on macrophages for a productive infection. [1]

Trofile assay

The Trofile assay is a blood test that identifies the tropism of a patient's HIV. [3] A molecular assay, Trofile was developed by Monogram Biosciences for use in HIV treatment. The assay's purpose is to identify the tropism of an individual patient's HIV strain – R5, X4, or a combination of these known as dual/mixed (D/M). The results show whether the patient is infected with virus that enters cells using the R5 co-receptor, the X4 co-receptor, or both (dual/mixed). Patients with strains of HIV that prefer the R5 receptor tend to remain healthy longer than those with the strains that prefer X4. However, over the course of the disease, a patient's viral population may undergo a "tropism switch" from R5 to X4.

Related Research Articles

HIV Human retrovirus, cause of AIDS

The human immunodeficiency viruses (HIV) are two species of Lentivirus that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive. Without treatment, average survival time after infection with HIV is estimated to be 9 to 11 years, depending on the HIV subtype. In most cases, HIV is a sexually transmitted infection and occurs by contact with or transfer of blood, pre-ejaculate, semen, and vaginal fluids. Research has shown that HIV is untransmittable through condomless sexual intercourse if the HIV-positive partner has a consistently undetectable viral load. Non-sexual transmission can occur from an infected mother to her infant during pregnancy, during childbirth by exposure to her blood or vaginal fluid, and through breast milk. Within these bodily fluids, HIV is present as both free virus particles and virus within infected immune cells.

Chemokine

Chemokines, or chemotactic cytokines, are a family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, as well as other cell types, including endothelial and epithelial cells. In addition to playing a major role in the activation of host immune responses, chemokines are important for biological processes, including morphogenesis and wound healing, as well as in the pathogenesis of diseases like cancers.

CCR5 Immune system protein

C-C chemokine receptor type 5, also known as CCR5 or CD195, is a protein on the surface of white blood cells that is involved in the immune system as it acts as a receptor for chemokines.

Viral pathogenesis is the study of the process and mechanisms by which viruses cause diseases in their target hosts, often at the cellular or molecular level. It is a specialized field of study in virology.

Following infection with HIV-1, the rate of clinical disease progression varies between individuals. Factors such as host susceptibility, genetics and immune function, health care and co-infections as well as viral genetic variability may affect the rate of progression to the point of needing to take medication in order not to develop AIDS.

CXCR4 Protein

C-X-C chemokine receptor type 4 (CXCR-4) also known as fusin or CD184 is a protein that in humans is encoded by the CXCR4 gene. The protein is a CXC chemokine receptor.

A co-receptor is a cell surface receptor that binds a signalling molecule in addition to a primary receptor in order to facilitate ligand recognition and initiate biological processes, such as entry of a pathogen into a host cell.

Entry inhibitors, also known as fusion inhibitors, are a class of antiviral drugs that prevent a virus from entering a cell, for example, by blocking a receptor. Entry inhibitors are used to treat conditions such as HIV and hepatitis D.

Host tropism is the infection specificity of certain pathogens to particular hosts and host tissues. This type of tropism explains why most pathogens are only capable of infecting a limited range of host organisms.

Maraviroc Antiretroviral drug

Maraviroc, sold under the brand names Selzentry (US) and Celsentri (EU), is an antiretroviral drug in the CCR5 receptor antagonist class used in the treatment of HIV infection. It is also classed as an entry inhibitor. It also appeared to reduce graft-versus-host disease in patients treated with allogeneic bone marrow transplantation for leukemia, in a Phase I/II study.

Vicriviroc Chemical compound

Vicriviroc, previously named SCH 417690 and SCH-D, is a pyrimidine CCR5 entry inhibitor of HIV-1. It was developed by the pharmaceutical company Schering-Plough. Merck decided to not pursue regulatory approval for use in treatment-experienced patients because the drug did not meet primary efficacy endpoints in late stage trials. Clinical trials continue in patients previously untreated for HIV.

CCR8 (gene)

Chemokine receptor 8, also known as CCR8, is a protein which in humans is encoded by the CCR8 gene. CCR8 has also recently been designated CDw198.

GPR15

GPR15 is a class A orphan G protein-coupled receptor. The GPR15 gene is localized at chromosome 3q11.2-q13.1. It is found in epithelial cells, synovial macrophages, endothelial cells and lymphocytes especially T cells. From the mRNA sequence a 40.8 kD molecular weight of GPR15 is proposed. In an epithelial tumour cell line (HT-29), however, a 36 kD band, composed of GPR15 and galactosyl ceramide, was detected. Protein expression in lymphocytes is strongly associated with hypomethylation of its gene.

CXCR6

C-X-C chemokine receptor type 6 is a protein that in humans is encoded by the CXCR6 gene. CXCR6 has also recently been designated CD186.

Monogram Biosciences Inc., a wholly owned subsidiary of LabCorp, is an international biotechnology laboratory located in South San Francisco, California, USA. Monogram develops and markets assays to help guide and improve the treatment of infectious diseases and cancer.

Gero Hütter is a German hematologist. Hütter and his medical team transplanted bone marrow deficient in a key HIV receptor to a leukemia patient, Timothy Ray Brown, who was also infected with human immunodeficiency virus (HIV). Subsequently, the patient's circulating HIV dropped to undetectable levels. The case was widely reported in the media, and Hütter was named one of the "Berliners of the year" for 2008 by the Berliner Morgenpost, a Berlin newspaper.

Tat (HIV)

In molecular biology, Tat is a protein that is encoded for by the tat gene in HIV-1. Tat is a regulatory protein that drastically enhances the efficiency of viral transcription. Tat stands for "Trans-Activator of Transcription". The protein consists of between 86 and 101 amino acids depending on the subtype. Tat vastly increases the level of transcription of the HIV dsDNA. Before Tat is present, a small number of RNA transcripts will be made, which allow the Tat protein to be produced. Tat then binds to cellular factors and mediates their phosphorylation, resulting in increased transcription of all HIV genes, providing a positive feedback cycle. This in turn allows HIV to have an explosive response once a threshold amount of Tat is produced, a useful tool for defeating the body's response.

CCR5 receptor antagonists are a class of small molecules that antagonize the CCR5 receptor. The C-C motif chemokine receptor CCR5 is involved in the process by which HIV, the virus that causes AIDS, enters cells. Hence antagonists of this receptor are entry inhibitors and have potential therapeutic applications in the treatment of HIV infections.

A small proportion of humans show partial or apparently complete inborn resistance to HIV, the virus that causes AIDS. The main mechanism is a mutation of the gene encoding CCR5, which acts as a co-receptor for HIV. It is estimated that the proportion of people with some form of resistance to HIV is under 10%.

Since antiretroviral therapy requires a lifelong treatment regimen, research to find more permanent cures for HIV infection is currently underway. It is possible to synthesize zinc finger nucleotides with zinc finger components that selectively bind to specific portions of DNA. Conceptually, targeting and editing could focus on host cellular co-receptors for HIV or on proviral HIV DNA.

References

  1. 1 2 3 Coakley, E.; Petropoulos, C. J.; Whitcomb, J. M. (2005). "Assessing chemokine co-receptor usage in HIV". Curr. Opin. Infect. Dis. 18 (1): 9–15. doi:10.1097/00001432-200502000-00003. PMID   15647694. S2CID   30923492.
  2. 1 2 Berger, EA; Doms, RW; Fenyö, EM; Korber, BT; Littman, DR; Moore, JP; Sattentau, QJ; Schuitemaker, H; et al. (1998). "A new classification for HIV-1". Nature. 391 (6664): 240. Bibcode:1998Natur.391..240B. doi: 10.1038/34571 . PMID   9440686. S2CID   2159146.
  3. ↑ Whitcomb, JM; Huang, W; Fransen, S; et al. (2007). "Development and characterization of a novel single-cycle recombinant virus assay to determine human immunodeficiency virus type 1 coreceptor tropism". Antimicrob Agents Chemother. 51 (2): 566–575. doi: 10.1128/aac.00853-06 . PMC   1797738 . PMID   17116663.
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