HIV Life Cycle and Inherited Co‐Receptors

Abstract

Human immunodeficiency virus (HIV) is a Lentivirus of the family Retroviridae, members of which cause a number of neurological and immunological diseases in humans and animals. HIV is the causative agent of the acquired immune deficiency syndrome. The disease is caused by virus‐mediated depletion of CD4+ T lymphocytes, preferentially CCR5‐positive memory T cells. Most of these cells localise to mucosal tissue, in particular gut mucosa, and disruption of the gut mucosal barrier is an early feature of HIV infection that determines the pathogenesis of the disease. More than 20 years of intensive studies identified the molecular mechanisms underlying viral replication and disease pathogenesis and provided the foundation for development of antiviral therapeutics and vaccine. This article provides a brief overview of the HIV life cycle and focuses on receptors that determine viral binding and entry into the target cells.

Key Concepts:

  • Virus entry into target cell is initiated by interaction between gp120 and cell receptors.

  • HIV preferentially targets memory CD4+ T cells that localise to mucosal lymphoid tissue, in particular the gut mucosa.

  • HIV replication includes a number of distinct steps: virus–cell fusion and entry, uncoating, reverse transcription and formation of the pre‐integration complex (PIC), PIC nuclear entry and integration, transcription and translation of proviral DNA, viral assembly and release of nascent virions and maturation and formation of infectious virions.

  • To infect a target cell, virus needs to counteract the activity of multiple cellular antiviral factors (APOBEC3, SAMHD1, tetherin), most of which activated by interferon. HIV accessory proteins have evolved to perform this function.

  • Receptors determine not only the first step of HIV interaction with the target cell, but also regulate post‐entry events in viral replication.

  • Characterisation of the molecular mechanisms underlying HIV replication and interaction with the target cells provides an opportunity to develop anti‐HIV therapeutics and vaccine.

Keywords: Lentivirus; macrophage; T lymphocyte; dendritic cell; CD4; chemokine receptor; integrin; lectin

Figure 1.

Composition of HIV‐1. Viral bilayer membrane is derived from cellular plasma membrane. Each knob is composed of three gp120 molecules noncovalently associated with a stem made of a gp41 trimer. Matrix antigen (MA) forms a layer beneath the envelope. The shell of the viral core is made of capsid antigen (CA). Only a few of the several hundred copies of integrase (IN), reverse transcriptase (RT), nucleocapsid (NC) and viral protein R (Vpr) molecules are shown. Vpr associates tightly with Gag p6, and RT most likely contacts IN. Not drawn to scale. Details are discussed in the text.

Figure 2.

HIV‐1 co‐receptors. HIV‐1 interacts with its receptors via the envelope protein, gp120, which binds to the D1 immunoglobulin‐like domain of CD4 and the extracellular domain of a chemokine receptor. Chemokines bind to extracellular loop 2 (ECL‐2) on the chemokine receptor. However, interaction between gp120 and ECL‐2 is required for virus–cell fusion and likely occurs shortly after initial binding interaction; therefore, gp120 inhibits binding of chemokines to receptor, whereas chemokines block virus–cell fusion and HIV‐1 infection. Both gp120 and chemokines initiate signal transduction through chemokine receptor‐coupled Gi protein, but gp120 can also signal through CD4‐associated Src kinase, p56lck. ICL, intracellular loop.

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Further Reading

Arhel N and Kirchhoff F (2010) Host proteins involved in HIV infection: new therapeutic targets. Biochimica et Biophysica Acta 1802: 313–321.

Jin T, Xu X and Hereld D (2008) Chemotaxis, chemokine receptors and human disease. Cytokine 44: 1–8.

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How to Cite close
Bukrinsky, Michael I(Sep 2014) HIV Life Cycle and Inherited Co‐Receptors. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0002240.pub4]