Scientific illustrations of human immunodeficiency virus (HIV)

Human immunodeficiency virus (HIV)

Date:

08.09.2010

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The process of virion binding to the host cell and the subsequent fusion of cell and viral membranes is mediated by the gp120/gp41 viral surface glycoprotein. The gp120/gp41 glycoprotein consists of two subunits that are encoded by the Env gene and are synthesized as a single precursor protein, gp160. This precursor is glycosylated by asparagine-linked high-mannose oligosaccharides and is processed by a host protease to form two non-covalently associated subunits [1].
HIV envelope proteins form trimers, and an average virion contains approximately 20 surface glycoprotein trimers [2, 3]. After processing, the gp41 subunit remains a transmembrane protein, whereas the gp120 subunit is non-covalently bound to gp41 and interacts with the host cell CD4 receptor [4].

Binding of the primary CD4 receptor induces conformational changes in gp120 that allow high-affinity interaction with the coreceptors CCR5 or CXCR4. This interaction triggers a series of conformational changes in gp41 that mediate the fusion of viral and cell membranes [5].
As it buds from the cell, the virion acquires lipid membrane from the plasma membrane. Therefore, some cellular membrane proteins, including cell adhesion molecules and MHC-receptors, are acquired and incorporated into the HIV particle [6]. In this model, we included the host membrane proteins ICAM-1, HLA-DR1 and CD55.
HLA-DR1 (Human Leukocyte Antigen) is a major histocompatibility complex class II molecule. These molecules present processed extracellular antigenic peptides to the helper T lymphocytes and can bind CD4 receptors. The presence of HLA molecules on the virion surface increases HIV infectivity [9]
ICAM-1 (Intercellular Adhesion Molecule 1), also referred to as CD54) functions in leukocyte trafficking, activation, and the formation of the immunological synapse. ICAM-1 is a member of the immunoglobulin superfamily of adhesion proteins. Structurally, ICAM-1 is an Ig-like homodimer [7] that also increases HIV infectivity [8].
CD55 (also referred to as DAF, Decay-accelerating factor) participates in down-regulating the complement system, which blocks the formation of the membrane attack complex. Incorporation of different levels of CD55 by different viral strains may account for differences in sensitivity to complement [10].

Although the HIV membrane is of host-cell origin, the precise lipid composition of the cellular and viral membranes may differ significantly. It has been shown that the fluidity of the HIV membrane is very low and highly ordered [1]
Phosphatidylcholine and phosphatidylethanolamine, major phospholipids in mammalian membranes, are present at lower levels in the viral membrane. In contrast, sphingomyelins and phosphatidylserine are enriched in HIV. Cholesterol content is also high in viral membranes [12]. The membrane composition is crucial for normal virus budding. The inhibition of sphingomyelin biosynthesis can decrease HIV infectivity [3].
It is thought that HIV particles bud from membrane microdomains called lipid rafts. These domains serve as protein delivery and enrichment areas in the cell membrane and are involved in protein trafficking and assembly of signaling complexes [4].
Matrix layer composed of MA protein (matrix protein, also referred as p17) lays directly below the viral lipid membrane [15]. The MA protein is the product of the viral gag gene. In mature virions, MA forms trimers. Each subunit of the trimer is myristoylated and anchored in the membrane [5, 16, 17].

The mature HIV particle has a condensed viral capsid, which contains RNA and a number of proteins. Some of the proteins are encoded by viral genes, and others are captured from the host cell [6].
P6, a small protein within the polyprotein encoded by the gag gene, is located between the matrix and the capsid. P6 is important for virion budding and for the incorporation of the virus-encoded Vpr protein into the particle [21, 22].
The Vpr protein performs several crucial functions in the HIV life cycle, including the induction of cell cycle arrest in the G(2) phase, induction of apoptosis, transactivation, enhancement of the fidelity of reverse transcription, and nuclear import of viral DNA [23].
Actin, shown in this model, is a cytoskeletal element that is commonly captured during HIV budding. It is believed that actin and a number of other cytoskeletal proteins are important for virion formation [24]. In addition, it is believed that after HIV budding, actin has no significant function.

The HIV capsid is a cone-shaped structure composed of approximately 250 hexamers and 12 pentamers of the CA protein (capsid protein, also referred as p24).
CA is also encoded by the gag gene [18]. Gag encodes the p55 polyprotein (sometimes referred to as assemblin), which initiates the formation of new HIV particles. During virion maturation, p55 is cleaved by the protease into 4 smaller structural proteins [19]. It is noteworthy that not all of the packaged CA molecules are involved in forming the mature capsid; some of these molecules appear to be located inside the virion in the form of dimers [20].
One of the host cell proteins, cyclophilin, is found in the virion attached to capsid hexamers.
Cyclophilin (or CypA) is a peptidylprolyl isomerase, which normally facilitates protein folding in the cell. After it enters the host cell cytoplasm, HIV requires cyclophilin to uncoat the capsid correctly [25].

The HIV capsid contains viral RNA, reverse transcriptase and integrase, which are needed for copying the viral RNA into DNA and inserting it into the host genome. In addition, inside the capsid are the cellular enzymes lysyl-tRNA synthetase and Lys-tRNAs, which serve as primers for the initiation of reverse transcription [6].
The HIV genetic material constitutes two copies of single-stranded positive-sense RNA molecules of approximately 10,000 nucleotides in length [26] that are tightly bound by NC proteins (nucleocapsid protein, or p7).
NC is also encoded by gag. When bound to RNA, a single NC molecule covers five nucleotides [27].
HIV RNA is 5’ capped and 3’ polyadenylated and contains the Lys tRNA primer-binding site (PBS).
Integrase. Similar to reverse transcriptase, it is also encoded by the viral Pol gene. Pol is composed of four identical subunits and is necessary for integration of the viral DNA into the host cell genome [32, 33].
Lys-tRNA is present in the mature capsid and binds not only to PBS but also to a number of other sites [29]. This tRNA is incorporated into the capsid in a complex with lysyl-tRNA synthetase [30].
Lysyl-tRNA synthetase interacts with viral protein p55 during the particle assembly [30].
Reverse transcriptase is needed to produce the DNA copy of the HIV genome. This enzyme is a heterodimer, and one of its subunits contains RNase H, which degrades the RNA in RNA-DNA complexes [31]. [31].

Human immunodeficiency virus (HIV) proteins

Proteins and genes of human immunodeficiency virus (HIV)

Major histocompatibility complex in HIV virion

Decay-accelerating factor CD55 in the HIV

The first strains of human immunodeficiency virus appeared in the early XX century in Africa (34). The closest evolutionary ancestors of HIV viruses were similar to simian immunodeficiency viruses, and the first infected humans could be hunters who butchered the dead monkeys. Currently, according to the World Health Organization, nearly 37 million people worldwide are HIV-infected, and the immunodeficiency caused by the virus killed more than a million people in 2015 (35).

What is HIV and AIDS?

The human immunodeficiency virus (HIV) is a retrovirus and a member of the lentivirus genus. HIV infects and destroys cells of the human immune system (CD4+ T-lymphocytes, macrophages and dendritic cells).

The decrease in CD4+ T-lymphocyte levels causes the development of acquired immunodeficiency syndrome (AIDS) (36).

There are two major species of HIV, HIV-1 and HIV-2, of which HIV-2 is less common. The HIV virion is a roughly spherical particle with a diameter measuring between 100 and 180 nm. The virion is surrounded by a cell-derived lipid membrane, which contains surface proteins. Some of these membrane proteins are products of the viral genome (surface glycoprotein gp120/gp41), and others are captured from the host cell during viral budding (e.g., ICAM-1, HLA-DR1, CD55 and others). The gp120/gp41 glycoprotein interacts with receptors on the cell surface promoting fusion of the viral and cell membranes. Other HIV surface proteins perform supporting functions (4, 6).

Trimers of the MA (p17) protein form a layer directly under the lipid membrane. Inside the HIV particle is a cone-shaped capsid, which is composed of CA (p24) proteins. The capsid contains two copies of positive single-stranded viral RNA bound by the NC (p7) protein and the enzymes (reverse transcriptase and integrase) necessary for replication of the virus (15, 37).

The HIV genome is approximately 10,000 nucleotides in length and contains 9 genes encoding 15 different proteins. The most important viral genes (open reading frames) are Gag, Pol and Env. Gag encodes the p55 protein, which is subsequently cut into the structural proteins MA, CA, NC and p6. The Pol reading frame encodes integrase, protease, and reverse transcriptase. Env encodes the two subunits of the surface glycoprotein complex. Other genes (Tat, Rev, Vif, Vpr, Vpu and Nef) produce accessory proteins, which modulate host cell metabolism and facilitate different stages of the HIV life cycle (38).

The HIV model

This human immunodeficiency virus model summarizes the results from more than 100 of the latest scientific publications in the fields of virology, X-ray analysis and NMR spectroscopy. The depicted spatial configurations of 17 different viral and cellular proteins found in the HIV particle are in strict accordance with known 3D structures.

The viral membrane in the model includes 160,000 lipid molecules of 8 different types in the proportion found in the HIV particle.

Scientifically verifying accurate models of viruses remains a challenging task. This becomes more complicated due to the fact that none of the currently available scientific approaches allow for obtaining an image of the whole virus particle in the atomic or molecular resolution. Nevertheless, hundreds of works by different authors from around the world have shed light on the structure and morphology of virion components and their interactions. The Visual Science team relies on several important sources to create models of the non-profit educational project “Viral Park”: careful analysis of the available scientific publications; opinions of recognized experts from the world's top research centers and the results of our own molecular dynamics and modeling simulations made by the experts of Visual Science’s Molecular modeling department, who employ structural bioinformatics methods to fill the gaps in the current understanding of the viral structure.

This model of the HIV virion has been awarded the first place at the 2010 Science and Engineering Visualization Challenge (SEVC), a competition organized by Science magazine and the National Science Foundation.

The model appeared on the cover of the special issue of Nature Medicine (September 8, 2010) prepared by the Global HIV Vaccine Enterprise. In this publication, the Enterprise published the strategic research plan to accelerate the development of vaccines against HIV (the “2010 Plan”). The 2010 Plan was developed by the Council of the Global HIV Vaccine Enterprise with the participation of hundreds of scientists, policy-makers, funders, and advocates worldwide.

The model also appeared on the cover of the International AIDS Vaccine Initiative (IAVI) Report. It is an authoritative guide that publishes information about all events and innovations, concerning the development of the vaccine against HIV. The IAVI report is published 6 times a year and its audience is represented by specialists in more than 130 countries. The mission of the InternationalAIDS Vaccine Initiative is to ensure the development of safe, effective, accessible, preventive HIV vaccines for use throughout the world. IAVI participates in research and development of candidate vaccines, addressing the legal issues concerning HIV and AIDS, supporting developing countries. The IAVI Innovation Fund is supported by the Bill and Melinda Gates Foundation. IAVI has representative offices in Africa, Europe, India, and the US.

In addition, our HIV model has been included in Stanley Plotkin's Vaccines, a textbook hailed as the “Bible of vaccinologists” by The Lancet; featured in presentations by the Nobel Prize-winning virologist Françoise Barré-Sinoussi; and covered by The New York Times, National Geographic, Wired, Popular Science, and other popular periodicals.

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Project manager, 3d technologist, 3d visualiser, molecular modeller:

Ivan Konstantinov
Science consultant:

Yury Stefanov, PhD
3D-modeller:

Alexander Kovalevsky
Science consultant:

Yegor Voronin (Ph. D, Global HIV Vaccine Enterprise)

Web-technology:

Kirill Grishanin
Flash-technology:

Maxim Grishaev

I would like to express my gratitude to Visual Science and all its employees who participated in the Second Nanotechnology International Forum organization. Thank you for your professionalism and the high quality product

A.B. Chubais

CEO of SC "Rusnanotech" RUSNANO