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Friday, June 23, 2023

Circulatory system

From Wikipedia, the free encyclopedia
 
Circulatory system
Circulatory System en.svg
The human circulatory system (simplified). Red indicates oxygenated blood carried in arteries. Blue indicates deoxygenated blood carried in veins. Capillaries join the arteries and veins.
Identifiers
MeSHD002319
TA98A12.0.00.000
TA23891
FMA7161

The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, that consists of the heart and blood vessels (from Greek kardia meaning heart, and from Latin vascula meaning vessels). The circulatory system has two divisions, a systemic circulation or circuit, and a pulmonary circulation or circuit. Some sources use the terms cardiovascular system and vascular system interchangeably with the circulatory system.

The network of blood vessels are the great vessels of the heart including large elastic arteries, and large veins; other arteries, smaller arterioles, capillaries that join with venules (small veins), and other veins. The circulatory system is closed in vertebrates, which means that the blood never leaves the network of blood vessels. Some invertebrates such as arthropods have an open circulatory system. Diploblasts such as sponges, and comb jellies lack a circulatory system.

Blood is a fluid consisting of plasma, red blood cells, white blood cells, and platelets that is circulated around the body carrying oxygen and nutrients to the tissues, and waste materials away. Circulated nutrients include proteins and minerals, other components transported are gases such as oxygen, and carbon dioxide, hormones, and hemoglobin; providing nourishment, help in the immune system to fight diseases, and in maintaining homeostasis by stabilizing temperature and natural pH.

In vertebrates, complementary to the circulatory system is the lymphatic system. This system carries excess plasma filtered from the capillaries as interstitial fluid between cells, away from the body tissues in an accessory route to return the excess fluid back to the blood circulation as lymph. The passage of lymph takes much longer than that of blood. The lymphatic system is a subsystem that is essential for the functioning of the blood circulatory system; without it the blood would become depleted of fluid. The lymphatic system works together with the immune system. Unlike the closed circulatory system, the lymphatic system is an open system. Some sources describe it as a secondary circulatory system.

The circulatory system can be affected by many cardiovascular diseases. Cardiologists are medical professionals which specialise in the heart, and cardiothoracic surgeons specialise in operating on the heart and its surrounding areas. Vascular surgeons focus on disorders of the blood vessels, and lymphatic vessels.

Structure

Blood flow in the pulmonary and systemic circulations showing capillary networks in the torso sections

The circulatory system includes the heart, blood vessels, and blood. The cardiovascular system in all vertebrates, consists of the heart and blood vessels. The circulatory system is further divided into two major circuits – a pulmonary circulation, and a systemic circulation. The pulmonary circulation is a circuit loop from the right heart taking deoxygenated blood to the lungs where it is oxygenated and returned to the left heart. The systemic circulation is a circuit loop that delivers oxygenated blood from the left heart to the rest of the body, and returns deoxygenated blood back to the right heart via large veins known as the venae cavae. The systemic circulation can also be defined as two parts – a macrocirculation and a microcirculation. An average adult contains five to six quarts (roughly 4.7 to 5.7 liters) of blood, accounting for approximately 7% of their total body weight. Blood consists of plasma, red blood cells, white blood cells, and platelets. The digestive system also works with the circulatory system to provide the nutrients the system needs to keep the heart pumping.

Further circulatory routes are associated, such as the coronary circulation to the heart itself, the cerebral circulation to the brain, renal circulation to the kidneys, and bronchial circulation to the bronchi in the lungs.

The human circulatory system is closed, meaning that the blood is contained within the vascular network. Nutrients travel through tiny blood vessels of the microcirculation to reach organs. The lymphatic system is an essential subsystem of the circulatory system consisting of a network of lymphatic vessels, lymph nodes, organs, tissues and circulating lymph. This subsystem is an open system. A major function is to carry the lymph, draining and returning interstitial fluid into the lymphatic ducts back to the heart for return to the circulatory system. Another major function is working together with the immune system to provide defense against pathogens.

Heart

Diagram of the human heart showing blood oxygenation to the pulmonary and systemic circulation

The heart pumps blood to all parts of the body providing nutrients and oxygen to every cell, and removing waste products. The left heart pumps oxygenated blood returned from the lungs to the rest of the body in the systemic circulation. The right heart pumps deoxygenated blood to the lungs in the pulmonary circulation. In the human heart there is one atrium and one ventricle for each circulation, and with both a systemic and a pulmonary circulation there are four chambers in total: left atrium, left ventricle, right atrium and right ventricle. The right atrium is the upper chamber of the right side of the heart. The blood that is returned to the right atrium is deoxygenated (poor in oxygen) and passed into the right ventricle to be pumped through the pulmonary artery to the lungs for re-oxygenation and removal of carbon dioxide. The left atrium receives newly oxygenated blood from the lungs as well as the pulmonary vein which is passed into the strong left ventricle to be pumped through the aorta to the different organs of the body.

Pulmonary circulation

The pulmonary circulation as it passes from the heart. Showing both the pulmonary and bronchial arteries.

The pulmonary circulation is the part of the circulatory system in which oxygen-depleted blood is pumped away from the heart, via the pulmonary artery, to the lungs and returned, oxygenated, to the heart via the pulmonary vein.

Oxygen-deprived blood from the superior and inferior vena cava enters the right atrium of the heart and flows through the tricuspid valve (right atrioventricular valve) into the right ventricle, from which it is then pumped through the pulmonary semilunar valve into the pulmonary artery to the lungs. Gas exchange occurs in the lungs, whereby CO2 is released from the blood, and oxygen is absorbed. The pulmonary vein returns the now oxygen-rich blood to the left atrium.

A separate circuit from the systemic circulation, the bronchial circulation supplies blood to the tissue of the larger airways of the lung.

Systemic circulation

Capillary bed
 
Diagram of capillary network joining the arterial system with the venous system.

The systemic circulation is a circuit loop that delivers oxygenated blood from the left heart to the rest of the body through the aorta. Deoxygenated blood is returned in the systemic circulation to the right heart via two large veins, the inferior vena cava and superior vena cava, where it is pumped from the right atrium into the pulmonary circulation for oxygenation. The systemic circulation can also be defined as having two parts – a macrocirculation and a microcirculation.

Blood vessels

The blood vessels of the circulatory system are the arteries, veins, and capillaries. The large arteries and veins that take blood to, and away from the heart are known as the great vessels.

Arteries

Depiction of the heart, major veins and arteries constructed from body scans

Oxygenated blood enters the systemic circulation when leaving the left ventricle, via the aortic semilunar valve. The first part of the systemic circulation is the aorta, a massive and thick-walled artery. The aorta arches and gives branches supplying the upper part of the body after passing through the aortic opening of the diaphragm at the level of thoracic ten vertebra, it enters the abdomen. Later, it descends down and supplies branches to abdomen, pelvis, perineum and the lower limbs.

The walls of the aorta are elastic. This elasticity helps to maintain the blood pressure throughout the body. When the aorta receives almost five litres of blood from the heart, it recoils and is responsible for pulsating blood pressure. As the aorta branches into smaller arteries, their elasticity goes on decreasing and their compliance goes on increasing.

Capillaries

Arteries branch into small passages called arterioles and then into the capillaries. The capillaries merge to bring blood into the venous system.

Veins

Capillaries merge into venules, which merge into veins. The venous system feeds into the two major veins: the superior vena cava – which mainly drains tissues above the heart – and the inferior vena cava – which mainly drains tissues below the heart. These two large veins empty into the right atrium of the heart.

Portal veins

The general rule is that arteries from the heart branch out into capillaries, which collect into veins leading back to the heart. Portal veins are a slight exception to this. In humans the only significant example is the hepatic portal vein which combines from capillaries around the gastrointestinal tract where the blood absorbs the various products of digestion; rather than leading directly back to the heart, the hepatic portal vein branches into a second capillary system in the liver.

Coronary circulation

The heart itself is supplied with oxygen and nutrients through a small "loop" of the systemic circulation and derives very little from the blood contained within the four chambers. The coronary circulation system provides a blood supply to the heart muscle itself. The coronary circulation begins near the origin of the aorta by two coronary arteries: the right coronary artery and the left coronary artery. After nourishing the heart muscle, blood returns through the coronary veins into the coronary sinus and from this one into the right atrium. Backflow of blood through its opening during atrial systole is prevented by the Thebesian valve. The smallest cardiac veins drain directly into the heart chambers.

Cerebral circulation

The brain has a dual blood supply, an anterior and a posterior circulation from arteries at its front and back. The anterior circulation arises from the internal carotid arteries to supply the front of the brain. The posterior circulation arises from the vertebral arteries, to supply the back of the brain and brainstem. The circulation from the front and the back join (anastomise) at the circle of Willis. The neurovascular unit, composed of various cells and vasculature channels within the brain, regulates the flow of blood to activated neurons in order to satisfy their high energy demands.

Renal circulation

The renal circulation is the blood supply to the kidneys, contains many specialized blood vessels and receives around 20% of the cardiac output. It branches from the abdominal aorta and returns blood to the ascending inferior vena cava.

Development

The development of the circulatory system starts with vasculogenesis in the embryo. The human arterial and venous systems develop from different areas in the embryo. The arterial system develops mainly from the aortic arches, six pairs of arches that develop on the upper part of the embryo. The venous system arises from three bilateral veins during weeks 4 – 8 of embryogenesis. Fetal circulation begins within the 8th week of development. Fetal circulation does not include the lungs, which are bypassed via the truncus arteriosus. Before birth the fetus obtains oxygen (and nutrients) from the mother through the placenta and the umbilical cord.

Arteries

Animation of a typical human red blood cell cycle in the circulatory system. This animation occurs at a faster rate (~20 seconds of the average 60-second cycle) and shows the red blood cell deforming as it enters capillaries, as well as the bars changing color as the cell alternates in states of oxygenation along the circulatory system.

The human arterial system originates from the aortic arches and from the dorsal aortae starting from week 4 of embryonic life. The first and second aortic arches regress and form only the maxillary arteries and stapedial arteries respectively. The arterial system itself arises from aortic arches 3, 4 and 6 (aortic arch 5 completely regresses).

The dorsal aortae, present on the dorsal side of the embryo, are initially present on both sides of the embryo. They later fuse to form the basis for the aorta itself. Approximately thirty smaller arteries branch from this at the back and sides. These branches form the intercostal arteries, arteries of the arms and legs, lumbar arteries and the lateral sacral arteries. Branches to the sides of the aorta will form the definitive renal, suprarenal and gonadal arteries. Finally, branches at the front of the aorta consist of the vitelline arteries and umbilical arteries. The vitelline arteries form the celiac, superior and inferior mesenteric arteries of the gastrointestinal tract. After birth, the umbilical arteries will form the internal iliac arteries.

Veins

The human venous system develops mainly from the vitelline veins, the umbilical veins and the cardinal veins, all of which empty into the sinus venosus.

Function

About 98.5% of the oxygen in a sample of arterial blood in a healthy human, breathing air at sea-level pressure, is chemically combined with hemoglobin molecules. About 1.5% is physically dissolved in the other blood liquids and not connected to hemoglobin. The hemoglobin molecule is the primary transporter of oxygen in vertebrates.

Clinical significance

Many diseases affect the circulatory system. These include a number of cardiovascular diseases, affecting the heart and blood vessels; hematologic diseases that affect the blood, such as anemia, and lymphatic diseases affecting the lymphatic system. Cardiologists are medical professionals which specialise in the heart, and cardiothoracic surgeons specialise in operating on the heart and its surrounding areas. Vascular surgeons focus on the blood vessels.

Cardiovascular disease

Diseases affecting the cardiovascular system are called cardiovascular disease.

Many of these diseases are called "lifestyle diseases" because they develop over time and are related to a person's exercise habits, diet, whether they smoke, and other lifestyle choices a person makes. Atherosclerosis is the precursor to many of these diseases. It is where small atheromatous plaques build up in the walls of medium and large arteries. This may eventually grow or rupture to occlude the arteries. It is also a risk factor for acute coronary syndromes, which are diseases that are characterised by a sudden deficit of oxygenated blood to the heart tissue. Atherosclerosis is also associated with problems such as aneurysm formation or splitting ("dissection") of arteries.

Another major cardiovascular disease involves the creation of a clot, called a "thrombus". These can originate in veins or arteries. Deep venous thrombosis, which mostly occurs in the legs, is one cause of clots in the veins of the legs, particularly when a person has been stationary for a long time. These clots may embolise, meaning travel to another location in the body. The results of this may include pulmonary embolus, transient ischaemic attacks, or stroke.

Cardiovascular diseases may also be congenital in nature, such as heart defects or persistent fetal circulation, where the circulatory changes that are supposed to happen after birth do not. Not all congenital changes to the circulatory system are associated with diseases, a large number are anatomical variations.

Investigations

The function and health of the circulatory system and its parts are measured in a variety of manual and automated ways. These include simple methods such as those that are part of the cardiovascular examination, including the taking of a person's pulse as an indicator of a person's heart rate, the taking of blood pressure through a sphygmomanometer or the use of a stethoscope to listen to the heart for murmurs which may indicate problems with the heart's valves. An electrocardiogram can also be used to evaluate the way in which electricity is conducted through the heart.

Other more invasive means can also be used. A cannula or catheter inserted into an artery may be used to measure pulse pressure or pulmonary wedge pressures. Angiography, which involves injecting a dye into an artery to visualise an arterial tree, can be used in the heart (coronary angiography) or brain. At the same time as the arteries are visualised, blockages or narrowings may be fixed through the insertion of stents, and active bleeds may be managed by the insertion of coils. An MRI may be used to image arteries, called an MRI angiogram. For evaluation of the blood supply to the lungs a CT pulmonary angiogram may be used. Vascular ultrasonography may be used to investigate vascular diseases affecting the venous system and the arterial system including the diagnosis of stenosis, thrombosis or venous insufficiency. An intravascular ultrasound using a catheter is also an option.

Surgery

There are a number of surgical procedures performed on the circulatory system:

Cardiovascular procedures are more likely to be performed in an inpatient setting than in an ambulatory care setting; in the United States, only 28% of cardiovascular surgeries were performed in the ambulatory care setting.

Other animals

The open circulatory system of the grasshopper – made up of a heart, vessels and hemolymph. The hemolymph is pumped through the heart, into the aorta, dispersed into the head and throughout the hemocoel, then back through the ostia in the heart and the process repeated.

While humans, as well as other vertebrates, have a closed blood circulatory system (meaning that the blood never leaves the network of arteries, veins and capillaries), some invertebrate groups have an open circulatory system containing a heart but limited blood vessels. The most primitive, diploblastic animal phyla lack circulatory systems.

An additional transport system, the lymphatic system, which is only found in animals with a closed blood circulation, is an open system providing an accessory route for excess interstitial fluid to be returned to the blood.

The blood vascular system first appeared probably in an ancestor of the triploblasts over 600 million years ago, overcoming the time-distance constraints of diffusion, while endothelium evolved in an ancestral vertebrate some 540–510 million years ago.

Open circulatory system

In arthropods, the open circulatory system is a system in which a fluid in a cavity called the hemocoel bathes the organs directly with oxygen and nutrients, with there being no distinction between blood and interstitial fluid; this combined fluid is called hemolymph or haemolymph. Muscular movements by the animal during locomotion can facilitate hemolymph movement, but diverting flow from one area to another is limited. When the heart relaxes, blood is drawn back toward the heart through open-ended pores (ostia).

Hemolymph fills all of the interior hemocoel of the body and surrounds all cells. Hemolymph is composed of water, inorganic salts (mostly sodium, chloride, potassium, magnesium, and calcium), and organic compounds (mostly carbohydrates, proteins, and lipids). The primary oxygen transporter molecule is hemocyanin.

There are free-floating cells, the hemocytes, within the hemolymph. They play a role in the arthropod immune system.

Flatworms, such as this Pseudoceros bifurcus, lack specialized circulatory organs.

Closed circulatory system

Two-chambered heart of a fish

The circulatory systems of all vertebrates, as well as of annelids (for example, earthworms) and cephalopods (squids, octopuses and relatives) always keep their circulating blood enclosed within heart chambers or blood vessels and are classified as closed, just as in humans. Still, the systems of fish, amphibians, reptiles, and birds show various stages of the evolution of the circulatory system. Closed systems permit blood to be directed to the organs that require it.

In fish, the system has only one circuit, with the blood being pumped through the capillaries of the gills and on to the capillaries of the body tissues. This is known as single cycle circulation. The heart of fish is, therefore, only a single pump (consisting of two chambers).

In amphibians and most reptiles, a double circulatory system is used, but the heart is not always completely separated into two pumps. Amphibians have a three-chambered heart.

In reptiles, the ventricular septum of the heart is incomplete and the pulmonary artery is equipped with a sphincter muscle. This allows a second possible route of blood flow. Instead of blood flowing through the pulmonary artery to the lungs, the sphincter may be contracted to divert this blood flow through the incomplete ventricular septum into the left ventricle and out through the aorta. This means the blood flows from the capillaries to the heart and back to the capillaries instead of to the lungs. This process is useful to ectothermic (cold-blooded) animals in the regulation of their body temperature.

Mammals, birds and crocodilians show complete separation of the heart into two pumps, for a total of four heart chambers; it is thought that the four-chambered heart of birds and crocodilians evolved independently from that of mammals. Double circulatory systems permit blood to be repressurized after returning from the lungs, speeding up delivery of oxygen to tissues.

No circulatory system

Circulatory systems are absent in some animals, including flatworms. Their body cavity has no lining or enclosed fluid. Instead, a muscular pharynx leads to an extensively branched digestive system that facilitates direct diffusion of nutrients to all cells. The flatworm's dorso-ventrally flattened body shape also restricts the distance of any cell from the digestive system or the exterior of the organism. Oxygen can diffuse from the surrounding water into the cells, and carbon dioxide can diffuse out. Consequently, every cell is able to obtain nutrients, water and oxygen without the need of a transport system.

Some animals, such as jellyfish, have more extensive branching from their gastrovascular cavity (which functions as both a place of digestion and a form of circulation), this branching allows for bodily fluids to reach the outer layers, since the digestion begins in the inner layers.

History

Human anatomical chart of blood vessels, with heart, lungs, liver and kidneys included. Other organs are numbered and arranged around it. Before cutting out the figures on this page, Vesalius suggests that readers glue the page onto parchment and gives instructions on how to assemble the pieces and paste the multilayered figure onto a base "muscle man" illustration. "Epitome", fol.14a. HMD Collection, WZ 240 V575dhZ 1543.

The earliest known writings on the circulatory system are found in the Ebers Papyrus (16th century BCE), an ancient Egyptian medical papyrus containing over 700 prescriptions and remedies, both physical and spiritual. In the papyrus, it acknowledges the connection of the heart to the arteries. The Egyptians thought air came in through the mouth and into the lungs and heart. From the heart, the air travelled to every member through the arteries. Although this concept of the circulatory system is only partially correct, it represents one of the earliest accounts of scientific thought.

In the 6th century BCE, the knowledge of circulation of vital fluids through the body was known to the Ayurvedic physician Sushruta in ancient India. He also seems to have possessed knowledge of the arteries, described as 'channels' by Dwivedi & Dwivedi (2007). The valves of the heart were discovered by a physician of the Hippocratean school around the 4th century BCE. However, their function was not properly understood then. Because blood pools in the veins after death, arteries look empty. Ancient anatomists assumed they were filled with air and that they were for the transport of air.

The Greek physician, Herophilus, distinguished veins from arteries but thought that the pulse was a property of arteries themselves. Greek anatomist Erasistratus observed that arteries that were cut during life bleed. He ascribed the fact to the phenomenon that air escaping from an artery is replaced with blood that enters between veins and arteries by very small vessels. Thus he apparently postulated capillaries but with reversed flow of blood.

In 2nd-century AD Rome, the Greek physician Galen knew that blood vessels carried blood and identified venous (dark red) and arterial (brighter and thinner) blood, each with distinct and separate functions. Growth and energy were derived from venous blood created in the liver from chyle, while arterial blood gave vitality by containing pneuma (air) and originated in the heart. Blood flowed from both creating organs to all parts of the body where it was consumed and there was no return of blood to the heart or liver. The heart did not pump blood around, the heart's motion sucked blood in during diastole and the blood moved by the pulsation of the arteries themselves.

Galen believed that the arterial blood was created by venous blood passing from the left ventricle to the right by passing through 'pores' in the interventricular septum, air passed from the lungs via the pulmonary artery to the left side of the heart. As the arterial blood was created 'sooty' vapors were created and passed to the lungs also via the pulmonary artery to be exhaled.

In 1025, The Canon of Medicine by the Persian physician, Avicenna, "erroneously accepted the Greek notion regarding the existence of a hole in the ventricular septum by which the blood traveled between the ventricles." Despite this, Avicenna "correctly wrote on the cardiac cycles and valvular function", and "had a vision of blood circulation" in his Treatise on Pulse. While also refining Galen's erroneous theory of the pulse, Avicenna provided the first correct explanation of pulsation: "Every beat of the pulse comprises two movements and two pauses. Thus, expansion : pause : contraction : pause. [...] The pulse is a movement in the heart and arteries ... which takes the form of alternate expansion and contraction."

In 1242, the Arabian physician, Ibn al-Nafis described the process of pulmonary circulation in greater, more accurate detail than his predecessors, though he believed, as they did, in the notion of vital spirit (pneuma), which he believed was formed in the left ventricle. Ibn al-Nafis stated in his Commentary on Anatomy in Avicenna's Canon:

...the blood from the right chamber of the heart must arrive at the left chamber but there is no direct pathway between them. The thick septum of the heart is not perforated and does not have visible pores as some people thought or invisible pores as Galen thought. The blood from the right chamber must flow through the vena arteriosa (pulmonary artery) to the lungs, spread through its substances, be mingled there with air, pass through the arteria venosa (pulmonary vein) to reach the left chamber of the heart and there form the vital spirit...

In addition, Ibn al-Nafis had an insight into what would become a larger theory of the capillary circulation. He stated that "there must be small communications or pores (manafidh in Arabic) between the pulmonary artery and vein," a prediction that preceded the discovery of the capillary system by more than 400 years. Ibn al-Nafis' theory, however, was confined to blood transit in the lungs and did not extend to the entire body.

Michael Servetus was the first European to describe the function of pulmonary circulation, although his achievement was not widely recognized at the time, for a few reasons. He firstly described it in the "Manuscript of Paris" (near 1546), but this work was never published. And later he published this description, but in a theological treatise, Christianismi Restitutio, not in a book on medicine. Only three copies of the book survived but these remained hidden for decades, the rest were burned shortly after its publication in 1553 because of persecution of Servetus by religious authorities.

A better known discovery of pulmonary circulation was by Vesalius's successor at Padua, Realdo Colombo, in 1559.

Finally, the English physician William Harvey, a pupil of Hieronymus Fabricius (who had earlier described the valves of the veins without recognizing their function), performed a sequence of experiments and published his Exercitatio Anatomica de Motu Cordis et Sanguinis in Animalibus in 1628, which "demonstrated that there had to be a direct connection between the venous and arterial systems throughout the body, and not just the lungs. Most importantly, he argued that the beat of the heart produced a continuous circulation of blood through minute connections at the extremities of the body. This is a conceptual leap that was quite different from Ibn al-Nafis' refinement of the anatomy and bloodflow in the heart and lungs." This work, with its essentially correct exposition, slowly convinced the medical world. However, Harvey was not able to identify the capillary system connecting arteries and veins; these were later discovered by Marcello Malpighi in 1661.

In 1956, André Frédéric Cournand, Werner Forssmann and Dickinson W. Richards were awarded the Nobel Prize in Medicine "for their discoveries concerning heart catheterization and pathological changes in the circulatory system." In his Nobel lecture, Forssmann credits Harvey as birthing cardiology with the publication of his book in 1628.

In the 1970s, Diana McSherry developed computer-based systems to create images of the circulatory system and heart without the need for surgery.

Structure and genome of HIV

The genome and proteins of HIV (human immunodeficiency virus) have been the subject of extensive research since the discovery of the virus in 1983. "In the search for the causative agent, it was initially believed that the virus was a form of the Human T-cell leukemia virus (HTLV), which was known at the time to affect the human immune system and cause certain leukemias. However, researchers at the Pasteur Institute in Paris isolated a previously unknown and genetically distinct retrovirus in patients with AIDS which was later named HIV." Each virion comprises a viral envelope and associated matrix enclosing a capsid, which itself encloses two copies of the single-stranded RNA genome and several enzymes. The discovery of the virus itself occurred two years following the report of the first major cases of AIDS-associated illnesses.

Structure

Diagram of HIV
 
Structure of the immature HIV-1 capsid in intact virus particles
 
A diagram of the HIV spike protein (green), with the fusion peptide epitope highlighted in red, and a broadly neutralizing antibody (yellow) binding to the fusion peptide

The complete sequence of the HIV-1 genome, extracted from infectious virions, has been solved to single-nucleotide resolution. The HIV genome encodes a small number of viral proteins, invariably establishing cooperative associations among HIV proteins and between HIV and host proteins, to invade host cells and hijack their internal machineries. HIV is different in structure from other retroviruses. The HIV virion is ~100 nm in diameter. Its innermost region consists of a cone-shaped core that includes two copies of the (positive sense) ssRNA genome, the enzymes reverse transcriptase, integrase and protease, some minor proteins, and the major core protein. The genome of human immunodeficiency virus (HIV) encodes 8 viral proteins playing essential roles during the HIV life cycle.

HIV-1 is composed of two copies of noncovalently linked, unspliced, positive-sense single-stranded RNA enclosed by a conical capsid composed of the viral protein p24, typical of lentiviruses. The two copies of RNA strands are vital in contributing to HIV-1 recombination, which occurs during reverse transcription of viral replication. The containment of two copies of single-stranded RNA within a virion but the production of only a single DNA provirus is called pseudodiploidy. The RNA component is 9749 nucleotides long and bears a 5’ cap (Gppp), a 3’ poly(A) tail, and many open reading frames (ORFs). Viral structural proteins are encoded by long ORFs, whereas smaller ORFs encode regulators of the viral life cycle: attachment, membrane fusion, replication, and assembly.

The single-strand RNA is tightly bound to p7 nucleocapsid proteins, late assembly protein p6, and enzymes essential to the development of the virion, such as reverse transcriptase and integrase. Lysine tRNA is the primer of the magnesium-dependent reverse transcriptase. The nucleocapsid associates with the genomic RNA (one molecule per hexamer) and protects the RNA from digestion by nucleases. Also enclosed within the virion particle are Vif, Vpr, Nef, and viral protease. The envelope of the virion is formed by a plasma membrane of host cell origin, which is supported by a matrix composed of the viral p17 protein, ensuring the integrity of the virion particle. At the surface of the virion can be found a limited number of the envelope glycoprotein (Env) of HIV, a trimer formed by heterodimers of gp120 and gp41. Env is responsible for binding to its primary host receptor, CD4, and its co-receptor (mainly CCR5 or CXCR4), leading to viral entry into its target cell.

As the only proteins on the surface of the virus, the envelope glycoproteins (gp120 and gp41) are the major targets for HIV vaccine efforts. Over half of the mass of the trimeric envelope spike is N-linked glycans. The density is high as the glycans shield underlying viral protein from neutralisation by antibodies. This is one of the most densely glycosylated molecules known and the density is sufficiently high to prevent the normal maturation process of glycans during biogenesis in the endoplasmic reticulum and Golgi apparatus. The majority of the glycans are therefore stalled as immature 'high-mannose' glycans not normally present on secreted or cell surface human glycoproteins. The unusual processing and high density means that almost all broadly neutralising antibodies that have so far been identified (from a subset of patients that have been infected for many months to years) bind to or, are adapted to cope with, these envelope glycans.

The molecular structure of the viral spike has now been determined by X-ray crystallography and cryo-electron microscopy. These advances in structural biology were made possible due to the development of stable recombinant forms of the viral spike by the introduction of an intersubunit disulphide bond and an isoleucine to proline mutation in gp41. The so-called SOSIP trimers not only reproduce the antigenic properties of the native viral spike but also display the same degree of immature glycans as presented on the native virus. Recombinant trimeric viral spikes are promising vaccine candidates as they display less non-neutralising epitopes than recombinant monomeric gp120 which act to suppress the immune response to target epitopes.

Genome organization

Structure of the RNA genome of HIV-1

HIV has several major genes coding for structural proteins that are found in all retroviruses as well as several nonstructural ("accessory") genes unique to HIV. The HIV genome contains nine genes that encode fifteen viral proteins. These are synthesized as polyproteins which produce proteins for virion interior, called Gag, group specific antigen; the viral enzymes (Pol, polymerase) or the glycoproteins of the virion env (envelope). In addition to these, HIV encodes for proteins which have certain regulatory and auxiliary functions as well. HIV-1 has two important regulatory elements: Tat and Rev and few important accessory proteins such as Nef, Vpr, Vif and Vpu which are not essential for replication in certain tissues. The gag gene provides the basic physical infrastructure of the virus, and pol provides the basic mechanism by which retroviruses reproduce, while the others help HIV to enter the host cell and enhance its reproduction. Though they may be altered by mutation, all of these genes except tev exist in all known variants of HIV; see Genetic variability of HIV.

HIV employs a sophisticated system of differential RNA splicing to obtain nine different gene products from a less than 10kb genome. HIV has a 9.2kb unspliced genomic transcript which encodes for gag and pol precursors; a singly spliced, 4.5 kb encoding for env, Vif, Vpr and Vpu and a multiply spliced, 2 kb mRNA encoding for Tat, Rev and Nef.

Proteins encoded by the HIV genome
Class Gene name Primary protein products Processed protein products
Viral structural proteins gag Gag polyprotein MA, CA, SP1, NC, SP2, P6
pol Pol polyprotein RT, RNase H, IN, PR
env gp160 gp120, gp41
Essential regulatory elements tat Tat
rev Rev
Accessory regulatory proteins nef Nef
vpr Vpr
vif Vif
vpu Vpu

Viral structural proteins

The HIV capsid consists of roughly 200 copies of the p24 protein. The p24 structure is shown in two representations: cartoon (top) and isosurface (bottom)
  • gag (group-specific antigen) codes for the precursor gag polyprotein which is processed by viral protease during maturation to MA (matrix protein, p17); CA (capsid protein, p24); SP1 (spacer peptide 1, p2); NC (nucleocapsid protein, p7); SP2 (spacer peptide 2, p1) and P6 protein.
  • pol codes for viral enzymes reverse transcriptase (RT) and RNase H, integrase (IN), and HIV protease (PR). HIV protease is required to cleave the precursor Gag polyprotein to produce structural proteins, RT is required to transcribe DNA from RNA template, and IN is necessary to integrate the double-stranded viral DNA into the host genome.
  • env (for "envelope") codes for gp160, which is cleaved by a host protease, furin, within the endoplasmic reticulum of the host cell. The post-translational processing produces a surface glycoprotein, gp120 or SU, which attaches to the CD4 receptors present on lymphocytes, and gp41 or TM, which embeds in the viral envelope to enable the virus to attach to and fuse with target cells.

Essential regulatory elements

  • tat (HIV trans-activator) plays an important role in regulating the reverse transcription of viral genome RNA, ensuring efficient synthesis of viral mRNAs and regulating the release of virions from infected cells. Tat is expressed as 72-amino acid one-exon Tat as well as the 86–101-amino-acid two-exon Tat, and plays an important role early in HIV infection. Tat (14–15 kDa) binds to the bulged genomic RNA stem-loop secondary structure near the 5' LTR region forming the trans-activation response element (TAR).
  • rev (regulator of expression of virion proteins): The Rev protein binds to the viral genome via an arginine-rich RNA-binding motif that also acts as a NLS (nuclear localization signals), required for the transport of Rev to the nucleus from cytosol during viral replication. Rev recognizes a complex stem-loop structure of the mRNA env located in the intron separating coding exon of Tat and Rev, known as the HIV Rev response element (RRE). Rev is important for the synthesis of major viral proteins and is hence essential for viral replication.

Accessory regulatory proteins

  • vpr (lentivirus protein R): Vpr is a virion-associated, nucleocytoplasmic shuttling regulatory protein. It is believed to play an important role in replication of the virus, specifically, nuclear import of the preintegration complex. Vpr also appears to cause its host cells to arrest their cell cycle in the G2 phase. This arrest activates the host DNA repair machinery which may enable integration of the viral DNA. HIV-2 and SIV encode an additional Vpr related protein called Vpx which functions in association with Vpr.
  • vif - Vif is a highly conserved, 23 kDa phosphoprotein important for the infectivity of HIV-1 virions depending on the cell type. HIV-1 has been found to require Vif to synthesize infectious viruses in lymphocytes, macrophages, and certain human cell lines. It does not appear to require Vif for the same process in HeLa cells or COS cells, among others.
  • nef- Nef, negative factor, is a N-terminal myristoylated membrane-associated phosphoprotein. It is involved in multiple functions during the replication cycle of the virus. It is believed to play an important role in cell apoptosis and increase virus infectivity.
  • vpu (Virus protein U) - Vpu is specific to HIV-1. It is a class I oligomeric integral membrane phosphoprotein with numerous biological functions. Vpu is involved in CD4 degradation involving the ubiquitin proteasome pathway as well as in the successful release of virions from infected cells.
  • tev: This gene is only present in a few HIV-1 isolates. It is a fusion of parts of the tat, env, and rev genes, and codes for a protein with some of the properties of tat, but little or none of the properties of rev.

RNA secondary structure

HIV pol-1 stem loop
RF01418.png
Predicted secondary structure of the HIV pol-1 stem loop
 
Identifiers
Symbolpol
RfamRF01418
Other data
RNA typeCis-reg
PDB structuresPDBe

Several conserved secondary structure elements have been identified within the HIV RNA genome. The HIV viral RNA structures regulates the progression of reverse transcription.  The 5'UTR structure consists of series of stem-loop structures connected by small linkers. These stem-loops (5' to 3') include the trans-activation region (TAR) element, the 5' polyadenylation signal [poly(A)], the PBS, the DIS, the major SD and the ψ hairpin structure located within the 5' end of the genome and the HIV Rev response element (RRE) within the env gene. Another RNA structure that has been identified is gag stem loop 3 (GSL3), thought to be involved in viral packaging. RNA secondary structures have been proposed to affect the HIV life cycle by altering the function of HIV protease and reverse transcriptase, although not all elements identified have been assigned a function.

An RNA secondary structure determined by SHAPE analysis has shown to contain three stem loops and is located between the HIV protease and reverse transcriptase genes. This cis regulatory RNA has been shown to be conserved throughout the HIV family and is thought to influence the viral life cycle.

V3 loop

The third variable loop or V3 loop is a part or region of the Human Immunodeficiency Virus. The V3 loop of the viron's envelope glycoprotein, gp120, allows it to infect human immune cells by binding to a cytokine receptor on the target human immune cell, such as a CCR5 cell or CXCR4 cell, depending on the strain of HIV. The envelope glycoprotein (Env) gp 120/41 is essential for HIV-1 entry into cells. Env serves as a molecular target of a medicine treating individuals with HIV-1 infection, and a source of immunogen to develop AIDS vaccine. However, the structure of the functional Env trimer has remained elusive.

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