TYPES OF VIRUSES

Poxviruses pathogenic to human beings fall in two genera–Orthopoxvirus and Parapoxvirus.

Small Pox: Smallpox is transmitted to humans by person-toperson contact or by fomites. The incubation period for human infections ranges between 7 to 17 days. The virus enters through respiratory tract. The prodromal phase is characterised by fever, chills, headache, backache, vomiting, pain in the limbs and prostration. Through haematogenous route, the virus reaches internal organs, multiplies there and again appears in blood. The skin eruptions appear on 3rd to 4th day. The eruption develops through the stages of macule, papule, vesicle and pustule within 5 to 6 days. The distribution of the eruption characteristically involves the face and the limbs. The lesions begin to dry up by 10th day of appearance and scabs are shed by third week.

Human Monkey pox: Monkey pox was first discovered as a disease of captivemonkeys in 1958. This was found to be a disease entityof human beings in 1970 in Zaire. Since then around400 cases of monkey pox have been reported in theworld.Clinically the disease is indistinguishable fromsmallpox and laboratory help is needed to establishthe diagnosis. Usually the patient recovers in 2-4 weeksbut monkey pox also carries a case fatality rate of 15%in human beings.Monkey pox is of public health importance notbecause of the magnitude of the problem but because ofits similarity in clinical appearance with that of smallpox.

Tanapox: The disease is also called as ‘river smallpox’ and getsthe name Tanapox from the river Tana in Kenya fromwhere initial outbreaks of this poxvirus in humans werereported in 1957 and 1962. The disease can begin inhuman beings as a febrile illness with backache,headache, and prostration. Lesions seen on uncoveredareas are few, usually one or two. These lesions appearon the skin of the upper arms, face, neck or trunk. It isdifficult to extract fluid from the vesicles of this disease.The lesions heal without becoming pustules. Healingtime extends to 7 weeks. The disease is believed to betransmitted by mosquitoes. The reservoir of infection is unknown but monkeys are suspected.

4. HEPATIC VIRUSES

Viral hepatitis is inflammation of liver by viruses. Various viruses which cause damage to liver are: Epstein-Barr virus; Cytomegalovirus; Herpes simplex virus; Rubella; Mumps; ECHO viruses; Yellow fever and Hepatitis viruses.

Of all these, only hepatitis viruses primarily attack hepatocytes and hence are considered agents of viral hepatitis. Viral hepatitis refers specifically to a primary infection of the liver by one of the seven etiologically associated but different hepatotropic viruses. These types are designated as types A, B, C, D, E, F and G. The clinical manifestations of almost all these types are similar. Hepatitis B and C viruses are also responsible for hepatocellular cancer. Status of hepatitis F virus is yet unclear.

HEPATITIS A VIRUS (Also Known as Infectious Hepatitis, Epidemic Hepatitis, Epidemic Jaundice, Catarrhal Jaundice). The morphological and physiochemical properties of HAV are similar to those of picornaviruses and hence it has been classified as a member of family Picornaviridae and designated as enterovirus type 72. The virus is spherical, non-enveloped particle, 27 nm in diameter with an icosahedral symmetry.

Pathogenesis

HAV is transmitted from person to person by fecal – oral route. Occasionally it is acquired through sexual contact and blood transfusion. The average incubation period of HAV infection is about one month. The pathogenesis is not fully understood. It appears that HAV enters the portal blood from the intestine and is transported to liver. Onset of hepatitis A is heralded by a variety of nonspecific symptoms which include fever, chills, headache, fatigue and vague pains. These are followed by anorexia, nausea, vomiting and pain in right upper quadrant of abdomen. Appearance of dark urine, clay colored stool and jaundice of sclera and skin help in establishing clinical diagnosis of hepatitis. Jaundice usually deepens during the first few days and persists for 1-2 weeks. It gradually diminishes over next 2 weeks or so. Convalescence is prolonged and recovery in adults takes place in few months. There is no evidence of progression of hepatitis A to chronic liver disease. HAV infection is endemic globally. All age groups are susceptible to HAV. The highest incidence is seen in children of school age. Hepatitis A virus generally causes less severe disease than some of other hepatitis viruses and never progresses to chronicity. It is, however, the cause of significant human morbidity and loss of productivity.

HEPATITIS B VIRUS (Also known as Serum Hepatitis, Australia Antigen Hepatitis, Type B Hepatitis, Homologous Serum Jaundice). Hepatitis B virus (HBV), also referred to as Dane particle belongs to a new family called as Hepadnaviridae.

Pathogenesis: Body substances capable of transmitting HBV include blood and blood products, saliva, CSF, peritoneal, pleural, pericardial, synovial and amniotic fluids, semen, vaginal secretions and unfixed organs and tissues. The transmission occurs by per cutaneous and per mucosal exposure to infective body fluids. The incubation period of HBV is usually about three months, with a range between 45-180 days. Although HBV is transmitted predominantly by the percutaneous route, it is also recognized that it can be transmitted by other means, because HBsAg has been detected in almost every body fluid. Spread of HBV by oral and genital contact has been demonstrated. The clinical manifestations of hepatitis B are identical to those of hepatitis A. Hepatitis B virus may give rise to persistent infection, prolonged carrier state and progression to chronic liver disease. Substantial evidence is now available regarding association between HBV and hepatocellular carcinoma. The most frightening statistics regarding hepatitis B are the tremendous number of chronic carriers of this virus (estimated 300 million globally) and the immense mortality (25-30%) that would result among the carriers who may progress to cirrhosis or hepatocellular carcinoma.

HEPATITIS C (Also known as Parenterally Transmitted Non-A, Non-B Hepatitis (PT-NANB) and Non-B Transfusion Associated Hepatitis). Hepatitis C virus is a small, enveloped, positive sense, single stranded RNA virus.

Pathogenesis and Pathology: Percutaneous exposure to blood and plasma derivatives, use of contaminated needles and syringes, needle stick injury in health care settings, sharing of needles by intravenous drug users, tattooing and skin piercing are the most common methods of transmission of HCV. Sexual transmission does not appear to be a substantial contributor to the spread of HCV infection. The virus has an average incubation period of 5-12 weeks, with peak of onset of disease 7-8 weeks after infection. The majority of acute cases are asymptomatic. Fatigue is common, but it is rarely clinically significant. Jaundice manifests in less than 25% of patients.

HEPATITIS E (Also known as Enterically Transmitted Non-A, Non-B Hepatitis (ET-NANB) Epidemic Non-A, Non-B Hepatitis, Faeco-oral Non-A, Non-B, HEV Infection). Hepatitis E virus (HEV) is small, round, nonenveloped, positive strand RNA virus.

Pathogenesis: Humans are the only natural host for HEV. Monkeys and chimpanzees have been experimentally infected with this virus. Natural infections have been described in pigs, chicken and cattle in endemic area. Primarily by faeco-oral route. Faecally contaminated water is the most common vehicle. Person to person transmission probably occurs through faeco-oral route.How HEV travels from gastrointestinal tract to liver is not known. Hectic viral replication is usually the first event and occurs before hepatocellular changes and inflammatory alterations manifest. Hepatitis and anti- HEV antibody appear to develop concurrently. The pathogenesis of fulminant hepatitis in pregnant women is not understood.

HEPATITIS D (Also known as Delta Agent Hepatitis, Hepatitis Delta Virus). Hepatitis D virus is a 35-37 nm particle. It contains HBsAg on the surface and delta antigen and a small RNA genome in the interior.

Pathogenesis and Clinical Features:  Since presence of HBV is necessary for the replicationof HDV, it can cause disease only in the presence ofHBV. There are three situations where it can happen.These are:

a. Patient gets simultaneous infection with HBV and HDV (coinfection). Replication of HDV shall depend upon the spread of progeny of HBV in sufficient number to ensure dual infection of susceptible liver cells. The disease shall resemble typical acute HBV infection and may progress to fulminant hepatitis.

b. Patient is already having HBV infection and gets superinfection with HDV (superinfection). A serious acute delta related hepatitis superimposes on the existing disease.

c. An asymptomatic carrier of HBV gets infected with HDV and acute hepatitis results. This can be confirmed by the absence of an HBV specific anti- HBc-IgM response.

Pathogenesis:  The incubation period of hepatitis D varies from 2-12weeks and is shorter in those who are carriers of HBV.The liver damage in hepatitis D has been associatedwith a virus mediated cytopathic mechanism, thusexplaining the failure of conventional immunosuppressivetherapy to alter the course of disease. Theactivity of chronic hepatitis correlates with the presencebut not with the amount of delta antigen in liver.It has been observed that children who develop mildHBV infection, often suffer severe and even fatal attacksof HDV infection.

HEPATITIS G

A new flavivirus-like agent was identified in the second half of 1994 which causes hepatitis in humans. This virus is distinct from HCV and has been labelled as hepatitis G virus (HGV). The transmission of HGV through blood transfusion and by other parenteral routes of exposure, such as through intravenous drug use, may occur. The majority of individuals infected with HGV do not have clinical evidence of liver disease. Although HGV has been linked to acute and chronic hepatitis, it is yet to be proved whether HGV is the causal agent for viral hepatitis.

5. HUMAN IMMUNODEFICIENCY VIRUS

Origin and Discovery of Causative Agent: First few cases of AIDS were detected in June, 1981, when the US. Centers for Diseases Control and Prevention (CDC) reported a cluster of Pneumocystis pneumonia (PCP) caused by a form of Pneumocystis carinii, now recognized as a distinct species Pneumocystis jiroveci, in five homosexual men in Los Angeles. In 1981, the CDC introduced the term AIDS to describe the newly recognized syndrome, though it was still casually referred to as GRID. In 1983, scientists led by Luc Montaginer at the Pasteur Institute in France first discovered the virus that causes AIDS. They called it lymphadenopathy associated virus (LAV). A year later a team led by Robert Gallo of the United States confirmed the discovery of the virus, but they renamed it human T lymphotropic virus type III (HTLV-III). HIV infection in humans is now pandemic. As of January 2006, the Joint United Nations Programmes on HIV/AIDS (UNAIDS) and the World Health Organization (WHO) estimated that AIDS has killed more than 25 million people since it was first recognized on December 1, 1981, making it one of the most destructive pandemics in recorded history. In 2005 alone, AIDS claimed an estimated 2.4 – 3.3 million lives, of which more than 570,000 were children. It is estimated that about 0.6% of the world’s living population is infected with HIV. A third of these deaths are occurring in sub- Saharan Africa, retarding economic growth and increasing poverty. According to current estimates, HIV is set to infect 90 million people in Africa, resulting in a minimum estimate of 18 million orphans.

Structure and Genome:

HIV is different in structure from other retroviruses. It is about 120 nm in diameter (around 60 times smaller than a red blood cell) and roughly spherical. It is composed of two copies of positive single stranded RNA that codes for the virus’s nine genes enclosed by a conical capsid composed of 2,000 copies of the viral protein p24. The single stranded RNA is tightly bound to nucleocapsid proteins, p7 and enzymes needed for the development of the virion such as reverse transcriptase, proteases, ribonuclease and integrase. A matrix composed of the viral protein p17 surrounds the capsid ensuring the integrity of the virion particle. This is, in turn, surrounded by the viral envelope which is composed of two layers of fatty molecules called phospholipids taken from the membrane of a human cell when a newly formed virus particle buds from the cell. Embedded in the viral envelope are proteins from the host cell and about 70 copies of a complex HIV protein that protrudes through the surface of the virus particle. This protein, known as env, consists of a cap made of three molecules called glycoprotein (gp) 120, and a stem consisting of three gp 41 molecules that anchor the structure into the viral envelope. This glycoprotein complex enables the virus to attach to and fuse with target cells to initiate the infectious cycle. Both these surface proteins, especially gp120, have been considered as targets of future

treatments or vaccines against HIV.

Diagram: Structure of the HIV

Mode of Transmission:  Epidemiological studies throughout the world haveshown four modes of HIV transmission. Unsafe sexualcontact, transfusion of contaminated blood, use of contaminatedsyringes and from infected mother to the newbornchild are the major routes of transmission of HIV.

Susceptibility of HIV:  Fortunately, HIV is a very fragile virus. It is susceptibleto heat, a temperature of 56°C for 30 minutes or boilingfor a few seconds kills the virus. Most of the chemicalgermicides used in hospital/laboratories and healthcare settings kill HIV at much lower concentrations.Thus 0.5 to 1% sodium hypochlorite, 70% ethanol, 2%glutaraldehyde, acetone, ether, beta propiolactone(1:400 dilution) and sodium hydroxide (40 m Mol/litre) inactivate the virus.

Replication:  Glycoprotein 120/140 of HIV binds to a receptor/receptor on HIV permissive host cell. Predominantreceptor is the CD4 molecule present on T lymphocytesand macrophages, though others such as galactosylceramide (gel C) have also been proposed. Receptorsare molecules (proteins and or glycoproteins) presenton the surface of host cells which facilitate theattachment and entry of viruses in to the cell. Once the gp41/36 of the virusfuses with the host cell membrane the capsid isuncoated and a ribonucleoprotein complex capable ofreverse transcription is formed. During the process ofreverse transcription cDNA is formed under the effectof viral enzyme, the reverse transcriptase. Reverse transcription is inefficient in quiescent cells suggestingthe involvement of host components in the process.The nucleoprotein complex formed after transcriptioncomprises of linear double stranded DNA, the gagmatrix (MA) protein, the accessory vpr protein and theviral integrase (IN). This is called pre-integrationcomplex and is transported into the host cell nucleus.IN mediates a complex series of enzymatic steps andintegration occurs at cellular loci with open chromatinstructure. Integration probably is an essential step forviral replication. Virus expression can be stimulatedby many viral, cellular and exogenous factors. Other,co-existent viral infections, e.g. cytomegalovirus, herpesvirus, etc. can make the non-permissive cells permissive.Maturation of virus also takes place after virus assemblyand budding.

Genetic Variability:  HIV differs from many other viruses as it has veryhigh genetic variability. This diversity is a result of itsfast replication cycle, with the generation of 109 to 1010virions every day, coupled with a high mutation rateof approximately 3 × 105 per nucleotide base per cycleof replication and recombinogenic properties of reversetranscriptase. This complex scenario leads to thegeneration of many variants of HIV in a single infectedpatient in the course of one day.

Tropism:  The term viral tropism refers to which cell types HIVinfects. HIV can infect a variety of immune cells suchas CD4+ T cells, macrophages, and microglial cells.HIV-1 entry to macrophages and CD4+ T cells ismediated through interaction of the virion envelopeglycoproteins (gp120) with the CD4 molecule on thetarget cells and also with chemokine coreceptors.

Clinical Course of Infection:  Infection with HIV-1 is associated with a progressivedecrease of the CD4+ T cell count and an increase inviral load. The stage of infection can be determined bymeasuring the patient’s CD4+ T cell count, and thelevel of HIV in the blood. The first stage of infection, the primary,or acute infection, is a period of rapid viral replicationthat immediately follows the individual’s exposure to

HIV leading to an abundance of virus in the peripheral blood with levels of HIV commonly approaching several million viruses per mL. This response is accompanied by a marked drop in the numbers of circulating CD4+ T cells. This acute viraemia is associated in virtually all patients with the activation of CD8+ T cells, which kill HIV-infected cells, and subsequently with antibody production, or sero-conversion. A strong immune defense reduces the number of viral particles in the bloodstream, marking the start of the infection’s clinical latency stage. Clinical latency can vary between two weeks and 20 years. During this early phase of infection, HIV is active within lymphoid organs, where large amounts of virus become trapped in the follicular dendritic cells (FDC) network. The surrounding tissues that are rich in CD4+ T cells may also become infected, and viral particles accumulate both in infected cells and as free virus. Individuals who are in this phase are still infectious. During this time, CD4 + CD45 RO + T cells carry most of the proviral load. When CD4 + T cell numbers decline below a critical level, cell-medicated immunity is lost, and infections with a variety of opportunistic microbes appear. The first symptoms often include moderate and unexplained weight loss, recurring respiratory tract infections (such as sinusitis, bronchitis, otitis media, pharyngitis), prostatitis, skin rashes, and oral ulcerations. Common opportunistic infections and tumors, most of which are normally controlled by robust CD4 + T cell-mediated immunity then start to affect the patient. Typically, resistance is lost early on to oral Candida species and to Mycobacterium tuberculosis, which leads to an increased susceptibility to oral candidiasis (thrush) and tuberculosis. Later, reactivation of latent herpes viruses may cause worsening recurrences of herpes simplex eruptions, shingles, Epstein Barr virus-induced B-cell lymphomas, or Kaposi’s sarcoma, a tumor of endothelial cells that occurs when HIV proteins such as Tat interact with Human Herpesvirus-8.

Mechanism of Cell Death:

• Increase in cell permeability due to budding of virus.

Virus punches holes and kills the cell.

• Increase in cell permeability due to toxic effects of

virus replication.

• Syncytia formation – involving uninfected cells.

• Apoptotic cell death of activated T cells.

• Autoimmune phenomenon involving CD4 molecule.

• ADCC, i.e. antibody dependent cell cytotoxicity.