2 курс / Микробиология 1 кафедра / Доп. материалы / Kartikeyan_HIV and AIDS-Basic Elements and Properties

poliomyelitis and diphtheria, high levels of herd immunity may lead to elimination of the diseases, in course of time. The eradication of smallpox was not due to high levels of herd immunity (achieved by immunisation programme) but due to elimination of the source of infection (by surveillance and containment measures).

2.11 – HYPERSENSITIVITY

Hypersensitivity leads to immuno-inflammation or immunologically mediated tissue damage. Coombs and Gell (1963) described the types of hypersensitivity reactions.

Type I (Immediate Hypersensitivity): In allergic individuals, IgE is produced in response to antigens like pollen, food, clothing, dust, and drugs. Sensitised mast cells and basophils release vasoactive amines. Systemic anaphylaxis occurs when a majority of the body’s mast cells are sensitised. Localised immuno-inflammation can occur in the skin (urticaria), nasal mucous membrane (allergic rhinitis), or bronchial mucous membrane (extrinsic asthma).

Type II (Cytotoxicity): Types of type II hypersensitivity reactions are: (a) com- plement-mediated hypersensitivity, e.g. drug-induced haemolytic anaemia, immune-mediated thrombocytopenic purpura, acute glomerulonephritis, rheumatic heart disease, and Goodpasteur syndrome; (b) stimulatory hypersensitivity (or Type-V hypersensitivity) in which, the antibody binds to receptors on the cell membrane causing stimulation (not destruction). Hyperthyroidism due to antithyroid antibodies is an example; (c) ADCC, also called Type-VI hypersensitivity, which involves killer T-cell mediated cell damage. Hashimoto’s disease is an example.

Type III (Immune Complex Diseases): Normally, macrophages or monocytes remove antigen–antibody complexes. In type III hypersensitivity, antigen–antibody complexes are slowly cleared from circulation or tissues. Immuno-inflammation is initiated in joints, kidney, lung, and choroid plexus. Examples of immune complex diseases are Arthus reaction, erythema nodosum leprosum, and serum sickness.

Type IV (Delayed-Type Hypersensitivity or DTH): Immuno-inflammation is initiated by T-lymphocytes that secrete lymphokines. The types of DTH include infection-type of DTH (caseation in tuberculosis, nerve damage in tuberculoid leprosy, and granuloma formation in chronic diseases), and chronic dermatitis-type DTH (contact dermatitis).

2.12 – IMMUNE DEFICIENCY

A compromised host lies open, as a form of exposed, all-purpose culture plate. He not only admits many kinds of ambient organisms with ease, but usually does so in relative silence – Paul Russel (cited by Rubin & Young, 1994).

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CHAPTER 3

HUMAN IMMUNODEFICIENCY VIRUS (HIV)

Abstract

The causative organism, HIV, is classified within Lentivirus (Latin: lenti = slow) subgroup of a new family of viruses, Retroviridae. During replication of these viruses, the flow of genetic information is in the opposite direction (from RNA to DNA). Hence, they are called retroviruses. Their unique enzyme reverse transcriptase copies the viral RNA into DNA, which is eventually inserted into the genome of the host cells. Hence, the virus persists within the host cells for years and cannot be eradicated from the host cells with any of the currently available ARV drugs. A unique two-layered envelope derived from the host cell membrane surrounds a cone-shaped protein core. HIV is a fragile virus that is easily inactivated by heat, drying, and chemical agents. There are two distinct antigenic variants of this virus: HIV-1 and HIV-2. An epidemic of HIV-2 is occurring in parallel with that of HIV-1 in India, indicating the presence of a considerable epidemic of HIV-2 outside West Africa and has implications for designing HIV vaccines for India.

Key Words

Clades, Co-receptor, Dual infection, HIV-1, HIV-2, HIV subtypes, Lentivirus, Origin of HIV, Replication, Retrovirus

3.1 – RETROVIRUSES AND HIV

Replication in most organisms involves the flow of genetic information from DNA to RNA. However, during replication of viruses belonging to Retroviridae family, the flow of genetic information is in the opposite direction (from RNA to DNA). Hence, these organisms are called retroviruses (Latin: retro = backwards). Retroviruses have a unique enzyme, reverse transcriptase (RNA-directed DNA polymerase), which prepares a DNA copy of the RNA genome in the host cell. This DNA copy is eventually inserted into the genome of the host cells. Hence, the virus persists within the host cells for years and cannot be eradicated from the host cells with any of the currently available ARV drugs. Based on biological properties, appearance in cell cultures and later, on sequences of nucleotides, family Retroviridae is newly classified into five groups.

Lentiviruses: Their name refers to their association with slowly progressive diseases. (Latin: lenti = slow). They are not associated with neoplasia. They include 39

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HTLV-II is not linked to any particular disease, though it was first isolated from a patient with rare T-hairy cell leukaemia. Both HTLV-I and HTLV-II are cell-associated viruses and are transmitted by transfer of infected cells during sexual intercourse, breastfeeding, blood transfusion, and sharing injecting equipment. Assays are available for detecting antibodies to HTLV-I. Proviral sequences can be detected by polymerase chain reaction (PCR). PCR can also differentiate between HTLV-I and HTLV-II (Simmonds & Peutherer, 2006).

3.1.3 – Discovery of HIV

AIDS was first recognised in the United States in 1981 amongst a small cohort of young homosexuals and drug addicts in whom Kaposi’s sarcoma and Pneumocystis pneumonia (PCP) were associated findings (Gottlieb et al., 1981b; Gottlieb et al., 1981c). In 1983, Luc Montagnier and his colleagues from Pasteur Institute, Paris, isolated a virus from a patient with lymphadenopathy syndrome and called it “lymphadenopathy-associated virus” (LAV) (Barre-Sinoussi et al., 1983). In 1984, Robert Gallo and his colleagues from National Institutes of Health, Maryland (USA), reported that a retrovirus named “human T-lymphotrophic virus-III” (HTLV-III) caused AIDS (Gallo et al., 1984; Sarangadharan et al., 1984). The same virus was named “AIDS associated retrovirus” by Levy and colleagues from San Francisco, USA (Levy et al., 1984). In May 1986, the International Committee on Virus Nomenclature and Taxonomy gave the HIV virus its present name. In 1986, Luc Montagnier and his associates isolated a second type of HIV (called “HIV-2”) from West African patients (Clavel et al., 1986).

3.2 – STRUCTURE OF HIV

HIV is an enveloped icosahedral sphere (i.e. a solid with 20 plane faces; Greek: eikosi = twenty; hedra = seat). The diameter of the virus is 80–120 nm. Two identical, non-complementary strands of RNA (the viral genome) and three enzymes (reverse transcriptase, integrase, and protease) are packaged in a coneshaped protein core. This core is surrounded by a protein coat called “capsid”. The capsid, along with the enclosed nucleic acid, is called “nucleocapsid”. The capsid comprises a large number of polypeptides known as “capsomers”. The functions of the capsid are to form a protective shell around the nucleic acid core, and to introduce the viral genome into host cell by adsorbing readily to host cell surfaces.

A unique two-layered envelope derived from the host cell membrane surrounds this core. This envelope is acquired by progeny viruses during release through host cell membrane by a process called “budding”. The outermost envelope is made of glycoprotein subunits that are exposed as spikes (or knobs). These projecting structures are called “peplomers” (Greek: peplos = envelope). The surface glycoprotein 120 (gp120) is bound to the virus by a transmembrane

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and specifies a transactivating factor that increases synthesis of viral proteins. The rev (regulatory of virus) gene: the rev protein activates expression of structural and enzymatic genes. The nef (negative factor) gene: nef protein regulates pathogenicity and probably the latent state of HIV. The vif (viral infectivity factor) gene: vif protein is responsible for viral budding and infectivity of free virions. The vpr gene: vpr protein stimulates promoter region of HIV. The vpu gene exists only in HIV-1 and codes for small proteins whose function is not known. Vpu protein promotes release of budding progeny viruses from host cell. The vpx gene exists only in HIV-2 and performs the same functions as vpu gene of HIV-1. Long terminal repeat (LTR) sequences at either end give signals for enhancing and integrating to the promoter region of the virus (Simmonds & Peutherer, 2006).

3.3 – VARIANTS OF HIV

Within the host cells, viral RNA may break and recombine with RNA of other HIV subtypes, producing further inter-subtype variations. It is estimated that a change in one nucleotide base of viral RNA (called a “single point mutation”) occurs about 105 times in a day in an infected individual. This mutation results in production of genetically diverse types of viruses in the same individual. The differences in the genetic sequences usually occur in the regions that code for most immunogenic viral proteins, such as gp120 and gp41. Hence, a vaccine developed from one strain of HIV may be ineffective against other strains, especially in different geographical regions. However, cross-protection has been experimentally demonstrated in monkeys vaccinated with HIV-1, HIV-2, and SIVs. Variants of HIV can be subdivided into antigenic variants, and syncytium-inducing (SI) and non-syncytium-inducing (NSI) variants.

3.3.1 – Antigenic Variants

The core and envelope antigens of HIV undergo frequent mutations. There are two distinct antigenic variants of this virus, called HIV-1 and HIV-2, both of which undergo genetic variations and differ in their envelope antigens. Their core polypeptides exhibit cross-reactivity. As the virus continues to mutate, new subtypes may be discovered in future.

HIV is genetically labile due to continuous mutations in its genome due to a high error rate of reverse transcriptase. These viruses lack mechanisms for “proof reading” and repair of errors that occur during replication. These uncorrected errors change the genetic composition during replication and the existing strain is replaced by a new antigenic variant. Thus, HIV has the ability to mutate into drug-resistant or more virulent forms. The genetic sequencing of the full genome of HIV has helped in determining the recombination between subtypes, also called “clades” (McCutchan, 2000; Piyasirisilp et al., 2000; Tovanabutra et al., 2001).

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Subtypes B and C among IDUs in southern Yunnan Province of China yielded mutants CRF07_BC and CRF08_BC, which subsequently became the predominant subtypes as the HIV-1 epidemic spread to the north and east (Yu et al., 2003; Su et al., 2000; Beyner et al., 2000). A recent outbreak of HIV-1 infection in southern China was initiated by two highly homogenous, geographically separated strains, circulating recombinant form AE, and a novel BC recombinant (Piyasirisilp et al., 2000).

In India, HIV-1 subtype C predominates (91 per cent), followed by subtypes B, A, and E (Mandal et al., 2000; Chakrabarti et al., 2000; Gadkari et al., 1998; Halani et al., 2001; Sahni et al., 2002; Tripathy et al., 1996). Inter-subtype recombinants (A/C, B/C) have also been described in India (Lele et al., 1999). HIV-2 is also circulating in India. Due to increasing international travel and population migration, increasing numbers of variants are being detected in India. Knowledge of the local subtypes would be useful in choice of appropriate vaccines for clinical trials.

3.3.1.2 – HIV-2

Though the routes of transmission and clinical manifestations are similar, there are biological differences between HIV-1 and HIV-2 (Gnann, et al., 1987). This is a distinct virus but it exhibits 40–50 per cent homology with gag and pol genes of HIV-1. It has closer nucleotide similarities with some SIVs (75 per cent nucleotides are similar), as compared to HIV-1. HIV-2 has five subtypes from A to E (Donley et al., 1993; UNAIDS, 2000). As compared to HIV-1, HIV-2 is less easily transmitted (i.e. less infectious), has a longer incubation period between infection and manifestation of illness, patients with HIV-2 infection have a lower viral load, and the progress of the disease is slower (Cunningham et al., 1997).

Highest rates of HIV-2 infection are seen in West African countries. It is also seen in migrants or travellers from endemic areas or their sexual or injecting drug-using partners. Prevalence of HIV-2 infection in India is around 1.7–4.6 per cent (Hira et al., 1996; Dattatray et al., 1996). HIV-1, HIV-2 and their subtypes may be detected only if the test kit contains the prevalent subtypes in that locality. Certain subtypes are more readily transmitted by certain routes. Genetic variation in HIV-1 and HIV-2 has tremendous implications for design of HIV vaccines. A vaccine that offers protection against a serotype may not effectively protect against another serotype or inter-serotype recombinant (Excler, 2005).

3.3.1.3 – Dual Infection with HIV-1 and HIV-2

Prevalence of dual (HIV-1 and HIV-2) infection in India is about 3.3–20.1 per cent (Hira et al., 1996; Dattatray et al., 1996). Dual infection has also been reported among injecting drug users from Manipur in northeastern India (Singh et al., 1995). Studies have revealed that epidemic of HIV-2 is occurring in parallel with that of HIV-1 in India (Rubasamen-Waigmann et al., 1991; Nandi et al., 1994; Singh et al., 1995). These results imply the presence of a considerable

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