Viral Structure

 Human immunodeficiency virus is a member of the family Retroviridae, a type D retrovirus that belongs to the lentivirus subfamily. Included in this family are oncoviruses (e.g., HTLV-I, HTLV-II), which primarily induce proliferation of infected cells and formation of tumors. Since the discovery of this virus, much has been learned about the impact of HIV on human cells. Two distinct HIV viruses, types 1 and 2 (HIV-1 and HIV 2), cause AIDS. HIV-1 is divided into nine subtypes: group M (subtypes A-H), group N, and group O. HIV-2 is divided into two subtypes, groups A and B.

The HIV-1 virus (Fig. 1) is composed of a lipid mem brane, structural proteins, and glycoproteins that protrude. The viral genome consists of three important structural com ponents—pol, gag, and env. These gene components code for various products (Table 1). Long terminal redundancies (LTRs) border these three components. HIV-2 has a different envelope and slightly different core proteins.

Fig1. The human immunodeficiency virus. The envelope is  made up of glycoproteins (gp) of 120 kDa and 41 kDa. The main core  protein is p24. As an RNA virus, it relies on reverse transcriptase to  produce complementary DNA for transcription and translation. (From Peakman M, Vergani D: Basic and clinical immunology, ed 2, London, 2009, Churchill Livingstone.)

Table1. Viral Genome Components

Cells infected with HIV can be examined with an electron microscope. The virus may appear as buds of the cell membrane particles. The virion has a double-membrane envelope and an electron-dense laminar crescent or semicircular cores. An inter mediate, less electron-dense layer lies between the envelope and core. In a mature, free extracellular virion, the core appears as a bar-shaped nucleoid structure in cross section. This structure appears circular and is frequently located eccentrically. It is composed of structural proteins and glycoproteins that occupy the core and envelope regions of the particle. The virion consists of knoblike structures composed of a protein called glycoprotein (gp) 120, which is anchored to another protein called gp41. Each knob includes three sets of these protein molecules. The core of the virus includes a major structural protein called p25 or p24 encoded for by the gag gene. After human exposure, these and other viral components may induce an antibody response important in serodiagnosis (Table 2).

Table2. HIV Proteins of Serodiagnostic Importance

Retroviruses contain a single, positive-stranded ribonucleic acid (RNA) with the genetic information of the virus and a special enzyme called reverse transcriptase in their core. Reverse transcriptase enables the virus to convert viral RNA into deoxyribonucleic acid (DNA). This reverses the normal process of transcription in which DNA is converted to RNA— thus, the term retrovirus.

The genomes of all known retroviruses are organized in a similar way. In the provirus, which is formed when complementary DNA (cDNA) synthesis is completed from the retro viral RNA template, viral core protein, envelope protein, and reverse transcriptase are encoded by the gag, env, and pol genes, respectively, whereas viral gene expression is regulated by tat, trs, sor, and 3′orf gene products. The gag gene encodes a poly protein found at high levels in infected cells and is subsequently cleaved to form p17 and p24, both of which are associated with viral particles. The pol gene encodes for reverse transcriptase, endonuclease, and protease activities. The sor gene stands for small open-reading frame. The sor gene product is a protein that induces antibody production in the natural course of infection. The tat gene also represents a small open-reading frame; the protein product has not been identified to date.

The env gene encodes for a polyprotein that contains numerous glycosylation sites. The glycoprotein gp160 is found on infected cells but is deficient on viral particles; however, gp160 gives rise to two glycoproteins, gp120 and gp41, which are associated with the viral envelope. The encoding genes and gene products, or antigens, of the AIDS virus may induce an antibody response after human exposure (Table 3).

Table3. Encoding Genes and Antigens of AIDS Virus

LTRs, which exist at each end of the proviral genome, play an important role in the control of viral gene expression and the integration of the provirus into the DNA of the hosts. Although a structural similarity exists between the genomes of HIV-1 and HIV-2 (HTLV-IV), the nucleotide sequence homology is limited. There is a nucleotide sequence homology of only 60% between the gag genes and 30% to 40% between the remainder of the genes of HIV-1 and HIV-2.

Viral Replication

The replication of HIV is complicated and involves several steps (Fig. 2). The HIV life cycle is that of a retrovirus (Box 1). Retroviruses are so named because they reverse the normal flow of genetic information. In body cells, the genetic material is DNA. When genes are expressed, DNA is first transcribed into messenger RNA (mRNA), which then serves as the template for the production of proteins. The genes of a retrovirus are encoded in RNA; before they can be expressed, the RNA must be converted into DNA. Only then are the viral genes transcribed and translated into proteins in the usual sequence.

Fig2. HIV replication cycle. Steps in the HIV replication cycle. 1. Fusion of the HIV cell to the host cell surface; 2. HIV RNA, reverse  transcriptase, integrase, and other viral proteins enter the host cell; 3. viral DNA is formed by reverse transcription; 4. viral DNA is transported  across the nucleus and integrates into the host DNA; 5. new viral RNA is used as genomic RNA and to make viral proteins; 6. new viral RNA and  proteins move to the cell surface and a new, immature, HIV virus forms; 7. the virus matures by protease releasing individual HIV proteins. (Courtesy National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.)

Box1. Summary of HIV-1 Life Cycle

Target Cells. The infectious process begins when the gp120 protein on the viral envelope binds to the protein receptor, called CD4, located on the surface of a target cell. HIV-1 has a marked preference for the CD4+ subset of T lymphocytes (Fig.3). In addition to T lymphocytes, macrophages, peripheral blood monocytes, and cells in the lymph nodes, skin, and other organs also express measurable amounts of CD4 and can be infected by HIV-1. About 5% of the B lymphocytes may express CD4 and may be susceptible to HIV-1 infection. Macrophages may play an important role in spreading HIV infection in the body, both to other cells and to the target organs of HIV. Monocyte-macrophages enable HIV-1 to enter the immune-protected domain of the central nervous system (CNS), including the brain and spinal cord.

Fusion of the virus to the membrane of a host cell enables the viral RNA and reverse transcriptase to invade the cytoplasm of the cell. However, CD4 receptors are not sufficient for HIV envelope fusion with the T4 cell membrane or for HIV penetration or entry into the interior of the cell. Chemokine coreceptors to CD4, which HIV uses to enter a host cell after binding to it, have been identified. Beta chemokine receptors are cell surface proteins that bind small peptides. They are classified into three groups, depending on the location of the amino acid cysteine (C) in the peptide. These receptors are identified by the individual chemokine(s) that bind(s) to them. In essence, the reference to a specific chemokine also identifies its receptor. The first example of a coreceptor was CXCKR-4 (FUSIN R-4). Other coreceptors include CCKR-2 (R-2), CCKR-3 (R-3), and CC-CKR-5 (R-5). Current research involves exploring ways to block or fill the chemokine receptors with a harmless molecule, thus blocking the binding site of the HIV on the host cell.

Although some cells do not produce detectable amounts of CD4, they contain low levels of mRNA encoding the CD4 protein, which indicates that they do produce some CD4. Because these cells can be infected by HIV in culture, the expression of only minimal CD4 or an alternate receptor molecule may be sufficient for HIV infection to occur. These cell types include certain brain cells, neuroglial cells, a variety of malignant brain tumor cells, and cells derived from bowel cancers. Cells of the gastrointestinal system do not produce appreciable amounts of CD4, although chromaffin cells sometimes appear to be infected by HIV in vivo.

Replication. Retroviruses carry a single, positive-stranded RNA and use reverse transcriptase to convert viral RNA into DNA. The life cycle of the HIV-1 virus consists of five phases (see Box 1):

1. The virus attaches and penetrates target cells (e.g., lymphocytes) that express the CD4 receptor. After penetration, the virus loses its protein coat, exposing the RNA core.

2. Reverse transcriptase converts viral RNA into proviral DNA.

 3. The proviral DNA is integrated into the genome (genetic complement of the host cell).

4. New virus particles are produced as a result of normal cellular activities of transcription and translation.

 5. These new particles bud from the cell membrane.

Once the viral genome is integrated into host cell DNA, the potential for viral production always exists and the viral infection of new cells can continue.

Immunologic activation of CD4+ cells latently infected with HIV induces the production of multiple viral particles, leading to cell death. The extensive destruction of cells leads to the gradual depletion of CD4+ lymphocytes. Progressive defects in the immune system include a severe B cell failure, defects in monocyte function, and defects in granulocyte function.

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Rhabdoviridae

Human T-cell Lymphotropic Viruses, Types 1 and 2

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Acute and Chronic Hepatitis C

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Pathogenesis and clinical significance of HIV

Transmission of HIV

HIV replication