Retroviruses and Retroviral Diseases

Retrovirus

Contain RNA, not DNA.

Family Retroviridae

Contain enzyme called Reverse Trascriptase

When a retrovirus infects a cell, it injects its RNA and reverse trancriptase enzyme into the cytoplasm of that cell.

The enzyme reverse transcriptase, which causes synthesis of a complementary DNA molecule using virus RNA as a template.

HIV,  the AIDS ( Acquired Immune Deficiency Syndrome) virus is a retrovirus.

The retroviridae family encompasses a group of viruses
in which the replicative life cycle requires reverse transcription of the viral ribonucleic acid (RNA) genome into doublestranded deoxyribonucleic acid (DNA). In fact, discovery of the enzyme that performs this task, reverse transcriptase,
revolutionized the understanding of genetic structure and produced the enzymatic tools used in all modern molecular biology laboratories to study the structure of messenger RNA (mRNA) and evaluate gene expression. Retroviridae initially were identified in a variety of animal species in association with neoplasms such as leukemia and lymphoma; it subsequently was discovered that endogenous retroviral sequences are abundant in humans, comprising at least 1% of the human genome and demonstrating Mendelian inheritance patterns. Although the origins of these endogenous retroviral sequences are not known, one hypothesis is that they represent integrated remnant sequences of ancient infectious diseases. These sequences have remarkable similarity to exogenous retroviral genes and may be involved in autoimmune or neoplastic pathogenesis in both
animals and humans .
All retroviruses replicate in a specific and unique fashion from which the family derives its name. The virus first attaches to the host cell by means of knoblike structures on the viral surface that recognize specific receptors on the surface of the host cell. Penetration of the virus occurs by fusion of the virion and host cell lipid bilayers. The virus RNA genome is uncoated in the host cell cytoplasm where viral-encoded reverse transcriptase is required to produce a double-stranded DNA copy that is transported to the nucleus of the cell, where it is integrated into the host cell nuclear DNA genome. This integrated
viral DNA, called the ‘‘provirus,’’ subsequently is transcribed into viral RNA that can be used either to make more virion genomic RNA or to create RNA from which viral proteins may be synthesized. Translation and processing of viral mRNAs and their products are followed by assembly of viral RNA and structural proteins at the cell membrane, packaging, maturation and, finally, budding of mature progeny virions from the infected cell. 

Seven genera of the retroviridae are recognized, the most important of which from the standpoint of human disease are the lentiviruses, which include human immunodeficiency viruses (HIV) 1 and 2, and the oncoviruses, which include
the human T-lymphotropic viruses (HTLV) I and II. 

LENTIVIRUSES

Whereas oncoviruses generally transform the cells they infect, producing tumors (discussed later), lentiviruses fuse and kill cells, producing slowly progressive disease, the most important of which is the acquired immune deficiency syndrome (AIDS).

ORGANIZATION AND GENOMIC STRUCTURE Lentiviridae nucleic acid consists of two homologous single-stranded RNA molecules of about 9.5 kb in length. The RNA genome is diploid and contains both structural and non-structural genes. Three critical structural genes found in all lentiviruses are called gag, pol, and env. Gag produces several proteins, including the matrix and capsid proteins that are involved in virion assembly, and the nucleocapsid protein that coats the viral RNA. Pol codes for the critical enzymes involved in viral replication including reverse transcriptase, protease, and integrase. Of these, reverse transcriptase is the most important.

Reverse transcriptase acts in three ways: as an RNA-dependent DNA polymerase, as a DNA-dependent DNA polymerase, and as a ribonuclease. The gene for reverse transcriptase does not have a 3′ exonuclease-proofreading activity, resulting in a high error rate during replication—approximately one error in 104 nucleotides—and this contributes to the marked genetic variability of HIV. Env produces a precursor glycoprotein, gp160, which is cleaved to form two smaller glycoproteins, gp120 and gp41, both of which are required for binding and fusion of the virus to host cells. The lentivirus genome also has long terminal repeats (LTRs) that are required for integration, reverse transcription, and gene expression. Other essential determinants are required for initiation of transcription, encapsidation, transcription of the plus strand of RNA, and integration of the viral DNA into genomic regions. Other genes have multiple but non-essential functions. Two of the most important are tat and rev. These genes play a role in upregulation of viral transcription and export of viral mRNAs, respectively. In addition, multiple accessory genes in lentiviruses have a variety of functions including determining viral infectivity, decreasing immune surveillance by altering major histocompatability complex class I expression,

and producing infectious virions.

LIFE CYCLE

The lentivirus life cycle commences with attachment of virus, initially through gp120, to the host cell via the surface receptor CD4 and coreceptors such as CXCR4, CKR5, CKR2b, or CKR3. Productive infection does not require dividing host cells, but rather occurs in terminally differentiated cells, increasing the number of potential host cells for lentiviral infections and increasing the potential gene delivery value for lentiviral vectors in gene therapy. Although direct infection of cells may ultimately lead to cell death or depletion, functional impairment may result from secondary dysfunction of other cell types leading
to systemic signs or symptoms, thought to be relevant in HIV-associated encephalopathy or diarrhea. Primary host target cells include T lymphocytes, monocytes/macrophages, dendritic cells, and microglial cells.
Once host-cell entry is achieved, the viral genome undergoes reverse transcription into the DNA provirus, the provirus integrates into the host genome, and viral products are produced using both host and viral-encoded machinery. Replication competence requires all three of the major open reading frames—gag, pol, and env—in order to make a productive infection, that is then regulated by the accessory genes.
Host immunologic responses include development of cytotoxic lymphocytes with specificity for the gp120 or gp41  proteins as well as generation of neutralizing antibodies to decrease viral attachment to the host cell. Immunologic escape from these mechanisms results from the selection of new viral strains with generation of new immunogenic epitopes.

POTENTIAL THERAPEUTIC TARGETS IN

LENTIVIRUS INFECTIONS

The lipid envelope renders the lentiviral virion exquisitely susceptible to environmental insults, such as inactivation by drying or physical agents such as heat, disinfectants (e.g.,glutaraldehyde and hypochlorite), or even soap and water.
Multiple potential targets for anti-lentiviral pharmacologic therapy have been considered. These include: 

(a) inhibitors of virion infectivity by decreasing attachment or fusion;
(b) inhibitors of the translation and integration enzymes of the viral genome including reverse transcriptase, RNAase, and integrase;
(c) inhibitors of viral gene expression through
regulatory genes and products;
(d) inhibitors of virion formation through decreasing viral protease activity.

Once integration into the host genome occurs, a persistent infection develops that cannot be cleared from the genome. The current and approved therapies for lentiviral infections include inhibitors of reverse transcriptase and protease.

Reverse transcriptase can be inhibited by nucleoside analogs such as zidovudine (AZT), didanosine, stavudine, abacavir, and lamivudine. Nonnucleoside inhibitors of reverse transcriptase are nevirapine and efavirenz. Although multiple reverse transcriptase inhibitors are typically used therapeutically, drug-resistance is a problem and occurs through mutations of the reverse transcriptase gene and viral RNA recombination. Multiple protease inhibitors, including indinavir, nelfinavir, saquinavir, and ritonavir have been developed and are in clinical use, being assessed in therapeutic trials, or both.

HUMAN IMMUNODEFICIENCY VIRUSES 1 AND 2

HIV-1 was first identified and characterized by groups in the United States and France and initially was called by several different names, including the ‘‘lymphadenopathy associated virus,’’ ‘‘human T-lymphotropic virus type III,’’ and ‘‘the acquired immune deficiency retrovirus’’. Subsequently, the term ‘‘human immunodeficiency virus type 1’’ became universally accepted. It is estimated that about 40 million individuals throughout the world are infected with HIV and that about 5 million people die annually from HIV-associated disease, confirming that HIV is one of the most significant worldwide threats to health.
Analysis of HIV-1 DNA sequences shows that there is significant virus variation throughout the world. A number of factors contribute to the variability of nucleotide sequences of HIV seen within and among individuals and within geographic regions. These include the lack of proofreading of viral and cellular replicative enzymes, resulting in high error rates and production of variants; thus, multiple rounds of viral replication lead to the generation of
a large number of variants.

Reference by, Lynn K. Gordon.