The first phase of HIV replication, which includes viral entry, reverse transcription, and integration of the virus into the host genome, is accomplished by proteins provided by the virus. The second phase of replication, which includes the synthesis and processing of viral genomes, mRNAs, and structural proteins, uses the host cell machinery for transcription and protein synthesis. The end result of HIV replication in most cell types is cell death.

1. Attachment to a specific cell surface receptor: Attachment is accomplished via the gp120 fragment of the env gene product on the HIV surface, which preferentially binds to a CD4 receptor molecule (Figure1). Thus, the virus infects helper T cells, lymphocytes, monocytes, and dendritic cells, which contain this protein in their cell membranes (Figure 2).

Fig1. Binding of human immunodeficiency virus (HIV) to surface of lymphocyte.

Fig2. Attachment and entry of human immunodeficiency virus (HIV).

 2. Entry of virus into the cell: An additional coreceptor, a chemokine receptor, is required for entry of the viral core into the cell (see Figure 1). [Note: A chemokine is a cytokine with chemotactic properties, produced by lymphocytes and macrophages.]

Macrophages and T cells express different chemokine receptors that fulfill this function. Two chemokine receptors that are employed by HIV as coreceptors are CCR5 and CXCR4, which are expressed differentially on different cell types. The tropism of particular variants of HIV is determined, in part, by which coreceptor is present. Binding to a coreceptor activates the viral gp41 gene product, triggering fusion between the viral envelope and the cell membrane (Figure 3).

Fig3. The human immunodeficiency virus (HIV) replication cycle. ssRNA = single strand RNA.

3. Reverse transcription of viral RNA: After entering the host cell, the HIV RNA is not translated. Instead, it is transcribed into DNA by reverse transcriptase, an RNA-directed DNA polymerase that enters host cells as part of the viral nucleocapsid (see Figure 3). A host cellular transfer RNA (tRNA) is hydrogen-bonded to a specific site on each viral RNA molecule, where it functions as a primer for initiation of reverse transcription. This process takes place in the cytoplasm. The viral reverse transcriptase first synthesizes a DNA-RNA hybrid molecule, and then its RNase activity degrades the parental RNA molecule while synthesizing the second strand of DNA. This process results in duplication of the ends to form the LTRs. The resulting linear molecule of double-stranded DNA is the provirus. LTRs at either end of the provirus contain promoter and enhancer sequences2 that control expression of the viral DNA. Because the reverse transcriptase enzyme has no proofreading capacity, errors often occur during the conversion of genomic RNA into the DNA provirus. This error-prone process gives rise to 1 to 3 mutations per newly synthesized virus particle.

 4. Integration of the provirus into host cell DNA: The provirus, still associated with virion core components, is transported to the nucleus with the aid of p17 (MA). In the nucleus, viral integrase cleaves the chromosomal DNA and covalently inserts the provirus. The integrated provirus, thus, becomes a stable part of the cell genome and can never be eliminated (see Figure 3). The insertion is random with respect to the site of integration in the recipient DNA. Therefore, HIV has two genomic forms: namely, single-stranded RNA present in the extracellular virus and proviral double-stranded DNA within the cell.

5. Transcription and translation of integrated viral DNA sequences: The provirus is transcribed into a full-length mRNA by the cell RNA polymerase II. The genome-length mRNA has at least three functions: 1) Some copies will be the genomes of progeny virus and are transported to the cytoplasm in preparation for viral assembly. 2) Some copies are translated to produce the virion gag proteins. Further, by reading past the stop codon at the end of the gag gene about one of twenty times, a gag-pol polyprotein is produced. This is the source of the viral reverse transcriptase and integrase that will be incorporated into the virion. 3) Still other copies of viral RNA are spliced, creating new translatable sequences (see Figure 3). In all retroviruses, one of the spliced mRNAs is translated into the envelope proteins. In the complex viruses, such as HIV and HTLV, additional spliced molecules produce accessory proteins that are important in regulating transcription and other aspects of replication.

6. Regulation: Nonstructural genes encode a variety of regulatory proteins that have diverse effects on the host cell and on viral replication. The nef and vpu gene products down-regulate host cell receptors, including CD4 and major histocompatibility com plex class I molecules. These products enable efficient virus replication and viron production. The Rev and Tat proteins are produced from differentially spliced mRNAs. The Tat protein causes the host cell RNA polymerase to be more processive by preventing premature dissociation from the DNA template, which results in full-length HIV RNAs. The Rev protein interacts with specific viral mRNAs to enable their transport out of the nucleus, bypassing the splicing machinery. This process, therefore, enables viral mRNAs to be correctly translated into polypeptides, which will be packaged into new virions.

 7. Assembly and maturation of infectious progeny: These pathways differ from most other enveloped viruses. The Env polyprotein is processed and transported to the plasma membrane by the usual cellular route through the Golgi apparatus and cleaved into SU and TM molecules by a host cell protease. Assembly begins as the genomes and uncleaved Gag and Gag-Pol polyproteins associate with the TM-modified plasma membrane. As the virion buds from the surface, viral protease is activated and cleaves the polyproteins into their component proteins, which then assemble into the mature virion (Figure 4). Cleavage is a necessary step in the maturation of infectious virus.

Fig4. Processing of gag and gag-pol polyprotein precursor proteins by the viral protease.

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المزيد

مواضيع ذات صلة

Pathogenesis and clinical significance of HIV

Transmission of HIV

Hepatitis D

Prevention and Treatment of hepatitis B

Differentiating Acute and Chronic Hepatitis and the Chronic Carrier State

Flaviviridae

Togaviridae

Caliciviridae

Picornaviridae

Laboratory Assays of Hepatitis B

Epidemiology of Hepatitis B

Hepatitis A