Molecular Structure and Function of HIV-1

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The HIV-1 genome, like other retroviral genomes, is diploid, consisting of two identical viral RNA molecules assembled in a hydrogen-bonded 70S complex. These genomic subunits are plus strands of viral RNA in that they have the same chemical polarity as the mRNA from which viral products are translated. Like eukaryotic mRNAs, the genomic viral RNA contains a 5 methylated-G nucleotide, a poly(A) tract of 100 to 200 nucleotides at its 3 end, and a number of methylated(A) residues. Host cell-derived tRNA incorporated within the virion is base paired over a stretch of 18 nucleotides to the primer binding site of the genomic viral RNA near its 5 terminus and serves to prime the synthesis of minus-strand DNA during the initial stages of viral replication following infection.

The HIV-1 genome is bounded by long terminal repeat (LTR) elements and contains genes encoding structural and enzymatic proteins ( gag, pol, and env) found in all other replication-competent retroviruses. In addition to these, however, HIV-1 contains genes encoding other viral functions unique to this family of viruses that are responsible for their biologic behavior. The LTR sequences of HIV-1 direct and regulate expression of the viral genome.

The gag gene encodes a precursor protein of 55 kilodaltons (p 55), which is cleaved into four smaller products with the linear order NH₂ -p18-p24-p9-p7-COOH. These proteins constitute the core protein structure of the virus and also subserve nucleic acid and lipid membrane binding functions. The gag proteins of HIV-1, like those of other retroviruses, are synthesized as a polyprotein precursor that subsequently is cleaved during the viral maturation process. This facilitates the assembly of the different components of the virus core structure into a three-dimensional configuration that, when cleaved by a specific virus-derived protease, acquires the specialized functions characteristic of the mature virion. The polymerase gene products are translated from the same genomic RNA message as the gag proteins but in a different, overlapping reading frame as a result of ribosomal frame shifting. The pol gene encodes three proteins that are cleaved from a larger precursor polypeptide. These genes include NH₂ -protease(p13)-reverse transcriptase (p66/p51)-integrase(p31)-COOH. The HIV-1 protease plays a critical role in virus biology, acting specifically to cleave gag and pol precursor polypeptides into functionally active proteins. The reverse transcriptase of HIV-1 is a magnesium-requiring, RNA-dependent DNA polymerase responsible for replicating the RNA viral genome. The integrase protein is required for proviral integration into the host cell genome. The envelope gene (env) encodes a glycosolated polypeptide precursor (gp160) that is processed to form the exterior envelope glycoprotein (gp120) and the transmembrane glycoprotein (gp41), which anchors the envelope complex to the virus surface. It is the viral envelope that is responsible for CD4 binding, fusion, and virus entry.

Within the HIV-1 genome, there are additional genes that serve important viral functions and that distinguish HIV-1 from oncogenic retroviruses. These include the vif, vpr, and vpu genes located between pol and env; the nef gene located 3 to the env and extending into the U3 region of the viral LTR; and the tat and rev genes, both of which exist as bipartite coding exons in the central and 3 end of the virus. The tat gene encodes a 14-kDa protein that is essential for HIV-1 replication, upregulating HIV-1 expression at both transcriptional and post-transcriptional levels. The target sequence for tat-mediated upregulation of HIV-1 expression is the trans-acting responsive region (TAR) of the LTR, which apparently interacts with cellular factors induced by tat because the tat protein itself has not been shown to bind and activate TAR directly. The rev gene is also absolutely required for HIV-1 replication, facilitating transport of unspliced viral mRNA from the nucleus to cytoplasm. In the absence of rev genes, gag and env mRNA, transcripts are multiply spliced such that gag and env proteins are not made.

The vif gene encodes a protein product of 23 kDa, which is required for the production of virions that are fully infectious. The mechanisms of vif action are currently unknown. The vpr gene encodes a protein of 15 kDa which is involved in transport of the viral preintegration complex to the nucleus. The vpu gene encodes a 16-kDa protein that is involved in virus assembly and release. The nef gene encodes a 27-kDa protein that decreases CD4 expression in virally infected cells, and by this or other means, accentuates viral pathogenesis in vivo.

In summary, HIV-1 encodes the usual structural and enzymatic proteins typical of other replication-competent retroviruses, including gag, pol, and env, but in addition it encodes a group of at least six regulatory or auxiliary proteins ( vif, vpr, vpu, tat, rev, and nef) whose activities are critically important in regulating the lifecycle and pathogenesis of the virus.

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