Molecular Structure and Function of HIV-1

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.