Structure and Genome of HIV - Genome Organization

Genome Organization

HIV has several major genes coding for structural proteins that are found in all retroviruses, and several nonstructural ("accessory") genes that are unique to HIV. HIV has three major genes, 5'gag-pol-env-3', encoding major structural proteins as well as essential enzymes. These are synthesized as polyproteins which produce proteins for virion interior, called Gag, group specific antigen; the viral enzymes (Pol, polymerase) or the glycoproteins of the virion env (envelope). In addition to these, HIV encodes for proteins which have certain regulatory and auxiliary functions as well. HIV-1 has two important regulatory elements: Tat and Rev and few important accessory proteins such as Nef, Vpr, Vif and Vpu which are not essential for replication in certain tissues. The gag gene provides the basic physical infrastructure of the virus, and pol provides the basic mechanism by which retroviruses reproduce, while the others help HIV to enter the host cell and enhance its reproduction. Though they may be altered by mutation, all of these genes except tev exist in all known variants of HIV; see Genetic variability of HIV.

• gag (group-specific antigen):encodes for the precursor gag polyprotein, which is processed by viral protease during maturation to MA (matrix protein, p17); CA (capsid protein, p24); SP1 (spacer peptide 1, p2); NC (nucleocapsid protein, p7); SP2 (spacer peptide 2, p1) and p6.
• pol: encodes for viral enzymes reverse transcriptase(RT) and RNase H, integrase (IN), and HIV protease (PR). HIV protease is required to cleave the precursor gag polyprotein to produce structural proteins, RT required to transcribe DNA from RNA template as well as IN to integrate the ds viral DNA into the host genome.
• env (for "envelope"): codes for gp160, which is cleaved by cellular protease rather than viral to produce the surface (SU) lipoprotein gp120(SU)which attaches to the CD4 receptors present on lymphocytes and gp41(transmembrane, TM), proteins embedded in the viral envelope that enable the virus to attach to and fuse with target cells.
• Essential regulatory elements: Tat and Rev

• Tat- HIV trans-activator(Tat)plays an important role in regulating the reverse transcription of viral genome RNA ensuring efficient synthesis of viral mRNAs as well as regulating the release of the virions from the infected cells. Tat is expressed as 72-amino acid one-exon Tat as well as the 86-101 amino-acid two-exon Tat playing an important role early in HIV infection.Tat(14-15kDa) binds to the bulged genomic RNA stem-loop secondary structure near the 5' LTR region forming the Tat Responsive element (TAR).
• Rev recognizes a complex stem-loop structure of the mRNA env located in the intron separating coding exon of Tat and Rev which is known as the Rev response element (RRE). Rev is important for the synthesis of major viral proteins, hence essential for viral replication.

• Accessory regulatory proteins: Nef, Vpr, Vif and Vpu.
• "The lentivirus protein R (vpr): Vpr is a virion-associated, nucleocytoplasmic shuttling regulatory protein. It is believed to play an important role in replication of the virus. It is believed to play an important role in nuclear import of preintegration complex as well as inducing arrest in G2 of cycling cells which activates the DNA repair machinery which could be used by the virus for the integration of the viral DNA. HIV-2 and SIV encode an additional Vpr related protein called Vpx which functions sin association with Vpr.

• vif,- Vif is a highly conserved, 23 kDa phosphoprotein important for the infectivity of HIV-1 virions depending on the cell-type. Some cells such as lymphocytes, macrophages, and cell lines like H9 cells require Vif for synthesis of fully infectious viruses where as other cells such as Hela, Cos and others do not require Vif.

• nef- Nef, negative factor, is a N-terminal myristoylated membrane-associated phosphoprotein. It is involved in multiple functions during the replication cycle of the virus. It is believed to play an important role in cell apoptosis and increase in virus infectivity.

• vpu,Virus protein U- Vpu is specific to HIV-1, is a class I oligomeric integral membrane phosphoprotein with numerous biological functions. It is involved in the CD4 degradation involving the ubiquitin proteasome pathway as well as in the successful release of the virions from the infected cells.

• tev: This gene is only present in a few HIV-1 isolates. It is a fusion of parts of the tat, env, and rev genes, and codes for a protein with some of the properties of tat, but little or none of the properties of rev.

HIV employs a sophisticated system of differential RNA splicing to obtain nine different gene products from a less than 10kb genome. HIV has a 9.2kb unspliced genomic transcript which encodes for gag and pol precursors; a singly spliced, 4.5 kb encoding for env, Vif, Vpr and Vpu and a multiply spliced mRNA,2kb encoding for Tat, Rev and Nef.