HIV is a retrovirus: it ahs two identical, single-stranded, plus-sense RNA gehnomes that must be converted to double-stranded DNA by reverse transcription before being expressed and replicated.

HIV Models: 

Murine AIDS (MAIDS) which is caused by the murine leukaemia virus (MLV) has been used as a mouse model for AIDS. MAIDS develops in T-cells that carry the CD4 receptor in their cell membranes.

Viral Structure:

RNA genome: The genome of the HIV virus consists of 2 identical RNA molecules. The HIV genome is about 10 kb in length and organized similarly to that of other retroviruses. The sequence is flanked by 2long terminal repeates (LTRs) (which are important in transcriptional control) The 5′ LTR contains the enhancer promoter sequences for viral transcription and the 3′ LTR contains the polyadenylation signal. From 5′ to 3′ the viral genome contains the following genes:

gag (group specific antigen) proteins which make up viral capsid and are recognized by specific antigens of immune system of infected organism. The gag gene encodes a precursor polyprotein that is cleaved by pol-encoded protease to yield p24, p7, p9 and p17. P17 and p24 around the RNA genome with 2 layers forming a cylindrical protein core.

pol (polymerase) a gene which encodes for a polyprotein which is cleaved to generate 3 enzymes: reverse transcriptase, protease and integrase.

HIV protease: plays an essential role in HIV replication, performing the psttranslational processing of the Gag and Gag-Pol proteins into the functional core proteins and viral enzymes. Inhibition of this enzyme leads to the production of immature, noninfectious viral progeny, blocking further rounds of infection.

Env (envelope) codes for  integrated in viral lipid layer. The HIV envelope glycoprotein, gp160, is the precursor to the gp120, which specifically binds to the surface receptor (CD4) of CD4+ cells, and the gp41, the transmembrane (TM) glycoprotein which initiates cell-membrane fusion, leading to the formation of multinucleated giant cells commonly called syncytia. Specifically, the env gene encodes a glycoslylated precursor polyprotein (gp160) that is cleaved by a host cell protease to yield a small carboxyl terminal fragment (gp41) which spans the virus membrane and a larger amino terminal fragment (gp120) which remains noncovalently associated with gp41 on the virus membrane. The env protein is important in CD4 binding and syncytial formation.  Syncytia blocking activity has been equated with the blocking of gp120/CD4 binding.

The envelope glycoprotein of HIV-1 is encoded by a bicistronic mRNA which contains the vpu open reading frame (ORF) upstream of the env ORF. Translation of env message produces a protein of 90 KDa that is cotranslationally glycosylated in the endoplasmic reticulum. This glycoslyation reduces the antigenicity of Env, presumably by allowing the molecule to appear to the immune system as “self.” Addition of approximately 31 Asparagine-linked, mannose-rich oligosaccharide chains yield the gp160 env glycoprotein precursor. Partial amino-acid sequencing and oligopeptide mapping have shown that gp160 is cleaved to produce the two mature env proteins, gp120 and gp41. 

In virions, external gp120 is responsible for interaction with the CD4 receptor, while the transmembrane gp41 serves as an anchor for gp120 through non-covalent interactions and mediates membrane fusion with target cells. Regions of Env that are conserved because of their involvement in the binding interactions with cellular molecules required for infectivity are poorly accessible to antibodies. For example, the binding site on gp120 for CD4, the primary cellular receptor for the primate immunodeficiency viruses, is recessed and surround by variable glycosylated regions. Similarly, the binding site for the chemokines receptors, (coreceptors for these viruses is masked by the variable loops  V2 and V3 until CD4 is engaged).

The gp41 transmembrane glycoprotein is involved in the fusion step between HIV and the target cell and it cannot be shed from the surface of virally infected cells. Immunoreactive regions of HIV type 1 gp41 have been mapped by reaction (polyclonal) HIV-1 antibody-positive human sera with sequential overlapping synthetic epitopes which covered the transmembrane protein.  Map of sequential B cell epitopes of the HIV-1 transmembrane protein using human antibodies as a probe.

The surface gp120 component; Antisera generated in animals against this peptide have been demonstrated to exhibit neutralizing activity.

Biochemical studies of gp120 have suggested that a putative CD4 binding site extends from aa residue 413 to 456. The CD4 binding site also incorporates additional AA sequences on the N and/or C terminus sides of this site (region from 335 to 517. 

The primate immunodeficiency viral genomes contains 6 other genes. The products of these additional genes function via interactions with host cell proteins to optimize viral replication by a variety of mechanisms.:

tat, for transactivator. Once HIV has been integrated into the host genome, the viral DNA is transcribed by the cellular . However, the host polymerase usually terminates transcription prematurely in what is known as . When conditions for viral growth are optimal, this premature termination is prevented by a virus encoded protein called “Tat” which bind to a specific stem-loop structure in the nascent RNA that contains a “bulged base.” Once bound to this specific RNA structure (called Tar), Tat assembles several cellular proteins which allow the RNA polymerase to continue transcribing. 

Tat activates proviral expression by interacting with a short sequence of RNA located at the 5′ end of all transcripts just downstream of the start site. The RNA sequence known as the TAR element (for trans-acting responsive), forms a 59 nucleotide RNA stem loop structure. The binding of TAT to the structure increases the initiation of transcription and it stabilizes the RNA polymerase complex as it moves along the proviral DNA so that RNA transcription does not terminate prematurely. Thus transcription of the proviral genome increase by several thousand-fold in the presence of Tat.

rev, for regulator of expression of virion proteins. Rev binds to a specific RNA sequence (Rev responsive element, RRE) located within a viral intron. The Rev protein interacts with a nuclear export receptor (exportin 1), which directs the movement of viral RNAs through nuclear pores into the cytosol despite the presence of intron sequences. In early HIV infection, Rev is involved in the division of viral infection into an early phase (where Rev is translated form a fully spliced RNA and RNAs containing an intron are retained in the nucleus and degraded) and a late phase (where unspliced RNAs are exported due to Rev). Early in HIV infection, only the fully spliced RNAs (which contain the coding sequences for Rev, Tat, and Nef) are exported from the nucleus and translated. Once sufficient Rev protein has accumulated and been transported into the nucleus, unspliced viral RNAs can be exported from the nucleus.

Accessory Proteins: 

These proteins aid the regulatory proteins in controlling transcription.

nef, for negative regulatory factor. Several reports indicate that an attenuated nef-defective HIV mutant might be one of the reasons for the long-term non-progessor (LTNP) clinical status among some HIV infected patients. 

vpu

vpr, for viral protein R

vif, for viral infectivity factor

Transcription Factors: 

A cellular transcription factor responsible for inducing numerous cellular genes important in HIV replication