General Characteristics of HIV
HIV-1 and -2 are retroviruses that belong to the Lentiviridae family. Structurally are con-stituted by two identical strands of (+)RNA associated with matrix proteins, a double protein capsid, and a lipid envelope with inserted glycoproteins. The genome includes the usual retroviral genes:
gag, which codes for structural proteins
pol, which codes for the reverse transcriptase. In its native form or after fragmenta-tion the pol gene product has several enzymatic activities:
endonuclease (integrase, ligase)
env, which codes for envelope glycoproteins
In addition, the HIV genome codes for a protease and several regulatory proteins. A gene located at the gag-pol junction encodes the protease. The gene is read at a different frame than the structural proteins, and the protease cuts itself free from the large polypep-tide chain generated from cell-expressed viral RNA and proceeds to further split the re-maining of the polyprotein precursor into several other proteins and peptides. The genes coding for regulatory proteins include:
1. tat(transactivator of transcription). Its product, protein p16, binds to a regionnear the 5’ end of a nascent viral RNA strand known as TAR (transactivator re-sponse sequence) and promotes full and effective transcription of that strand. Soluble Tat protein (p16) is released by infected cells and taken up by both in-fected and noninfected cells. When taken up by infected cells it promotes viral genome expression; in noninfected cells it mainly induces transcription of cellu-lar genes, creating ideal conditions for infection of the cell. In low concentra-tions, it also induces the expression of bcl-2, thus protecting the infected cell from apoptosis, an important step to insure full replication. Finally, Tat protein has immunosuppressive effects on noninfected T cells.
2. rev(regulator of expression of viral proteins). Encodes for a second protein, p19,which promotes the expression of HIV-1 structural proteins by directing un-spliced of single spliced viral mRNA to perinuclear clusters where translation takes place.
3. nef (negative expression factor, 25–27 kDa) was believed to have a downregu-lating effect on viral expression based on in vitro observations; this view has been revised and several important biological properties have been attributed to Nef:
Downregulates MHC-I and CD4 expression facilitating the evasion from the immune response.
Blocks signal transduction pathways by inactivating p56lck, a CD4-associ-ated tyrosine kinase whose activity is essential for the activation of p59fyn and Zap kinase. Thus, the signaling cascade triggered by TcR occupation in CD4+ cells is interrupted.
Promotes viral replication.
Finally, several structural proteins result from the expression of the gag gene. These proteins are designated by letters designating their general composition (p= protein; gp=glycoprotein) and numbers indicating their molecular weight in kilodaltons (17, 24, 41, 120, 160).
Glycoprotein (gp160) is the major envelope glycoprotein and is composed of a trans-membrane segment (gp41) noncovalently bound to the external major glyco-protein (gp120), highly immunogenic. It contains a number of separate regions that are immunogenic, some conserved and others highly variable, and a region that binds to the CD4 molecule. gp41 is believed to be analogous to the fusion-inducing proteins of paramyxovirus. Penetration of HIV into a cell requires ini-tial attachment through the CD4-gp120 interaction, followed by interaction of gp120 with a chemokine receptor and fusion mediated by gp41 in-teracting with a possible third receptor, yet to be characterized. It is also be-lieved that the fusion protein may mediate penetration in some cells lacking CD4.
p24 and p17 form the inner core and the outer layer of the viral capsid, respectively. p66, p51 and p31 have enzymatic activity (p66 and 51 have reverse transcriptase properties, while p31 is an endonuclease/ligase). p6 and p7 are small nucleic-acid–binding proteins.
The major structural proteins and the peptides derived from them are immunogenic and are recognized by the different components of the immune system of infected patients.