HIV structure and organisation

HIV is classified into the family Retroviridae, subfamily Lentiviridae, and genus Lentivirus [20, 21]. The structure of HIV follows the typical pattern of a complex retrovirus family, comprising a single-stranded, positive-sense ribonucleic acid (RNA) genome of about 9.2 kilobases that encodes structural, enzymatic and accessory proteins. A HIV virion is largely spherical in shape, with a diameter of 100 to 120 nm, and encloses its genome within a fullerene (cone-shaped) capsid core. The virus is enveloped with a lipid bilayer derived from the host cell, thus incorporating proteins found in the host membrane, such as the major histocompatibility (MHC) molecules [22, 23], CD44 and lymphocyte function-associated antigen 1 (LFA-1) [24]. Embedded within this membrane are the viral glycoproteins; the gp120 surface glycoprotein and the gp41 transmembrane glycoprotein. Each envelope subunit displays on the virion surface as a trimer of the outer envelope glycoprotein gp120, non-covalently liked to a trimer of gp41, the transmembrane protein that anchors this glycoprotein complex to the surface of the virion. The envelope protein is the most variable component of HIV, although gp120 itself is structurally divided into highly variable (V) and more constant (C) regions. The constant regions of the gp120 envelope are often associated with the “non-neutralising face”, as they are buried within the trimer [25, 26]. In contrast, the variable domains are associated with the “neutralizing face” of the envelope glycoprotein that is exposed to antibodies. Variability of this regions underlies immune escape. The variable domains also give the capacity of the virus to change receptor usage. In particular, the V3 loop of HIV gp120 can change the  ability of the virus to use the HIV co-receptors CXCR4 and CCR5 (receptors for HIV will be covered later in this chapter). Finally, the envelope glycoprotein gp120 has over half of its molecular weight attributed to carbohydrate structures, in the form of complex and high mannose N-linked glycans. These glycans decorate the majority of the exposed outer gp120 surface, which is known as the “silent face” given its ability to protect the envelope from antibody responses [25, 26].

The viral structural proteins are derived from the Gag polyprotein, which is present in approximately 2,400 copies in an immature virion according to current estimates [27]. Viral maturation leads to the cleavage of the Gag polyprotein, giving rise to Matrix (MA; p17) and Capsid (CA; p24) proteins, as well as the smaller peptides Nucleocapsid (NC; p7), p6, p2 and p1 [28].  Matrix associates with the inner membrane of the mature virion, whilst Capsid forms the viral core, enclosing two single strands of viral RNA. The core structure is a cone shape comprised of approximately 1,500 Capsid proteins assembled into hexameric and pentameric rings [29, 30]. Viral proteins found within the capsid core include the NC, which is found associated with the viral RNA, as well as Protease (PR), Integrase (IN) and Reverse Transcriptase (RT) proteins [31].

 The genomic organisation of HIV is extremely efficient. Use of all three reading frames (the triplet codes) of the genetic sequence permits overlapping of gene-coding regions. There are nine genes of HIV. These encode proteins that may be broadly classified into structural, catalytic, regulatory, and accessory classes (Table 1).

 In addition to   the   functions   performed   by   these   proteins in the viral lifecycle, the nucleic acid sequence of the virus possesses intrinsic functions. For example, the Rev responsive element, within the coding region for gp41, interacts with the Rev protein to assist export of spliced RNA transcripts from the nucleus of the cell [32]. The long-terminal repeat (LTR) region has a transcription-promoter function in the integrated deoxyribonucleic acid (DNA) provirus [33] and contains regions essential for reverse transcription, integration into the host-cell genome and genomic RNA dimerization [34].

 Table 1. Summary of HIV-1 gene products and their functions