Structure and genome of HIV
HIV Structure and Genome
Structure
HIV is different in structure from previously described retroviruses. It is around 120 nm in diameter (120 billionths of a meter; around 60 times smaller than a red blood cell) and roughly spherical.
HIV-1 is composed of two copies of single-stranded RNA enclosed by a conical capsid comprising the viral protein p24, typical of lentiviruses (Figure 3). This is in turn surrounded by a plasma membrane of host-cell origin. The single-strand RNA is tightly bound to the nucleocapsid proteins, p7 and enzymes that are indispensable for the development of the virion, such as reverse transcriptase and integrase. The nucleocapsid (p7 and p6) associates with the genomic RNA (one molecule per hexamer) and protects the RNA from digestion by nucleases. A matrix composed of an association of the viral protein p17 surrounds the capsid, ensuring the integrity of the virion particle. Also enclosed within the virion particle are vif, vpr, nef, p7 and viral protease (Figure 2). The envelope is formed when the capsid buds from the host protein, taking some of the host-cell membrane with it. The envelope includes the glycoproteins gp120 and gp41, which are derived from the gp160 precursor; gp41 is a transmembrane protein that is covalently linked to gp120 [1].
HIV genome organisation and HIV protein function
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.
gag
Group specific antigen (gag)-derived proteins make up the cone-shaped viral capsid (p24, a 24-kilodalton protein), the nucleocapsid proteins (p6 and p7) and a matrix protein (p17).
pol
A gene that codes for the viral enzymes. The most important of which is the reverse transcriptase which performs the unique reverse transcription of the viral RNA into double-stranded DNA. The latter is integrated into the genome of the host, which means into a chromosome of an infected cell of an HIV-positive person by the pol-encoded integrase. Also, pol encodes a specific viral protease. This enzyme cleaves gag- and gag-pol-derived proteins into functional proteins.
env
Codes for the envelope proteins. The proteins derived from env are the surface (gp120) and a transmembrane (gp41) proteins. They are located at the outer part of the virus particle and enable the virus to attach to and fuse with the target cells to initiate the infectious cycle. The gene product has a knob-like structure.
tat
tat (Trans-Activator of Transcription) codes for a protein Tat, which consists of between 86 and 101 amino acids depending on the subtype [2][3] (Figure 4). The HIV RNA initially has a hairpin-structured portion which prevents full transcription occurring. However, a small number of RNA transcripts will be made, which allow the Tat protein to be produced. Tat binds to and phophorylates cellular factors, eliminating the effect of the hairpin RNA structure and allowing transcription of the HIV DNA [4]. This itself increases the rate of transcription, providing a positive feedback cycle. This in turn allows HIV to have an explosive response once a threshold amount of Tat is produced, a useful tool for defeating the body's response. Despite the lack of a signal sequence, Tat is released by infected cells and is found in detectable levels (more than 40nM) in the culture supernatants of cells infected with HIV-1, and in the sera of HIV-1 infected patient’s [5]. It is also efficiently taken up by a variety of HIV-1 uninfected cells. Extracellular Tat has many functions that are thought to play a major role in enabling HIV to escape immune surveillance and to act as a viral toxin in AIDS pathology. One such role of Tat is in the apoptosis of uninfected naive bystander T cells, contributing to the progressive loss of these cells and the progression towards AIDS [6].
rev
rev (Regulator of Virion) codes for Rev, a protein that allows fragments of HIV mRNA that contain a Rev Response Unit (RRE) to be exported from the nucleus to the cytoplasm. In the absence of rev, RNA splicing machinery in the nucleus quickly splices the RNA so that only the smaller, regulatory proteins can be produced; in the presence of rev, RNA is exported from the nucleus before it can be spliced, so that the structural proteins and RNA genome can be produced. Again, this mechanism allows a positive feedback loop to allow HIV to overwhelm the host's defenses, and provides time-dependant regulation of replication (a common process in viral infections) [7].
nef
nef (Negative Regulatory Factor) codes for Nef. The expression of Nef early in the viral life cycle ensures T cell activation and the establishment of a persistent state of infection, two basic attributes of HIV infection. Nef also promotes the survival of infected cells by downmodulating the expression of several surface molecules important in host immune function. These include major histocompatibility complex-I (MHC I) and MHC II present on antigen presenting cells (APCs) and target cells, and CD4 and CD28 present on CD4+ T cells. One group of patients in Sydney were infected with a nef-deleted virus and took much longer than expected to progress to AIDS [8]. A nef-deleted virus vaccine has not been trialed in humans and has failed in nonhuman animals.
vif
vif (Viral Infectivity Factor) codes for a 23-kilodalton protein, Vif. Vif is essential for viral replication. The exact role of Vif is as yet unclear [9]. However, it is thought that vif helps the virus to infect other cells after it leaves a host cell; Vif appears to be involved in determining how the RNA genome and Gag protein bind to each other, and inhibits a cellular protein that modifies RNA.
vpr
vpr (Viral Protein R) codes for a 10-kilodalton protein, Vpr. Vpr plays an important role in regulating nuclear import of the HIV-1 pre-integration complex, and is required for virus replication in non-dividing cells. Vpr also induces cell cycle arrest in proliferating cells, which can result in immune dysfunction [10].
vpu
vpu (Viral Protein U) codes for Vpu. Vpu is involved in viral budding, enhancing virion release from the cell. In HIV-2, this gene is called vpx.
tev
This codes for a a chimeric Tat–Env–Rev fusion protein that has Tat transactivation activity but low detectable Rev activity. Only present in a few HIV-1 isolates (Figure 3).