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The human immunodeficiency virus (HIV) is one of the members of the genus Lentivirus in the Retroviridae family. Lentiviruses generally involve different groups of animal viruses. Lentiviruses were prime candidates when AIDS researchers looked for a causative agent of human immune disorders and later neurologic syndromes. In 1983, HIV isolates were recovered from the blood of many patients with AIDS as well as neurologic syndromes. From then, the role of HIV as an etiological agent on the disease was strongly supported. Nevertheless, the name HIV was not until 1986, when the International Committee on Taxonomy of Viruses decided to give the AIDS virus a separate name. HIV was found in two distinct subtypes, HIV-1 and HIV-2; where HIV-2 was recovered from AIDS patients in West Africa soon after the discovery of HIV-1. Both subtypes can cause AIDS, although HIV-2 has less pathogenic nature.
HIV-1 versus HIV-2
The genome of HIV-1 is very similar to that of HIV-2 except for the presence of vpx gene and the absence of vpr gene in HIV-2. The major serologic difference between the two HIV subtypes is found in the glycoproteins of the viral envelope. The HIV-2 antibodies can generally cross-react with HIV-1 proteins, but cannot even detect its envelope proteins and vice versa. In terms of pathogenesis, patients who develop AIDS due to solely HIV-2 infection survive longer without the disease than those infected with HIV-1.
Although it is still not clear why subtype HIV-2 differs from HIV-1 in terms of transmissibility and pathology, several features can offer an explanation. Low plasma viral load is observed in HIV-2 infected individuals, which could be 100 fold less than in HIV-1 infected individuals. Also, lower levels of HIV-2 compared to HIV-1 are found in semen. Moreover, the large number of circulating infected cells in case of HIV-2 impairs the ability of such cells to produce new HIV-2 particles compared to HIV-1. Another explanation indicates that there is reduced immune activation and T-cell apoptosis in case of HIV-2 infection compared to HIV-1 infection. In addition, HIV-2 envelope induces the production of ÎÂ²-chemokine that could have antiviral activity.
Fig. 1 A typical HIV virion with the structural and other virion proteins, where the location of Vif and Nef proteins still undefined
Another finding that is potentially related to some HIV-2 isolates is the reduced cytopathic properties in cell culture and the absence of the CD4 antigen modulation on the cell surface. These observations could suggest the presence of relatively non-cytopathic strains of HIV-2 in some cases. The delay in pathogenesis might also be due to strong immune response in the host, thus limiting HIV-2 replication.
The amplification of several viral genome parts and the subsequent DNA sequence help in comparison of different sequences derived from HIV-1 and HIV-2 isolates, especially in the envelope region. The full length viral genome sequencing revealed the presence of three HIV-1 subgroups named M (main), O (outlier), and N (non M or O). Eight HIV-2 subgroups are currently known.
The HIV virion structure
As revealed under electron microscopy, HIV-1 and HIV-2, like all Lentiviruses, have a cone-shaped core formed of the viral protein p24 Gag capsid (CA). The virion is measured to be approximately 100 to 120 nm in diameter, with different morphological shapes. By convention, the viral protein is designated as p followed by a number representing the protein size. Typically, HIV virion consists of envelope and three structural Gag proteins (see Fig. 1). The envelope is formed of proteins derived from a 160 kDa precursor glycoprotein (gp160). Cellular enzymes found in Golgi apparatus cleave gp160 into a gp120 that forms the external surface envelope, and a gp41 transmembrane protein. The three structural Gag proteins are: (1) matrix (MA, p17); it forms the inner shell of the virion just below the viral membrane, (2) CA (p24); it forms the cone-shaped core ââ‚¬"as determined above - that encloses the genomic RNA of the virus, and (3) nucleocapsid (NC, p7); that interacts with the viral RNA inside the capsid. These viral proteins are generated from the processing of the Gag precursor propolyprotein HVI-1 p55 by the viral protease.
Inside the Gag capsid, two often identical RNA strands are found, associated with the NC proteins, the viral RNA-dependent DNA polymerase (pol) - also known as reverse transcriptase - and integrase (IN) enzyme which helps in the integration of the viral cDNA. Thus, the assembly of HIV needs protein:nucleic acid interactions in the viral core. Other proteins are found in HIV, such as Nef and Vif proteins (from 7 to 20 Vif molecules per virion) which are associated with the viral core. Also, the viral accessory gene product Vpr (and Vpx for HVI-2) is found within the virion outside the core. It is suggested that the presence of these proteins play role in the early events of HIV infection:
Nef protein enhances viral infectivity, and it interacts with cellular proteins to help in cell activation and signal transduction. Usually, viruses lacking nef have no ability to replicate either in vivo or in vitro.
Vif protein increases the infectivity of virus and cell to cell transmission; and helps in proviral synthesis and virion assembly.
Vpr protein helps in virus replication
Vpx protein helps in entry and infectivity
The virion also contains certain cytoskeletal proteins (e.g. actin, ezrin, and emerin). Although their roles are still unknown, emerin is found to serve as a bridge between the inner nuclear envelope of virus and the chromatin so as to facilitate the interaction of the viral cDNA with chromatin and subsequent integration. Electron microscopy also reveals the presence of spikes on the surface of HIV virion, arranged as tripod-like structures. Finally, like other retroviruses, HIV isolates show the tendency to incorporate specific lipid membranes from the host cell membrane during viral budding.
The size of HIV genome is approximately 10 kb, involving open reading frames coding for many viral proteins. The full length mRNA transcript of the virus is translated into the Pol and Gag proteins. Splicing processes occur to produce many subgenomic mRNAs responsible for the synthesis of other viral proteins. In this context, Pol precursor polyprotein is autoclaved into the viral enzmes RT, PR and integrase (IN) by its own PR region. Also, the Gag precursor p55 is cleaved producing small viral proteins that include p24, p17, p9 and p6 mentioned above, in addition to p1 and p2. The ratio between Gag and Gag-pol synthesized products is about 20:1. Gene products of other spliced mRNAs involve various viral regulatory and accessory proteins that take part in HIV replication in different cell types. Generally, the ratio between the unspliced, and singly and multiply spliced mRNAs is determined by the rev gene, which itself produced from multiply spliced mRNA.
Rev protein ââ‚¬" the rev gene product ââ‚¬" regulates viral protein expression. It interacts with an RNA loop known as the Rev-responsive element, located in the mRNA of the viral envelope. Such interaction occurs between the cellular proteins and the Rev multimers allowing the unspcliced mRNA to enter the cytoplasm from the nucleus and produce the full length viral proteins needed for progeny production. Several studies on molecular features of HIV gene products found that the virus expression regulation involves the interaction of many viral proteins and cellular factors, leading to either high or low expression, or even a latent state. For example, the Rev produced in late phases of viral replicative cycle can down-regulate its own expression, and limiting the HIV replication in turn.
It is noticeable that the HIV genome encodes three major enzymes having key roles at different times during the viral replicative cycle. The RNA-dependent DNA polymerase functions early in the viral replicative cycle to produce double stranded cDNA copy of the viral RNA. The IN integrates the viral cDNA
Fig. 2 illustrates the mechanism of HIV infection
into the chromosomal DNA of the host inside the cell nucleus. The PR processes the Gag and Gag-pol polyproteins in the budding virus, thus helping in the maturation of the viral particles into an infectious HIV. Therefore, these three enzymes are prime targets for antiretroviral approaches.
HIV entry and replication
HIV is a cytopathic virus formed of a central cone-shaped core of RNA surrounded by a lipid envelope with glycoprotein (gp) surface markers. Many HIV-specific antigens are now identified such as gp120/160, p24 and p41 that are mentioned above. In order to successfully infect a cell, HIV must bind at two separate sites, the CD4+ receptor and a 7-transdomain chemokine receptor. The most important chemokines able to serve this function are CCR5 and CXCR4. CCR5 is the main co-receptor encountered by macrophage-tropical viral strains mostly found in early HIV infection, whilst CXCR4 is the principal co-receptor used by T-tropic viral strains that predominate later in HIV infection. As soon as the virus binds at the receptor/co-receptor complex, the virus fuses with the cell membrane and gain access to the host cell (see Fig. 2). In acute infection, the HIV first encounters the CCR5 receptors harbored on dendritic cells (DC) surface. The role of gastrointestinal tract in early HIV infection is still under investigation. It was observed that the CD4+ T-cells found in the gut are rapidly depleted during early HIV infection with limited recovery. However, early treatment can prevent gut CD4+ T-cell loss.
The HIV reverse transcriptase generates frequent errors in viral replication, giving the opportunity for rapid viral evolution and diversification. Thus, HIV can easily mutate and rid itself of immunologic and pharmacologic control. Once the HIV enters the cell, reverse transcription occurs to produce a cDNA copy from the viral RNA.
At this point, the HIV would have two possible pathways; either undergoes active viral replication, or become incorporated into host genome as proviral DNA and enters a latent state which can last indefinitely. The proviral DNA is transcribed into mRNA when activation occurs. After the viral proteins are formed using the host cell machinery, new virions are assembled and bud from the infected cells. The budding virions become infectious only when processed by viral protease. Such infectious virions circulate until they identify new target cells. Most stages of HIV cellular infection have been pharmacologically targeted. Untreated HIV infection leads to gradual decrease in immune function till reaches AIDS, which is characterized by deteriorated immunity and susceptibility to opportunistic infections and malegnancies.