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HIV-1 taxonomyBack to top
HIV-1 genome consists of 9 separate genes coding for 3 structural (Gag, polymerase, Env) and 6 accessory proteins (Vif, Vpr, Vpu, Rev, Tat, Nef). Similar to other retroviruses, HIV-1 had a long-terminal repeat (LTR), which served as the promoter region for transcription of the virus.
- gp160 (Env)
Envelope. A polyprotein precursor, which is processed by cellular proteases to produce a non-covalent complex of an external glycoprotein (SU / gp120) and a transmembrane glycoprotein (TM / gp41).
- gp41 (TM) Transmembrane (TM) protein that consists of an N-terminal ectodomain, a transmembrane domain, and a C-terminal intraviral segment that interacts with MA.
- gp120 (SU) Surface glycoprotein 120. Extensively glycosylated protein that is anchored to the virus via interactions with p41. It contains five variable regions (V1-V5), four of which (V1-V4) form surface-exposed loops with disulfide bonds at their bases. The resulting surface variability is important for evading an immune response. SU also binds to CD4 receptors and the chemokine co-receptors on the plasma membrane of the target cell.
- Structural proteins
- p17 (MA) Matrix. A matrix shell consists of approximately 2,000 copies of the matrix protein (MA, p17) that line the inner surface of the viral membrane.
- gp24 (CA) Capsid. A conical capsid core particle consisting of about 2,000 copies of the capsid protein (CA, p24). Located in the center of the virus. CA encapsidates two copies of the unspliced viral genome.
- p7 (NC) Nucleocapsid. Ribonucleoprotein complex consisting of about 2,000 copies of the nucleocapsid protein (NC, p7). NC is a small (7 kDa), highly basic protein characterized by the presence of two zinc-finger motifs. These zinc fingers are critical for genomic RNA encapsidation and for infectivity of viral particles. NC also functions as a nucleic acid chaperone to stimulate reverse transcription and integration. The presence of one or two zinc fingers in NC is one of the most highly conserved features of retroviral Gag protein.
- Viral enzymes
- Protease (PR) Protease was the first HIV-1 protein to be structurally characterized. As in other lentiviruses, PR is coded by Gag-Pol fusion product that is produced from a -1 ribosomal frameshift event, and is released from it by an autocatalytic mechanism. The enzyme plays an essential role in the viral life cycle by generating mature infectious viral particles through cleavage of the viral Gag and Gag-Pol precursor proteins. The Gag precursor codes for all the structural viral proteins: matrix (p17, MA), capsid (p24, CA) and nucleocapsid (p7, NC), the p6 protein and the two spacer proteins p2 (SP1) and p1 (SP2). The Gag-Pol polyprotein encodes MA, CA, p2, NC, the transframe protein (TFP) and all enzymes (protease, reverse transcriptase and integrase). The protease cleaves the two precursor proteins accumulating at the plasma membrane of the infected cell during or shortly after the assembled viral particles are released from the infected cells. So, HIV protease activity is not required for virus production and release per se, but is essential for viral maturation leading to infectious viral particles.
transcriptase (RT) The protein possesses two distinct enzymatic activities that are necessary during reverse transcription stage of viral life cycle. First, as DNA polymerase, RT copies an RNA and then a DNA templates to generate minus- and plus-strand viral DNA, respectively, and, second, as RNase H, it degrades the RNA strand within the RNA-DNA duplex(es) formed during the plus-strand DNA synthesis. The RNase activity also serves to create the plus-strand primers required for initiation of plus-strand DNA synthesis, as well as to remove the minus- and plus-strand primers once the synthesis is complete. Reverse transcription of the HIV-1 genome occurs mainly in the cytosol of the cell shortly after viral entry. DNA synthesis proceeds within a Reverse Transcription Complex (RTC) that comprises several viral proteins including MA, NC and perhaps Nef and Vif. RT is initially packaged into virions as a Gag-Pol precursor, with proteolytic cleavage initially producing a homodimer of two p66 molecules. p66 contains both a polymerase and an RNase H domain. Subsequent proteolytic removal of the RNase H domain of one of the subunits results in the mature p66-p51 RT heterodimer.
- Integrase (IN) HIV-1 integrase (IN) is essential for incorporation of the viral DNA into the chromosomal DNA of the target cell. As part of the Pre-Integration Complex (PIC), IN recognizes long terminal repeats (LTRs) at the 5′ and 3′ ends of the newly synthesized viral DNA duplex and cleaves two (or sometimes three) bases from the 3′ ends. IN then ligates the 3′ ends to the cellular DNA in the nucleus. The resulting unligated 3′ ends of the cellular DNA are subsequently extended to fill gaps, and additional processing leads to the complete covalent incorporation of the proviral DNA. HIV-1 IN consists of three separate structural and functional domains, including an N-terminal zinc binding domain that facilitates oligomerization, a central catalytic core domain, and a C-terminal DNA-binding domain.
- Accessory proteins
factor (Nef) HIV-1 negative factor (Nef) is a 27 kDa, N-terminally myristoylated regulatory factor of 206 amino acid residues that is expressed in high concentrations shortly after viral infection. This accessory protein is important for achieving and maintaining high viral loads in vivo. Nef has at least two distinct roles: it enhances viral replication and stimulates a reduction in the number of CD4 receptors on the surface of the infected cell. The downregulation of cell-surface CD4 levels appears to be important for preventing reinfection by budding virions and superinfection. Another important biological function of Nef is down-regulation of MHC-1 molecules on infected cells, which masks them from the immune system.
protein (Rev) Rev participates in the sequence-specific transport of unspliced and incompletely spliced viral mRNAs from the nucleus to the cytoplasm. Rev is not found in virion.
protein (Tat) Transcription of the integrated proviral DNA is initiated at the HIV-1 promoter, which is located in the U3 region of the 5′ long terminal repeat (LTR). Tat functions to enhance transcriptional elongation by binding to the TAR (trans -activating response element) stem-loop site on the nascent RNA transcript. This mode of transcriptional activation differs from that of most other well-characterized transcription factors that function by binding to the duplex DNA template.
R (Vpr) The viral protein R (Vpr) of HIV-1 is a small basic protein (14 kDa) of 96 amino acids, and is well conserved in HIV-1, HIV-2 and SIV. Despite its small size, Vpr has been shown to play multiple functions during virus replication, including an effect on the accuracy of the reverse-transcription process, the nuclear import of the viral DNA as a component of the pre-integration complex (PIC), cell cycle progression, regulation of apoptosis, and the transactivation of the HIV-LTR as well as host cell genes. Furthermore, Vpr is found in virions, in cells, and exists as free molecules found in the sera and the cerebrospinal fluid of AIDS patients, indicating that it may exert its biological functions through different machanisms.
protein U (Vpu) Vpu is an 81-amino acid type 1 integral membrane protein. Residues 1-27 constitute the N-terminal hydrophobic membrane anchor, followed by 54 residues that protrude into the cytoplasm. Vpu protein facilitates the release of virus particles from the surface of infected cells; down-modulates of CD4 in Endoplasmic Reticulum, is involved in Env maturation, and is not found in virion. Without Vpu, the assembled HV-1 virions remain attached to the surface of the host cell by host membrane protein tetherin that leads to their endocytosis and degradation in lyzosomes. In SIVcpz (Simian Immunodeficiency Virus infecting chimps), this function of counteracting tetherin is attributed to Nef. In lights of this, the hypothesis was advanced that switching from using Nef to using Vpu could've been one of important adaptations of SIVcpz to human populations.
factor (Vif) The viral infectivity factor (Vif) encoded by HIV-1 neutralizes a potent antiretroviral cellullar restriction factor APOBEC3G (also known as CEM-15), a cytidine deaminase nucleic acid−editing enzyme. Vif binds APOBEC3G and induces its rapid degradation, thus eliminating it from cells and preventing its incorporation into HIV-1 virions.Vif is packaged in virion.
Aspects of HIV-1 biology
Two copies of genomeAs other retroviruses HIV-1 viral particle encapsidates two RNA genomes. This characteristic is one of most important aspects of HIV-1 biology. During replicative cycle, catalyzed by reverse transcriptase, the nascent DNA transfer between the two copies (recombination) can occur multiple times. This type of recombination is referred as a copy-choice. Copy-choice events occur at a frequency of 2-5 events/genome/replication cycle. Primary advantage of recombination is recombinatorial repair of damaged ssRNA. It is known that infection by HIV-1 causes chronic oxidative stress leading to breaks in ssRNA genome. During reverse transcription, strand switching can generate an intact copy of genomic DNA from two damaged copies of ssRNA (HIV-1 recombination does not involve nucleic acid breakage and rejoining but instead results from reverse transcriptase (RT) template switching between viral RNAs during provirus synthesis). The process by which viral genomes containing inactivating genomic damage interact within the infected cell to form a viable genome is called Multiplicity Reactivation (MR). This could explain why retroviruses carry two complete genomes. Another benefit of packaging two copies of genome is manifested in allelic novelty of resultant genome when the two copies belonged to two different viral strains that happened to co-infect the host cell. This reassortment allows the virus not only to aqcuire resistance to anti-retroviral drugs but also potentially contributes to overcoming the immune defenses of the host.
The variabilitySources of HIV-1 variability: (1) errors in reverse transcription, (2) genetic recombination, (3) incompletely neutralized APOBEC3G hypermutation activity, (4) oxidative stress.
Because HIV-1 3'-5' exonuclease lacks "proof reading" activity misincorporation, insertion, deletion, or duplication of nucleotides occurs during reverse transcription with a frequency of 10-4 to 10-5. Only base substitutions introduce roughly 1 substitution per viral genome per generation. Thus, point mutation rates alone are sufficient to explain why retroviruses like HIV-1 exist as snowflake-like quasispecies in which nearly every virus in a population differs from every other one. Although the error frequency and high mutation rate potentially lead to production of attenuated or even non-viable viruses, it is compensated in excess by huge replication capacity - approximately a billion viral particles are produced and destroyed in an infected patient each day. Thus, the large number of affected individuals and the persistence of infection, affords HIV-1 tremendous scope for the generation of viral diversity.
Thus, one of most prominent feature of human immunodeficiency virus type 1 (HIV-1) is the genetic breadth and plasticity of its populations achieved by both, recombination and point mutations. For comparison, the total global genetic variation of influenza A is approximately the same as the variation found in a single HIV-infected individual (~5%). Mitochondrial genes across all mammalian lineages have only 15% genetic diversity, whereas HIV-1, present within human population for about a century, has developed greater than 30% genetic variation.Back to top
This model of HIV-1 combines results of more than 100 research publications. It reconstructs 3-D structures of 17 viral and cellular proteins in various conformations taking into account protein interactions. Modeling of viral envelope required more than 160,000 lipids of 8 types characteristic for intact HIV-1 particle.
Nielsen MH, Pedersen FS, Kjems J. Molecular strategies to inhibit HIV-1 replication. Retrovirology. 2005 Feb 16;2:10.
Schematic representation of the HIV-1 provirus and the different RNA species. Gag; group specific antigen, Gag-Pol; group specific antigen-polymerase, Env; envelope, Tat; trans-activator of transcription, Rev; regulator of expression of virion proteins, Nef; negative effector, Vif; virion infectivity factor, Vpr; viral protein r, Vpu; viral protein u, LTR; long terminal repeat.
Freer G, Matteucci D. Influence of dendritic cells on viral pathogenicity. PLoS Pathog. 2009 Jul;5(7):e1000384.
Viral patterns that activate the immune system. A virion can be envisioned as a concentration of different patterns recognized by the immune system: virtually all of its components can be used to start a response before the T cell compartment is active.