Human Immunodeficiency Virus 1
(HIV-1)

Life cycle

• Early phase
  • Entry
    • Attachment Attachment of virus to cellular membrane occurs when HIV envelope protein gp120 binds to CD4 cell receptor.
    • Co-receptor
      binding Receptor binding is followed by co-receptor binding. Attachment to CD4 induces conformational changes in gp120 exposing its co-receptor binding sites. Depending on viral tropism, determined by V3 loop of gp120, cellular co-receptors CCR5 or CXCR4 are engaged.
    • Fusion Fusion pore formation begins. A subsequent conformational change in gp41 then occurs, allowing its two helical regions, HR1 and HR2, to interact with each other to form a stable six-helix bundle structure, which completes the fusion of the two membranes thus allowing the viral core to enter the target cell. It has been suggested that approximately four to six co-receptors are sufficient for fusion to take place.
  • Uncoating Following the entry, the core partially disassembles (uncoats) to form the reverse transcription complex (RTC). Correct regulation of core uncoating is essential for completion of the early steps of the HIV-1 replication cycle. Host restriction factor, TRIM5 tripartite motif-containing 5 alpha (TRIM5α), targets this step of the retroviral life cycle. Active research is under way to develop therapeutic inhibitors of the viral uncoating.
  • Reverse
    transcription Reverse transcription (synthesis of DNA with RNA as a template), by which double-stranded DNA molecules are made from the single-stranded RNA, takes place inside the cell cytoplasm with the aid of the viral reverse transcriptase (RT). During this process that takes more than 3 hours viral genetic recombination occurs. The generation of retroviral DNA is not so simple as to copying of plus-sense RNA into minus-strand DNA, followed by the synthesis of a plus strand complement. Instead, two replicative template switches, also known as strong-stop strand transfers or "jumps", join and duplicate sequences found only once in gRNA (genomic RNA) to reconstitute the long terminal repeats at the boundaries of preintegrative DNA. In contrast to strong-stop switches, which occur at defined positions, recombinogenic template switching can take place anywhere in the genome. The recombination involves copying part of one gRNA, followed by RT switching to a homologous region of a co-packaged gRNA. Four to five recombinogenic crossovers take place during the synthesis of every HIV-1 DNA. In order for recombinant virus to emerge at least two conditions are required: (1) the establishment of a single cell infected with two or more genetically distinct proviruses and (2) the association of two different gRNA in an encapsidated dimer.
  • Entry into
    cell nucleus The viral DNA becomes circular and enters into the host cell nucleus in so-called preintegration complexes (PICs). It is generally believed that the nuclear membrane of non-dividing cells is a barrier to the transport of large complexes such as PICs, and that the barrier is removed when the membrane breaks down during cell division. Indeed, most retroviruses are unable to infect non-dividing cells and are dependent on the cell cycle. In contrast, lentiviruses including HIV-1 are capable to productively infect non-dividing cells like macrophages or quiescent T lymphocytes.
  • Integration Viral DNA integrates into the host cell's DNA with the aid of viral integrase (IN).
• Late phase
  • Transcription Once integrated into the host cell's DNA, the virus initiates transcription, produces large quantities of viral mRNA and releases it into the cell's cytoplasm.
  • Translation The viral mRNA utilizes almost all the cell resources to translate its genetic information into large glycoproteins and polyproteins.
  • Post-translation
    protein
    modifications These products then disintegrate into smaller building blocks of the viral membrane, enzymes, and nucleocapsid through the action of viral protease.
  • Viral assembly The reassembly of the viral building blocks produces new viral particles. The viral particle contains the viral envelope (Env), three structural proteins (matrix (MA), capsid (CA)), and nucleocapsid), and auxiliary proteins. The three structural proteins are generated by processing the HIV-1 p55 polyprotein precursor by viral protease (PR). Cleavage by the protease is not required for particle formation, but is necessary for the particle to become infectious. In the absence of auxiliary viral protein Vif, host's cellular restriction factor, apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3G (APOBEC3G), is incorporated into viral particles, and, during reverse transcription in the next round of infection, converts cytosines to uracils This cytosine deamination leads to G-to-A hypermutation in the newly synthesized viral DNA potentially leading to its instability, defects in reverse transcription and DNA integration. Vif counteracts this cellular defense mechanism by recruiting components of the proteasomal pathway to induce polyubuquination and degradation of APOBEC3G.
  • Budding Assembled virion must separate (bud) from cellular membrane in order to be disseminated. The budding of HIV-1, like in other retroviruses, proceeds via hijacking of cellular endosomal sorting machinery and exocytosis (the process by which late endosome/multivesicular bodies (LE/MVBs) or transport vesicles derived from intracellular organelles migrate to the plasma membrane, fuse, and release their contents into the extracellular environment). However, several studies indicated that not LE/MVBs but the plasma membrane may be the primary site of virus assembly and budding in both T cells and macrophages. The host BST2 bone marrow stromal cell antigen 2 (BST2 or tetherin) functions as a protein tether preventing virions' separation from cellular membrane. Viral protein U (Vpu) removes the protein from the cell surface thus stimulating the release of budded particles from the plasma membrane.
  • Maturation HIV-1 particle maturation occurs concomitant with virus release. Protease (PR) initiates the maturation process by cleaving the Gag and Gag-Pol polyprotein precursors. Gag is cleaved to generate the MA, CA, NC and p6 proteins and SP1 and SP2 spacer peptides; the Pol portion of Gag-Pol is cleaved into PR, RT and IN enzymes. Disrupting Gag processing represents an attractive therapeutic strategy for inhibiting HIV-1 replication. HIV-1 maturation produces a condensed conical core composed of CA lattice surrounding the viral RNA genome in complex with NC, RT, and IN. The function of the core is to facilitate the delivery and reverse transcription of the viral RNA genome following infection of the target cell.

Viral fitness

Environmental conditions in which HIV-1 performs its life cycle are not constant but rather fluctuate in time, and vary from cell to cell, from compartment to compartment and from host to host. Perturbations in environmental conditions impose selective pressures on the virus that shape the genotype and fitness of the virus. Consequently, viral fitness is highly dependent on the environment.

Viral fitness results from the interplay between the environment and all genes and processes that have a role in the viral life cycle, and is defined by the ability of an individual genotype to produce infectious progeny in a specified environment.

The replication rate is often used as a measure of viral fitness because it is a trait that takes the complete viral life cycle into account. The environment in which a virus completes its life cycle contains many different selectional cues that shape the genome and that severely complicate an accurate measurement of fitness.

Literature

• Freed EO, Mouland AJ. The cell biology of HIV-1 and other retroviruses. Retrovirology. 2006 Nov 3;3:77.

  

  Cartoon of the HIV-1 replication cycle, with cellular factors that promote virus replication shown in green, and inhibitory factors in red. Details are provided in the text.