Introduction
Retroviruses belong to the family Retroviridae and have a unique
replication cycle. Their genetic material is encoded by RNA rather than
DNA. These viruses contain an RNA-dependent DNA polymerase (reverse
transcriptase) which directs the synthesis of a DNA form of the viral
genome after host cell infection.
The family includes 3 subfamilies: Oncovirinae(HTLV), Lentivirinae(HIV) and Spumavirinae(foamy viruses)
Structure
Retroviruses are similar in structure, genome organization and
replication. These viruses are 70-130 nm in diameter and have a lipid
–containing envelope surrounding an icosahedral capsid with a dense
inner core. The envelope carries a virus-encoded glycoprotein, which
forms spikes in the membrane. The core contains two identical copies of
the single stranded RNA genome. The RNA molecules are complexed with
reverse transcriptase and tRNA. Other viral proteins like integrase are
also components of the virion particle.The outer envelope
glycoprotein (SU), is the major antigen of the virus, and is
responsible for receptor binding. The trans-membrane glycoprotein (TM),
holds the SU protein in the envelope, and is responsible for membrane
fusion.
Genome
Gene order in all retroviruses is invariant: 5' - gag - pol -
env - 3'. The gag (group-specific antigen, core protein) gene encodes
proteins that make up the nucleocapsid of the virus as well as a matrix
layer, the two of which surround the RNA. The pol gene (RNA-dependent
DNA polymerase) encodes three proteins, reverse transcriptase, which
copies the RNA into DNA, integrase, which integrates the DNA into the
host chromosome and protease, a protein that cleaves the Gag-Pol
polyprotein into smaller protein products. The env gene encodes the
envelope glycoproteins. Some retroviruses have incorporated viral
oncogene sequences. The genomes of complex retroviruses, such as human
T-cell lymphotropic virus (HTLV) contain additional genes (e.g., tax
and rex) for regulatory proteins.
Reverse Transcriptase
Reverse transcriptase converts the single-stranded RNA genome of
retrovirus into double-stranded DNA. This process reverses the typical
DNA to mRNA flow of genetic information. The DNA copy is transported
into the nucleus of the host cell to be integrated into the host
chromosome. This DNA copy of the retrovirus genome is referred to as
the provirus or proviral DNA. Structures called long terminal repeats
(LTR) are present at each end of the provirus. These LTRs contain
promoter elements and transcriptional start sites that enable the
retroviral genes to be expressed. They can also affect the expression
of nearby cellular genes.
Retrovirus Replication Cycle
There are seven steps in the replication cycle of the retrovirus. The first step
is attachment. Using one of its glycoproteins, the retrovirus binds to
one or more specific cell-surface receptors on the host cell. Some
retroviruses also employ a secondary receptor, referred to as the
co-receptor. Some retroviral receptors and co-receptors have been
identified. For example, CD4 and various members of the chemokine
receptor family on human T cells serve as the HIV receptors and
co-receptors. The second and third steps
are penetration and uncoating, respectively. Direct fusion of the
virion envelope with the plasma membrane of the host enables the
retrovirus to penetrate the host cell. This process of fusion continues
and ultimately results in the release of the viral capsid directly into
the host cell's cytoplasm, where it is partially disrupted. Step four
is replication. After the retrovirus has undergone partial uncoating,
replication occurs. During this stage, reverse transcriptase converts
the RNA genome into double-stranded DNA. The three enzymatic activities
of reverse transcriptase are, RNA-directed DNA polymerase, which makes
one DNA strand, DNA-directed DNA polymerase, which makes the
complementary strand, d RNAse H, wch degrades the viral RNA strand.
Cellular transfer RNA (tRNA) that is packaged into retrovirus virions,
primes the process of reverse transcription. The replication stage
concludes with the synthesis of a double-stranded copy of the
retroviral genome that is termed the provirus, or proviral DNA. This
proviral DNA is circularized and transported to the host cell's
nucleus, and integrated randomly into the genome by the retroviral
enzyme integrase. Following integration, the provirus behaves like a
set of cellular genes, while the LTRs function as promoters that begin
transcription back into mRNA. This transcription is carried out by RNA
polymerases in the host cell. Transcription of the proviral DNA is also
the means of generating progeny RNA. Viral proteins are made in the
cytoplasm of the host cell by cellular ribosomes.The fifth step
is assembly. Immature forms of the retrovirus capsids are assembled
at various locations in the host cell. The sixth step
is the egress stage. The virions are released from the cell by
budding from the membrane. The host cell membrane proteins are
frequently incorporated into the viral envelope. The seventh and final step
is maturation. The retroviral protease cleaves the Gag and Pol
proteins of the retrovirus. The mature and infectious forms of the
virus are thus formed.