What makes retroviruses difficult to control

This is important because the virus easily mutates, which can make it resistant to certain medications. Managing acute T-cell leukemia due to HTLV1 often involves chemotherapy or hematopoietic stem cell transplants. A combination of the drugs interferon and zidovudine may also be used. Both of these drugs help to prevent retroviruses from attacking new cells and replication.

Retroviruses are a type of virus that use a special enzyme called reverse transcriptase to translate its genetic information into DNA. Bacterial and viral infections are often transmitted in similar ways, but symptoms and treatment methods may vary depending on the cause of your…. There are several types of viral disease, depending on the underlying virus. While many rash-causing viral infections are more common in toddlers and children, they can affect….

Post-viral fatigue is a type of extreme tiredness that sometimes happens after a recent viral infection. We'll go over its common symptoms, how it's…. Other studies posit cap-independent translation initiation by internal ribosome entry at structural features of the 5' UTR of selected retroviruses. The retroviral armamentarium also commands mechanisms to counter cellular post-transcriptional innate defenses, including protein kinase R, 2',5'-oligoadenylate synthetase and the small RNA pathway.

This review will discuss recent and historically-recognized insights into retrovirus translational control. The expanding knowledge of retroviral post-transcriptional control is vital to understanding the biology of the retroviral proteome. In a broad perspective, each new insight offers a prospective target for antiviral therapy and strategic improvement of gene transfer vectors. Translation of mRNA is a multi-step process essential to all life.

The ability of an organism to regulate mRNA translation represents a rapid, potent and strategic mechanism to control gene expression. Defects in translational regulation can be deleterious to survival. Three phases of translation include initiation, elongation and termination, with initiation considered the rate-limiting step.

According to the ribosome scanning model of initiation, the mRNA template becomes activated for translation upon recognition of the 7-methyl-guanosine cap by eIF4E cap-binding protein, which complexes with other cytoplasmic initiation factors including eIF4G and eIF4A and eIF4B [ 1 , 2 ]. This 43S charged ribosome complex joins the activated mRNA and scans in a 5'-3' direction until an initiator AUG codon in appropriate Kozak consensus context is detected [ 1 , 3 ].

The 60S ribosomal subunit joins the complex to form the 80S complex and translation elongation ensues for general translation review, see [ 2 ]. The structural features of 5' UTR, and possibly features of the ribonucleoprotein complex RNP , impede ribosome scanning and reduce the efficiency of translation initiation.

Retrovirus proteins are synthesized from capped transcripts that uniformly contain long, highly structured 5' UTRs Figure 1. Given this inhibitory characteristic, alternative mechanisms are expected to govern retrovirus translation.

Investigation of mRNA translation in the retroviral model system has informed our understanding of virus-host interactions important for virus replication. These insights have also informed our understanding of specialized mechanisms that modulate translation of complex host cell mRNA templates. Properties of selected retrovirus transcripts. Red numbers below each mRNA indicate the nucleotide position of exon junctions. Dashed lines denote introns. The unused AUG in bicistronic transcripts is depicted in gray parentheses.

Predicted free energy values are derived from possible RNA structure calculated by Zuker mfold software version 3. In the cytoplasm, the retroviral primary transcript pre-mRNA plays a dual role as unspliced mRNA template for translation and as genomic RNA that is encapsidated into assembling virions [ 5 ]. The translational output of the transcript was increased in response to low concentrations of Gag and reduced in response to high concentrations of Gag.

Similar trends were observed in transient transfection assays. The implicit mechanism is that Gag binds to the 5' RNA packaging signal and facilitates genome encapsidation at the expense of translation Table 1 [ 6 ]. A long-standing issue in retrovirus biology is whether or not the processes of gag mRNA translation and virion precursor RNA encapsidation are mutually exclusive [ 5 ].

The take-home message differs between retroviruses. For example, HIV-2 has been shown to encapsidate RNA co-translationally [ 7 ], while murine leukemia virus MLV produces two functionally distinct pools of mRNA to be used for either translation or virion assembly [ 8 , 9 ]. The finding that unspliced RSV transcript can be a substrate for both translation and packaging into virions indicated that these processes are not mutually exclusive in this alpharetrovirus.

A comprehensive review of the relationship between gag translation and virion precursor RNA packaging is presented elsewhere [ 5 ]. The 5' UTR of retroviral gag pre-mRNA contains a collection of highly conserved cis -acting sequences required for several steps in virus replication. This proximal section of the 5' UTR has been shown to inhibit ribosome scanning and translation initiation of a reporter RNA [ 14 — 18 ].

Another complicating feature is that authentic initiator codons often are located within poor Kozak consensus sequences, which may provide another regulatory feature that modulates expression of the viral proteome reviewed in [ 22 ].

For example, a weak Kozak sequence surrounding the HIV-1 vpu AUG promotes translation of the downstream env gene, a process referred to as leaky scanning [ 14 , 23 ]. In spite of the multiple challenges to efficient cap-dependent translation initiation, sufficient retrovirus protein production prevails.

The potential dichotomy of mechanisms governing translation initiation of retroviruses is a topic of some controversy. The use of cap-independent initiation at an internal ribosome entry sequence IRES has been proposed to circumvent inhibition of scanning ribosomes by the complex 5' UTR.

Originally identified in the Picornaviridae , which includes poliovirus and encephalomyocarditis virus EMCV , the IRES promotes recruitment of the 43S ribosome independently of cap-binding [ 27 — 29 ]. Consequently, picornavirus transcripts are reliant on an IRES to initiate viral protein synthesis [ 27 , 28 , 33 ]. By contrast, transcripts of the Retroviridae are considered to bear a 5' cap and therefore IRES-dependent initiation is not necessarily critical.

In support of this idea, translation of the avian spleen necrosis virus is reduced when cap-dependent translation is inhibited by infection with EMCV [ 34 ]. Studies to identify internal initiation in isolated viral UTR segments have primarily utilized the transfection of bicistronic reporter plasmids. A caveat to this approach is false-positive IRES activity attributable to cryptic promoter activity or splicing of the test sequence.

The false-positive activity was validated by the observation that transfection of homologous in vitro transcribed RNA did not recapitulate IRES activity. The results determined that HIV-1 Gag protein synthesis is sustained from a heterologous reporter plasmid during poliovirus infection [ 36 ].

Unexpectedly, the putative IRES activity was conferred by sequences downstream of the gag translation initiation codon, rather than the 5' UTR. In summary, utilization of internal ribosome entry at retroviral IRES remains a controversial subject, and conditional IRES activity is an intriguing possible explanation for the disparate results. An alternative scenario is that features of the complex 5' UTR direct mechanistically uncharacterized virus-host interactions to modulate cap-dependent initiation.

This scenario and its perspective into the translation of complex cellular mRNAs are discussed in the next section. Retroviral RNA interacts with a collection of cellular and viral co-factors see Table 2.

Three examples of viral RNA-host protein interactions that facilitate retroviral translation will be discussed. These interactions offer the model that an active remodeling process balances appropriate viral RNA translation with efficient trafficking for RNA packaging into assembling virions.

In addition, RHA knockout in mice is embryonic lethal [ 54 ]. Hartman et al. The post-transcriptional processes of mRNA splicing, export, and translation are mechanistically linked and unspliced host pre-mRNA is typically a poor substrate for nuclear export or cytoplasmic translation [ 56 ]. However, retroviruses utilize the unspliced pre-mRNA as template for synthesis of essential structural and enzymatic proteins.

Retroviruses have therefore evolved specialized mechanisms to ensure efficient export and translation independently of cellular default controls.

Translation enhancement was also dependent on the presence of a retroviral promoter, which posited co-transcriptional recruitment of a cellular factor that is more available in Cos cells than cells.

These results provided an example of nuclear virus-host interaction that modulates translation. Overexpression of 9G8 in T cells produced a fold increase in Gag protein production from the reporter RNA [ 60 ]. The overexpression of 9G8 did not alter cytoplasmic accumulation of the reporter RNA but increased polyribosome association by fold.

Ribosomal profiles and immunoblots indicated that hyperphosphorylated 9G8 was associated with high molecular weight complexes that were sensitive to EDTA treatment, indicating that 9G8 likely associated with polyribosomes and not other heavy complexes referred to as "pseudo-polysomes" [ 67 ].

These results bolstered the recent realization that splicing regulatory proteins provide functional linkage between multiple steps of post-transcriptional gene regulation, and that the linkage is co-opted during retrovirus replication [ 68 , 69 ]. Sam68 has been shown to functionally synergize with Rev-like proteins of complex retroviruses to bolster viral post-transcriptional gene expression [ 71 , 72 ].

SamRNA interaction in the nucleus has been shown to facilitate the association of viral RNA with translation machinery in the cytoplasm, resulting in enhanced protein production [ 73 ].

Sam68 activity is addressed in more detail below. RHA, 9G8, and Sam68 are examples of nucleocytoplasmic shuttling proteins that promote efficient viral protein production.

The following list provides a summary:. Mixing of genetic material — The principal reason is the nature of HIV itself. Medicines can prevent an active viruses from multiplying and the patient can lead a normal life. But if the patient stops taking the drugs, hidden viruses begins to replicate once more. For example, the second most diverse virus in terms of sequence diversity, the influenza virus, has fewer viral strains circulating around the world compared to the number of strains doctors have found in individual human hosts — and influenza requires a vaccine every year.

The immune system produces antibodies to neutralise the foreign proteins that pathogens secrete. The HIV virus protects its proteins from being neutralised by coating them with glycans sugars , in a process called glycosylation. As a result, the immune system struggles to recognise the proteins hidden beneath the glycan cover. Lack of immune correlates of protection — One strategy that scientists have used to overcome a disease is to study the immune system of people who have naturally cleared the infection.

Most are non-broadly neutralizing antibodies, meaning that they only kill one or several pathogen types. To date, scientists have yet to identify an effective means to induce a bNAb response to levels where it may be considered protective, and that such a response would likely take months or even years to develop. With that being said, a lot of focus is being placed on the direct inoculation of a bNAbs into people with established HIV infection. Such an approach might one day allow for an alternative or complementary approach to therapy for people already infected with the virus.

Even if scientists were able to effectively induce the production of bnAbs, it would likely require a robust immune response. This is considered a major challenge as that HIV itself causes immune depletion by actively killing off "helper" CD4 T-cells. During chronic infection, the immune system will constantly regulate itself to ensure that it is not either overstimulated causing autoimmune disease or understimulated allowing pathogens to spread unhindered.

Particularly during long-term HIV infection, underactivation can result as CD4 cells are progressively wiped out and the body becomes less able to identify the pathogen a situation similar to that of patients with cancer. When this happens, the immune system inadvertently "puts the brakes" on an appropriate response, making it less and less capable of defending itself. Scientists at Emory University have begun to explore the use of cloned antibodies called ipilimumab , which may be able to "release the brakes" and reinvigorate CD8 T-cell production.

One of the more enthusiastically received pieces of research, currently in primate trials, involves the use of the disabled "shell" of a common herpes virus called CMV into which are inserted non-disease-causing fragments of SIV the primate version of HIV. When subjects are inoculated with the genetically altered CMV, the body responded to the "mock" infection by accelerating CD8 T-cell production to fight off what they believe to be SIV.

What makes the CMV model particularly compelling is the fact that the herpes virus is not eliminated from the body, like a cold virus, but keeps replicating on and on. Whether this confers to long-term immune protection has yet to be determined, but it does provide a compelling proof-of-concept.

One of the greatest obstacles to developing an HIV vaccine is the speed by which the virus is able to established latent reservoirs to evade immune detection.

It is believed that this can happen as quickly as four hours in case of anal sex transmission —moving quickly from the site of infection to the lymph nodes—to up to four days in other types of sexual or non-sexual transmission. Some of the most aggressive facets of research involve a so-called "kick-kill" strategy, using stimulating agents that can "kick" latent HIV out of hiding, thereby allowing a secondary agent or strategy to "kill" the newly exposed virus.

In this regard, scientists have had some success using drugs called HDAC inhibitors, which have been traditionally used to treat epilepsy and mood disorders. While studies have shown that newer HDAC drugs are capable of "waking" a dormant virus, none have yet been able to clear the reservoirs or even reduce their size. Hopes are currently being pinned on the combined use of HDAC and other novel drug agents include PEP, used to treat a type of sun-related skin cancer.

More problematic, however, is the fact that HDAC inhibitors can potentially cause toxicity and the suppression of the immune responses. As a result, scientists are also looking at a class of drugs, called TLA agonists, which appear to be able to spur an immune response rather than "jarring" the virus out of hiding.