7/31/2019 Retro Viral Evasion of The

http://slidepdf.com/reader/full/retro-viral-evasion-of-the 1/2

5ISSN 1746-0794

part of 

Future Virol. (2010) 5(1), 5–6

E  d 

i  t   or i   al  

10.2217/FVL.09.66 © 2010 Future Medicine Ltd

F  ut   ur  e

V i  

r  ol   o g y 

Retroviral evasion of theimmune system

“Further studies should be aimed at

determining mechanisms responsible

for recognition of retroviral pathogensand virally evolved mechanisms to

block this detection.”

Tatyana V Golovkina† & Leonid Yurkovetskiy†Author for correspondence: Department of Microbiology, University of Chicago, 920 East 58th street,Chicago, IL 60637, USA n Tel.: +1 773 834 7988 n Fax: +1 773 834 8150 n tgolovki@bsd.uchicago.edu

Retroviruses are unmatched at escaping

immune recognition

Throughout mammalian evolution, the con-stant challenge o viral inection has led to the

development o extraordinarily eective deensemechanisms. Some o these antiviral mechanismsare cell autonomous, whereas others depend onspecialized cell types. Numerous viral evasionmechanisms have been identifed through study o animal models, but it was not until patho-genic human retroviruses were frst discovered inthe 1980s that interest in antiretroviral immuneresponses was ueled. This interest is especially intense now because o the ailure to develop avaccine against HIV or almost 30 years.

The most successul vaccines are based onattenuated pathogens, as such vaccines mimic the

immune recognition events occurring during nat-ural inection. For retroviruses such as HIV, theuse o attenuated strains is not an option becauseo the ability o retroviruses to mutate owing totheir high replication and error rates. Retrovirusescan also recombine, generating large geneticalterations. One immune-evasion mechanism isunique to retroviruses and relies upon proviralintegration into the genome o susceptible cells.Integration into the genome o resting cells resultsin the establishment o a dormant inectious res-ervoir and, thus, indefnite virus persistence even

in the ace o an ongoing immune response.Several retroviruses, known as complex retro-

viruses, make use o virulence actors that helpthem evade immune pressure [1]. Interestingly,simple retroviruses can accomplish the same goalo persistent inection while lacking obvious viru-lence actors. Simple retroviruses oten contain asew as three genes (e.g., murine leukemia virus, which has  gag , pol , pro and env ) yet are able toreplicate eectively and remain unrecognized by the host. How is this eat achieved with so littlegenomic material? We propose that the struc-

tural genes o simple retroviruses have acquired

multiple unctions that contribute to their eva-sion strategy. Retrovirally produced structuralproteins have been shown to interact with hun-dreds o host actors. Some o these interactions

are required or successul virus replication, whileothers may be important or retroviral evasion o the host response. These ‘extrastructural’ roleso structural proteins could be activated/regu-lated in a specifc manner to exhibit an immuneevasion unction. Post-translational modifca-tions could, or example, result in an increasedprotein interactome or some retroviral proteins.Phosphorylation might change the structure o Gag to counteract a host-restriction actor in asimple retrovirus, whereas in a complex retro-virus, a new gene might be acquired to accom-plish the same evasion mechanism. Endosomal

acidifcation may cause conormational changesin viral capsid proteins enabling them to bind tohost actors to withstand an antiviral response. A deeper understanding o how retroviruses utilizetheir genome or immune evasion will lead tothe identifcation o overlooked evasion strategiesand novel  unctions or viral proteins.

It is also possible that retroviruses exploitmicroorganisms to evade the host response. Likemany pathogens, retroviruses have evolved inthe context o the commensal microora o theirhosts. One can hypothesize that retroviruses may 

take advantage o the commensals (i.e., as adju-vant) by tolerizing the host and, thus, suppress-ing the antivirus immune response. Incredibly,this evasion route requires no virulence actors toachieve the intended purpose. Gnotobiotic mod-els should be used to discern the role o normalora in retroviral evasion.

How is retroviral infection sensed?

 An adaptive immune response against a patho-gen begins with recognition o pathogen-associ-ated molecular patterns by the pattern-recogni-

tion receptors o the innate immune system [2,3].

“A deeper understanding

of how retroviruses

utilize their genome for

immune evasion will

lead to the identication

of overlooked evasion

strategies and

novel functions for

viral proteins.”

7/31/2019 Retro Viral Evasion of The

http://slidepdf.com/reader/full/retro-viral-evasion-of-the 2/2

Future Virol. (2010) 5(1)6 future science group

Editorial Golovkina & Yurkovetskiy

Pattern-recognition receptors sense replicativeintermediates o viruses by recognizing struc-tures not normally ound in the host cell, such asdsRNA, or recognizing nucleic acids in a cellularcompartment where they are normally absent(i.e., RNA/DNA in endosomes and DNA in the

cytosol). These detection events are then trans-lated into a pathogen-specifc adaptive immuneresponse [4]. Two observations indicate that theimmune response exerts extensive pressure onretroviral replication. First, defciencies in spe-cifc adaptive or innate immune pathways resultin increased retroviral titers and, second, retro-viruses have evolved numerous mechanisms toavoid immune recognition.

This raises the questions o what the retroviralpathogen-associated molecular patterns are andhow they are sensed. Retroviruses are enveloped

viruses with the genomic RNA packaged withina protein shell, termed the capsid [5]. Retrovirusentry is mediated through the interaction o itsEnv protein with a surace receptor. These eventsexpose the virus to endosomal and cytosolicinnate immune receptors. During transport tothe nucleus, reverse transcription occurs in thepreintegration complex, producing dsDNA mol-ecules, which are subsequently integrated into theinected cell’s genome, establishing a provirus. Ater integration, vira l RNA molecules tran-scribed rom the integrated provirus are trans-lated to produce the viral proteins. As viral parti-

cles are being ormed, genomic RNA and reversetranscriptase are packaged and the virus egressesrom the cell. Various replication intermediates,including dierent nucleic acid orms, couldpotentially be targeted by the innate immunesystem as they might have physical/structuralor subcellular localization dierences compared

 with similar orms made by the host. Clearly, weknow little about the initial events that lead tohost recognition o retroviral pathogens.

Conclusion & future perspective

Pathogens that cause chronic inections excel in

adapting to the host in a manner that ensureslong-term residence. Most viruses utilize numer-ous immune-evasion mechanisms, but are stilleliminated or eiciently controlled by theimmune system. However, inection with retro-viruses rarely leads to an immune response thatcan prevent ongoing virus replication, suggest-ing that they evolved highly efcient mecha-nisms to escape an immune attack. Furtherstudies should be aimed at determining mecha-nisms responsible or recognition o retroviralpathogens and virally evolved mechanisms to

block this detection. Knowledge gained romthese studies will lead to development o vac-cines that could recapitulate a live-virus vaccine without using live virus, by mimicking natu-ral detection events and subsequent adaptiveimmune responses. This is important or pro-ducing prophylactic vaccines, not only againstHIV, but also against the uture retrovirusesthat we are certain to encounter.

Financial & competing interests disclosure

This work was supported by PHS grant CA113784 

to Tatyana V Golovkina. The authors have no other 

relevant aliations or nancial involvement with

any organization or entity with a nancial interest 

in or nancial confict with the subject matter or 

materials discussed in the manuscript apart rom

those disclosed.

No writing assistance was utilized in the production

o this manuscript.

Bibliography

1. Malim MH, Emerman M: HIV-1

accessory proteins – ensuring viral survival in

a hostile environment. Cell Host Microbe 3,388–398 (2008).

2. Stetson DB: Connections between

antiviral deense and autoimmunity.

Curr. Opin. Immunol. 21, 244–250

(2009).

3. Medzhitov R: Approaching the asymptote:

20 years later. Immunity 30, 766–775

(2009).

4. Pasare C, Medzhitov R: Toll-like receptors:

linking innate and adaptive immunity.

 Adv. Exp. Med. Biol . 560, 11–18 (2005) .

5. Go SP: Host actors exploited by 

retroviruses. Nat. Rev. Microbiol. 5, 253–263

(2007).

Afliations

n Tatyana V Golovkina Associate Proessor, Department o 

Microbiology, University o Chicago,920 East 58th street, Chicago, IL 60637,USA Tel.: +1 773 834 7988Fax: +1 773 834 8150tgolovki@bsd.uchicago.edu

n Leonid Yurkovetskiy Predoctoral Trainee, Department o Microbiology, University o Chicago,920 East 58th street, Chicago, IL 60637,USA Tel.: +1 773 834 1073Fax: +1 773 834 8150leonidy@uchicago.edu