HIV infection and HERV expression: a review.

0.52 MB·English

by  van der Kuyl, Antoinette C

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REVIEW Open Access
HIV infection and HERV expression: a review
Antoinette C van der Kuyl
Abstract
The human genome contains multiple copies of retrovirus genomes known as endogenous retroviruses (ERVs) that
have entered the germ-line at some point in evolution. Several of these proviruses have retained (partial) coding
capacity, so that a number of viral proteins or even virus particles are expressed under various conditions. Human
ERVs (HERVs) belong to the beta-, gamma-, or spuma- retrovirus groups. Endogenous delta- and lenti- viruses are
notably absent in humans, although endogenous lentivirus genomes have been found in lower primates.
Exogenous retroviruses that currently form a health threat to humans intriguingly belong to those absent groups.
The best studied of the two infectious human retroviruses is the lentivirus human immunodeficiency virus (HIV)
which has an overwhelming influence on its host by infecting cells of the immune system. One HIV-induced
change is the induction of HERV transcription, often leading to induced HERV protein expression. This review will
discuss the potential HIV-HERV interactions.
Several studies have suggested that HERV proteins are unlikely to complement defective HIV virions, nor is HIV able
to package HERV transcripts, probably due to low levels of sequence similarity. It is unclear whether the expression
of HERVs has a negative, neutral, or positive influence on HIV-AIDS disease progression. A positive effect was
recently reported by the specific expression of HERVs in chronically HIV-infected patients, which results in the
presentation of HERV-derived peptides to CD8+ T-cells. These cytotoxic T-cells were not tolerant to HERV peptides,
as would be expected for self-antigens, and consequently lysed the HIV-infected, HERV-presenting cells. This novel
mechanism could control HIV replication and result in a low plasma viral load. The possibility of developing a
vaccination strategy based on these HERV peptides will be discussed.
Review hosts’ advantage, either as a novel regulatory sequence,
Retroviruses are unique among the viridae by inserting a novel protein, or as a means to protect against new
their genome into the host cellular DNA as an essential retrovirus infections (reviewed by [2]). This latter
step in the viral replication cycle. Some older members mechanism is called superinfection resistance (SIR), and
of the retrovirus family have found their way into the works best against closely related retroviruses by simple
vertebrate germ line while current members seem to mechanisms such as receptor occupancy (reviewed by
remain exogenous. Vertebrate genomes contain substan- [3]).
tial amounts of retroviral sequences in various states of Around 8% of the human genome is of retroviral ori-
inactivation since their integration (for a review on the gin, which includes proviruses that belong to beta-,
discovery, see [1]). Integrated endogenous retrovirus gamma-, and spuma- retroviruses (Figure 1). Human
(ERV) genomes commonly contain mutations, deletions, endogenous retroviruses (HERVs) are historically classi-
or are even reduced to single long terminal repeat fied by the tRNA specificity of their primer binding site
(LTR) elements by homologous recombination between (PBS), which can be confusing as unrelated species may
the two LTR’s. More recent integrations usually have share the same tRNA primer for reverse transcription
retained at least partial coding capacity. Some integrated [4]. Many HERV elements may have lost the ability to
ERV elements have been adopted and are used to the transfer, but several retain the capability to be tran-
scribed and translated under certain conditions, includ-
ing embryonic development and disease [2]. The most
Correspondence:[email protected]
recent and widespread human integrations belong to
LaboratoryofExperimentalVirology,DepartmentofMedicalMicrobiology,
CenterforInfectionandImmunityAmsterdam(CINIMA),AcademicMedical retroviruses with homology to mouse mammary tumour
CenteroftheUniversityofAmsterdam,Meibergdreef15,1105AZ virus (MMTV, a betaretrovirus) and are known as the
Amsterdam,TheNetherlands
©2012vanderKuyl;licenseeBioMedCentralLtd.ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommons
AttributionLicense(http://creativecommons.org/licenses/by/2.0),whichpermitsunrestricteduse,distribution,andreproductionin
anymedium,providedtheoriginalworkisproperlycited.
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Figure1Phylogenetictreeofhumanretroviruses.A183translatedaminoacidfragmentsurroundingtheYXDDmotifinthepolgeneshows
therelationshipbetweenendogenousandexogenousretrovirusesofhumans.SequenceswereretrievedfromtheGenBankdatabase[83],
translatedandalignedusingBioEditversion7.0[84].Aphylogenetictreewith500bootstrapreplicateswasconstructedwiththeneighbour-
joiningmethodbaseduponadistancematrixgeneratedwiththePoissonmodelforaminoacidsubstitutionswhileassuminguniformrates
amongsites,asimplementedinMEGA5.0[85].Schematicgenomeorganizationsfordifferentclassesofretrovirusesareshown.Drawingsarenot
toscale.Additionalreadingframesmayexistinotherstrains(e.g.non-primatelentivirusesencodeadUTPase).Abbreviations:HERV=human
endogenousretrovirus;HIV=humanimmunodeficiencyvirus;HTLV=humanT-celllymphotropicvirus;SFV=simianfoamyvirus.Accession
numbers:AF074086(HERV-KHML-2);NC_001436(HTLV-1);M10060(HTLV-2);K03455(HIV-1);M15390(HIV-2);U04327(SFV);NT_029419(from
whichaHERV-EPolsequencewasretrieved).Analysedbutnotshown:AF033807(MMTV,abetaretrovirus);J01998(MuLV,agammaretrovirus);
M12349(simianMason-Pfizermonkeyvirus,adeltaretrovirus);DQ399707(XMRV,agammaretrovirus),andthehorseendogenousbetaretrovirus
EqERV-beta1[86].LTR=longterminalrepeat,consistingoftheU3,RandU5regionsintheintegratedprovirus,gag=group-specific-antigen,
du=dUTPase,pro=protease,pol=polymerase(reversetranscriptaseandintegrase),env=envelope,bel1-3(bel1isalsoknownastas;thebel
2readingframeoverlapswithanotheronenamedbet),tax,rex,tat,rev,vpu,vif,nefandvprencodesmalladditionalproteins.TheHERV-KRec
proteinisalsoknownasK-Rev.HERV-KrecisfoundinHERV-KtypeIIproviruses,whilenp9isencodedbyHERV-KtypeIproviruses[87].In
spumavirus,eithergag-proorpro-polareencodedinthesametranslationalreadingframe.
HERV-K (HML-2) (human MMTV-like) family (for a human mammary carcinoma cell line T74-D was found
recent review, see [5]). Full-length proviral genomes of to release virions with B-type morphology that also con-
HML-2 family members are present, but these are not tain retroviral transcripts originating from different loci
replication competent, even the HERV-K113 element [8]. Infectious HML-2 viruses have now been recon-
that retains full coding capacity [6]. The human germ structed in the laboratory to delineate their characteris-
line tumour cell Tera-1 even produces (non-infectious) tics [9,10].
retrovirus particles containing HML-2 RNA, but the Humans are currently threatened by only two exogen-
assembly of these particles was found to depend on ous retrovirus species: human T-cell lymphotropic virus
trans-acting viral proteins and RNA genomes derived (HTLV, a deltaretrovirus) and human immunodeficiency
from a mosaic of HML-2 proviral genomes [7]. The virus (HIV, a lentivirus). A third putative human
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retrovirus, xenotropic murine leukaemia virus-related When protease inhibitors specifically designed to inhi-
virus (XMRV, a gammaretrovirus) has recently been dis- bit the HIV-PR enzyme were included in the drug regi-
carded as a contaminant [11,12]. No sequences with men offered to HIV-infected patients, there was some
homology to delta- or lenti- viruses have been found in concern as to whether endogenous proteases, likely
the human genome, although endogenous lentivirus resistant to the anti-HIV drugs because of remote
genomes were discovered in basal primates [13,14]. amino acid similarity, would be able to trans-comple-
Infection with the spumavirus simian foamy virus (SFV) ment the targeted enzyme. HERV-K10 protease is
occurs occasionally in persons exposed to non-human indeed highly resistant to HIV-PR inhibitors and able to
primates, but the virus does not seem to spread among process the HIV gag matrix-capsid protein at the
humans [15-17]. The only described human endogenous authentic cleavage site [22]. However, when a HERV-K
retrovirus element with (distant) homology to foamy PR was incorporated into virions of a PR-defective HIV-
viruses is HERV-L [18]. 1 strain, no complementation was achieved [23]. The
In this review, the effect of infection with an exogen- Gag-Pol precursors were found to be processed at unna-
ous retrovirus (HIV) on the resident endogenous virus tural sites, rendering the produced virion particles non-
population will be summarized with regard to viral gen- infectious. When HERV-K PR was incorporated into
ome expression, possible complementation, and immune wild type (wt) HIV-1 virions with the intention to
response. decrease their infectivity, no deleterious effect was seen,
and only small fractions of aberrantly cleaved proteins
Complementation of HERV and HIV proteins were detected [23].
All retroviruses have a similar genetic make-up, whereby HERV-K10 INT has been reported to be able to com-
long terminal repeat (LTR) regulatory sequences flank plement an INT-defective HIV-1 strain, although infec-
the reading frames for Gag, Pol, and Env proteins. Gag tivity was severely reduced to 3.7% of wt HIV-1 [24]. It
and Pol are processed by the viral protease into smaller, is nevertheless remarkable that HERV-K10 INT was
functional proteins, while a cellular protease processes able to recognize the dissimilar HIV-1 LTR sequences
Env. The Pol polyprotein is cleaved into the protease to achieve in vitro integration levels of 10-30% of HIV-1
(PR), reverse transcriptase (RT), and integrase (INT) INT.
enzymes. Homologous proteins encoded by one retro- Retroviral envelope proteins are quite versatile and can
virus could theoretically perform comparable functions often be used to package dissimilar viral genomes (pseu-
in trans for another member of the family, and could dotyping). A few HERV envelope genes, such as the
thus complement a (defective) virus. Examples of possi- gammaretroviral HERV-W derived envelope protein,
ble complementation between HERV and HIV proteins syncytin, that plays a role in the attachment of the
will be discussed next. human placenta, are expressed in vivo [25,26]. HERV-W
A first example of a potential supplementary function Env can still function as a viral envelope protein, as
is the dUTP pyrophophatase (dUTPase) enzyme. In infectious particles were generated when it was used to
betaretroviruses, a dUTPase domain is present at the N- complement an env-defective HIV-1 strain [27]. The
terminal part of the protease. In non-primate exogenous HERV-W pseudotyped particles were infectious for
lentiviruses, the dUTPase domain is located between the CD4-negative cells, suggesting a mechanism by which
RNase H domain and the integrase coding region of the HIV-1 can expand its cellular tropism during natural
pol gene. Such dUTPase activity is essential for retro- infection. Interestingly, env-deficient HIV-1 cannot be
virus replication by reducing the levels of dUTP during complemented by the Env protein of murine leukaemia
cDNA synthesis, thereby minimizing the incorporation virus (MuLV), also a gammaretrovirus [26,27]. In con-
of dUTP into the nascent DNA by the reverse transcrip- trast, the generation of pseudotypes between HIV-1 and
tase. In contrast to all other lentiviruses, exogenous pri- endogenous xenotropic MuLVs was proposed earlier as
mate lentiviruses (simian immunodefiency virus, SIV, an explanation for the increased tropism of HIV-1 parti-
and HIV) lack a dUTPase and depend upon the cellular cles harvested from a cell line that had been passaged in
uracil DNA-glycosylase UNG2 to provide this function immunosuppressed mice [28].
[19]. Some researchers have suggested that HIV-1 can Some classes of retroviruses, termed complex retro-
efficiently replicate without UNG2 [20], because it toler- viruses, encode several accessory proteins that simple
ates heavily uracilated DNA. Alternatively, the dUTPase retroviruses lack. For instance, HIV-1 encodes at least 6
encoded by active HERV-K proviruses could supply this additional proteins, betaretroviruses generally only one,
function [21]. Interestingly, the endogenous lentivirus and gammaretroviruses commonly none. An essential
elements carried by lemurs do contain a dUTPase gene additional protein that assists in transporting unspliced
[13,14], suggesting that this function was specifically lost and incompletely spliced viral mRNAs from the nucleus
in the extant SIV lineage. to the cytoplasm is named Rev in HIV-1 and Rex in
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HTLV. The trans-acting Rev protein binds to a viral was found compared to only 5-8% of the control sam-
RNA structure in Env-encoding sequences that is ples, which included hepatitis C virus (HCV) infected
denoted the Rev responsive element (RRE). A homolog patients and healthy individuals [40]. In contrast,
of Rev/Rex is encoded by HERV-K, where it is termed HERV-H RNA, which is upregulated in rheumatoid
K-Rev or Rec [29]. To some extent, Rev/Rex proteins arthritis patients, was not detected in HIV-1 infected
from complex retroviruses can complement each other, blood plasma [40]. The majority of the HERV tran-
e.g. the Rex protein of HTLV-1 can functionally replace scripts in HIV-1 infected samples belonged to the
the HIV-1 Rev protein [30]. However, Rev/Rex comple- HERV-K (HML-2) family and a minority to the HERV-
mentation studies are not always straightforward K (HML-3) cluster. These HERV-K transcripts were
because results often depend upon the experimental sys- derived from several genomic loci, but transcripts from
tem used (see e.g. [31] and references therein). HIV-1 the HML-2 type-2 provirus located at chromosome
Rev can bind the HERV-K RRE, but the reverse is not 4q35 predominated [42]. HML-2 type 1 and type 2 pro-
true as K-Rev does not interact with the HIV-1 RRE viruses differ from each other by a 292 nt deletion in
[29]. Thus, although no actual complementation studies the env gene that disables the expression of functional
between HIV-Rev and K-Rev have been performed, it is protein in type 1. Further analysis suggested that the
unlikely that K-Rev can complement HIV-1 Rev because observed transcripts likely represent full-length viral
RRE binding is essential for protein function. Patients RNAs that are protected from degradation by Gag pro-
harbouring viral genomes with a rev defect or attenuat- tein [40]. Indeed, immature virus particles that reacted
ing mutations have been described [32-34]. The disease only with anti-Gag Ig were observed using electron
phenotype in these patients is generally mild, suggesting microscopy in a follow-up study, although mature viral
that Rev defects in vivo are indeed not (completely) particles reacting with anti-HERV-K Env antibodies and
resolved by endogenous K-Rev. possessing condensed cores and symmetrically distribu-
ted spikes were also occasionally present in the blood
No HERV RNA in HIV-1 virions? plasma of HIV-1 infected patients [42]. HERV-K recom-
Retrovirus particles contain, apart from two copies of binant genomes were detected in blood plasma from
the viral RNA genome, spliced viral RNA’s, several some HIV-1 infected patients but not in breast cancer
tRNAs, and varying amounts of cellular mRNAs that are patients. Furthermore, genetic variation was observed in
co-packaged in a concentration dependent manner env (primarily synonymous substitutions indicative of
[35-37]. Some of the cellular RNAs, such as those cod- purifying selection), with preservation of glycosylation
ing for ribosomal proteins, are preferentially packaged in sites together suggestive of replication through reverse
HIV virions [35]. If HERV RNA would be co-packaged transcription [42].
into HIV-1 virions, this could result in effective mobili- Laderoute et al. focussed on a HERV-K102 member of
zation of these elements. This was investigated in several the HML-2 family that is upregulated during HIV-1
packaging cell lines used in retroviral vector systems. infection [43]. They reported that ~ 76% of blood
Zeilfelder et al. showed that HIV-1 derived vectors sys- plasma samples of HIV-1 infected patients test positive
tems incorporate very little HERV transcripts in parti- for particle associated HERV-K102 pol transcripts, ver-
cles in contrast to murine leukaemia virus (MLV) based sus ~ 3% of healthy controls. However, ~ 79% and ~
vectors [38]. Although the system used by Zeilfelder et 62% of individuals with hepatitis B virus (HBV), hepati-
al. is highly artificial, it nevertheless suggests that HIV-1 tis C virus (HCV) or herpes viremia also showed
does not readily encapsidate HERV transcripts or gen- increased particle associated HERV-K102 pol transcript
omes. An explanation could be that HIV-1 Gag does expression [43], suggesting a more general mechanism
not recognize the RNA packaging signals carried by the of HERV-K upregulation due to virus infection and
non-lentiviral HERVs, while MLV Gag is able to bind to immune stimulation. HERV-K upregulation was inde-
the more related HERV sequences. pendent of ethnicity as it was seen both in individuals of
European and African descent [43].
Increase of HERV viral RNA after HIV-1 infection In contrast, high throughput sequencing of transcripts
In vitro HIV-1 infection of either CD4 expressing T- cell from HIV-1 infected versus uninfected cells did not
lines or stimulated peripheral blood mononuclear cells demonstrate a significant increase in HERV expression
(PBMC’s) upregulates the production of HERV-K RNA upon HIV-1 infection [44]. Possibly, the genetically
and proteins compared to non-infected cells [39]. Analy- highly aberrant SupT1 T-cell line used in these experi-
sis of blood plasma samples from HIV-1 infected ments can account for this unexpected result. Either
patients also showed a significant increase of HERV-K HERV expression could already be at peak level before
RNA expression [40,41], with titers as high as 106-1010 HIV infection of these cells, or specific HERV integra-
copies/ml [42]. In > 95% of samples HERV-K pol RNA tions could simply be absent. Alternatively, the vesicular
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stomatitis virus (VSV)-G envelope protein pseudo-typed RT enzymes prefer certain tRNA molecules for initiation
HIV particles used could possibly explain the lack of of replication and e.g. HIV-1 RT has decreased activity
HERV induction, as Contreras-Galindo et al. [39] used when using other tRNA/PBS combinations [48,49]. This
complete HIV-1 viral particles in their infection assays. preference suggests that RT activity on non-self tem-
Besides, virus infection conditions differed significantly plates is probably greatly reduced, disabling the reverse
between the experiments. transcription of non-family members.
A significant upregulation of HERV-W and HERV-K Interestingly, the non-nucleoside RT inhibitors nevira-
RNA was detected in brain tissue from patients with pine and efavirenz can efficiently inhibit endogenous RT
AIDS dementia, whereas HERV-E expression was activity that is detectable in many human cell lines and
decreased [45]. The changes in HERV expression were leukaemic cells, thereby attenuating the malignant phe-
associated with monocyte differentiation and macro- notype of the cells [50,51]. Nevirapine was not active
phage activation. against LINE-1 retroposon-encoded RT, whereas several
nucleoside analogue RT inhibitors did inhibit LINE-1
HERV expression during antiretroviral therapy RT, albeit with varying degrees of efficacy [52].
As mentioned before, HERV-K RNA expression is
increased in a dose-dependent manner by infection of Mechanisms of HERV activation by HIV infection
peripheral blood mononuclear cells (PBMC’s) and var- It is not clear what the precise mechanism of HERV
ious cell lines with HIV-1 viral particles [39]. In vivo, it induction by HIV infection is. HERV expression is sup-
has not been examined whether HERV-K RNA levels pressed in the germ-line and during the first steps of
increase during acute or chronic HIV-1 infection. embryogenesis, while it is controlled during cell devel-
Highly-active antiretroviral therapy (HAART) against opment (reviewed in [53]). Increased HERV expression
HIV decreases the HIV plasma viral load (pVL) to < 50 is often seen during carcinogenesis and in autoimmune
copies/ml in most patients. Quantifying the HERV-K diseases such as multiple sclerosis [2], but it is unclear
RNA load in patients receiving HAART confirmed that whether the increased expression is a cause or conse-
the HERV-K load is linked to the HIV-1 pVL. Patients quence of the disease. HERVs including the HERV-K
that showed a good suppression of HIV-1 replication (HML-2) family [54] and HIV-1 proviruses [55] are nor-
had a HERV-K load that was around two orders of mag- mally transcriptionally silenced by CpG methylation that
nitude lower than the average HERV-K load in patients is subsequently guarded by DNA methyltransferase 1
with less efficient HIV-1 suppression [46]. HERV-K102 (DNMT1) (reviewed in [53]). Loss of methylation results
particle-associated nucleic acid could not be measured in activation of proviruses, either HERV or HIV, but it
in five patients on antiretroviral therapy (four of them has not been investigated whether HIV actively influ-
with good control of the HIV-1 pVL) in another study, ences proviral methylation levels. HERV expression in
in contrast to patients not receiving antiretroviral ther- HIV-infected cells could be enhanced if methylation
apy [43]. levels of proviral DNA are reduced by HIV. Other inves-
Longitudinal analysis of patients receiving HAART tigators proposed a more complex mechanism for the
demonstrated the long-term suppression of the HERV-K induction of HIV-1 latency that employs transcriptional
pVL to < 5000 copies/ml when the HIV-1 pVL interference [56,57]. Several mechanisms may cooperate
remained below 50 copies/ml [47]. When patients failed to restrict HIV provirus activation [58]. It is not clear
HAART, the HERV-K pVL increased rapidly, frequently whether changes in the pool of available transcription
preceding the HIV-1 pVL rebound [47]. It is unclear factors modulates HERV expression. Many HERV LTR
whether HERV-K is (partially) inhibited by the antiretro- promoters are probably not fully functional, e.g. not able
viral drugs, or whether the loss of activation by HIV-1, to bind these transcription factors, and thus do no
or possibly another mechanism, is responsible for the longer require such a repressive mechanism. Addition-
reduction in HERV-K load. Protease inhibitors targeted ally, the HIV-1 proviral integration site location might
at HIV are not active against the HERV-K enzyme [22], also select for viral latency, virus induction or stable
but other classes of antiretroviral drugs, in particular the expression [59]. Generally, HIV-1 favours integration
nucleotide analogues that target the RT enzyme, might into transcriptionally active genes, usually in introns
be. It is, however, not likely that the HERV-encoded that are part of local transcription hotspots, without
reverse transcriptases are appreciably involved in the apparent directional bias [60]. In contrast, HERV pro-
increase in HERV load, as copy numbers of both intact viruses are generally found outside genes, and com-
RT genes encoding functional proteins as well as intact monly in the reverse orientation compared to the
primer binding sites (PBS) and other motifs needed to nearby cellular gene. HERV integrations seen in contem-
initiate reverse transcription, such as the primer activa- porary genomes are the result of stringent evolutionary
tion domain (PAS) in HIV, are likely to be low. Also, selection, whereby HERV’s in the sense orientation
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(facilitates transcription with nearby genes) or within APOBEC3G was shown for HERV-K (HML-2) elements,
cellular genes were probably negatively selected for [60]. both during in vitro replication as well as in the muta-
In other words, observed HERV integrations do prob- tion pattern of ancient integrations [71,72].
ably not faithfully reflect HERV target site preferences.
Anyhow, the consequence is that HIV-1 proviruses are HERV proteins and antibodies in HIV infected
rarely found in the proximity of HERV integrations patients
[59,60], ruling out that there is a direct positional effect Increased expression of HERV-K Gag protein has been
of HIV-1 transcription upon HERV activation. detected in both the CD4+ and CD8+ T-cell fractions
Specific upregulation of endogenous proviruses by from HIV-infected patients compared to T-cells from
HIV proteins or cellular proteins upregulated by HIV is uninfected individuals [39]. It is remarkable that HERV-
another possibility. It has been suggested that the HIV-1 K Gag is also upregulated in CD8+ T-cells that are nor-
Tat protein is able to directly activate the HERV-K mally not infected by HIV-1, which would suggest a
(HML-2) LTR [47]. The HTLV-I encoded transactivator more general and indirect mechanism of activation. No
protein Tax is likewise able to activate HERV LTRs, significant correlation was found between the HIV-1
mainly of HERV-W and HERV-H [61]. HERV-K (HML- pVL, CD4+ or CD8+ T-cell counts and HERV-K protein
2) RNA is not, or only weakly, upregulated by common titers.
stimulation of donor PBMCs with phytohaemagglutinin, Antibodies to expressed HERV-K proteins are fre-
gamma irradiation or 5-azacytidine [62], suggesting that quently found in several groups of patients, which is
HERV upregulation requires undefined, yet specific interesting because HERVs should be classified as self-
conditions. antigens. Some studies did describe a HERV-K antibody
Another indirect mechanism of HERV upregulation by response in HIV-1 infected persons, while others did
HIV-1 infection could be through opportunistic viral not. No significant increase in serum antibodies against
infections. HIV infection deregulates and eventually recombinant human teratocarcinoma-derived virus
destroys the immune system. Loss of immune control (HTDV)-HERV-K Env protein was seen in HIV-1
facilitates the replication of diverse opportunistic patho- infected patients (15.2% versus 12.6% in healthy con-
gens. Some of these pathogens, e.g. herpesviruses, are trols) [73]. Similar negative results were obtained by
virtually ubiquitous in the human population and Vogetseder et al. [73] and Boller et al. [74], when exam-
remain latently present during the lifetime of the host. ining the antibody response against HTDV/HERV-K
Herpesviruses are reactivated from latency during Gag and Env proteins in HIV-1 positive individuals, and
chronic HIV infection [63]. Herpes simplex virus type 1 by Goedert et al. [75] in HIV-1 infected individuals with
(HSV-1) can specifically activate the HERV-W LTR, and testicular cancer. In contrast, 70% of HIV-1 infected
induce expression of HERV-W Gag and Env proteins in patients versus 3% of healthy controls tested positive for
cell lines [64-66]. Epstein-Barr virus (EBV), that has a antibodies against HTDV/HERV-K Env in a fourth
prevalence rate of around 75% in humans, induces tran- study [76]. A fifth study, employing HERV-K102 Env
scription of the env gene of HERV-K18 [67], and so do peptide serology reported similar numbers, with 70-80%
human herpesvirus 6A [68] and 6B [69]. Most likely, the of HIV-1 viraemic patients testing positive versus 2% of
other five human herpesviruses are also able to activate healthy controls and 18% of patients with herpes virae-
HERV transcription. HHV-6 and human herpesvirus 7 mia [43]. Interestingly, a patient seroconverting for anti-
(HHV-7), that have infection rates of 100% each in the HIV-1 antibodies showed a parallel seroconversion for
human population, infect, similar to HIV, CD4+ T-cells, anti-HERV-K Env antibodies in the study by Vogetseder
and could thus (partly) be responsible for HERV induc- et al. [73]. Cross-reactivity is unlikely to explain this
tion seen in PBMC’s after HIV-1 infection. EBV com- result, as the HERV-K and HIV-1 Env proteins have lit-
monly infects B-cells, while cytomegalovirus (CMV), tle amino acid similarity.
with a prevalence rate of around 50%, infects monocytes Testing urine specimens of HIV-1 infected individuals
and macrophages, and both could likewise contribute to and healthy controls for antibodies against a peptide
the observed rise in PBMC HERV expression. In addi- derived from the gammaretrovirus HERV-E Env protein
tion, infection by influenza A virus enhanced HERV-W showed that 36.4% and 81.3% of patients in the CDC
expression in cell culture as well [66], suggesting that AIDS categories A and B/C respectively, contained spe-
many more viruses have the potential to do so. cific antibodies, while none of the HIV-negative controls
Expression of the HIV accessory protein Vif counter- tested positive [77]. Fourteen peptides derived from var-
acts the viral restriction factor APOBEC3G and could ious endogenous retroviruses were used to search for
result in abrogation of cellular HERV control [70] and IgM and IgG antibodies in HIV-1 infected and unin-
de novo replication of HERV elements by reverse tran- fected immunosuppressed persons by Lawoko et al.
scription. Restriction during reverse transcription by [78]. Three peptides, corresponding to the C-terminal
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half of the murine leukaemia virus capsid protein, a the three patients described above. In a follow-up study,
conserved domain of the HERV-H transmembrane anti-HERV T-cell responses were analysed in a larger
domain, and part of HERV-K HML-3 encoded Pol, were cohort of untreated HIV-1 infected individuals [70]. The
found to bind IgG in both groups, with stronger binding breadth and magnitude of the HERV response were
of the latter two peptides in HIV-1 infected patients again inversely correlated with HIV-1 pVL and positively
[78]. No correlation of either IgM or IgG binding with associated with CD4+ T-cell counts. The peptide that
progression to AIDS was observed. evoked the largest number of responses was derived
In conclusion, it is difficult to summarize these studies from HERV-H Env. Other peptides tested originated
on anti-HERV antibodies in HIV-1 infected patients. from HERV-K (n = 14), HERV-L (n = 12), and HERV-
Studies on HERV-K remain contradictory, while others W (n = 1).
investigated HERV families whose RNA expression An HIV-1 positive patient who controlled the infec-
levels during HIV infection have not been characterized. tion for over 8 years showed HLA-B51 restricted
responses to the HERV-K Pol epitope FAFTIPAI as well
T-cell response to HERV in HIV infected patients as to the corresponding HIV-1 epitope TAFTIPSI. The
Although HERV proteins should be regarded as self- CD8+ T-cells responding to the HERV epitope were
antigens, tolerance is often broken during neoplastic found to be less activated and more differentiated than
processes and also during HIV infection as demon- the cells targeting the HIV-1 epitope [70]. The cytome-
strated by a study that measured T-cell responses galovirus-specific CD8+ T-cell population in this patient
against HERV during HIV infection [41]. Peptides corre- did mimic the HERV response.
sponding to HERV and HIV epitopes were tested for Overall, these results suggest that a robust CD8+ T-
their ability to evoke a T-cell response in vitro. Ten pep- cell response against the newly expressed HERV pep-
tides contained short regions of homology between tides presented by HIV infected cells may contribute to
HERV-H/-K/-L and HIV, respectively, and six others the control of HIV replication in blood. Indeed, a sec-
unique for HERV-L or HERV-W were used to estimate ond study in vertically infected children showed a simi-
both putative cross-reactive and virus-specific T-cell lar outcome: anti-HERV responses were inversely
responses. HERV-H and HERV-W cluster with the gam- correlated with the HIV-1 plasma viral load and posi-
maretroviruses, and HERV-L has similarity to spuma- tively correlated with the CD4+ T cell count [80]. Alter-
viruses [79]. PBMC samples were collected from HIV-1 natively, Tandon et al. suggest that instead of a direct
infected, HCV infected, and uninfected individuals. T- effect of anti-HERV responses, the correlations might be
cell responses against HERV epitopes were detected related to a more intact immune system in patients
only in HIV-1 positive patients, with no significant dif- showing considerable anti-HERV activity.
ference in reactions against unique HERV peptides ver-
sus HIV-related HERV peptides. This suggests that the Anti-HERV vaccines as an approach to combat
response against HERV epitopes is distinct from the HIV?
anti-HIV response. T-cell cross-reactivity was tested in T-cell responses that are effective in lowering the HIV-1
three patients with a response to either the HIV-RT pVL and thus assist in controlling HIV replication are
VL9 or HERV-L II9 peptide which share some amino potential vaccine targets. In contrast to the replicating
acid similarity, but was found to be absent. and rapidly mutating HIV-1 genome, HERVS are cellu-
Anti-HERV T cell responses were broad and varied lar genes that are not prone to mutation. Although
significantly among the study subjects [41]. The HERV- HERV integrations are present in every cell in the body,
specific T-cell responses were inversely correlated with they are expressed in a cell type and development speci-
the HIV-1 pVL, raising the exciting possibility that these fic way, making many HERV proteins rather specific
responses could be involved in the control of HIV repli- antigens. Indeed, a HERV-K env transcript, HERV-K-
cation. Reactivity to the unique HERV-L IQ10 peptide MEL, encoded a melanoma-specific antigen that was
was found in 5/16 HIV-1 infected patients. Longitudinal recognized by cytolytic T lymphocytes [81]. Vaccination
analysis of three patients showed persistent responses to with peptides derived from another melanoma-specific
this peptide that declined in two patients when HAART antigen had been successful earlier in inducing tumour
was started. The third patient with the highest response regression (see [81]), suggesting that vaccination with
to this peptide controlled HIV replication without ther- HERV-K-MEL peptides could be an effective strategy. A
apy. HERV-specific CD8+ T-cells were able to lyse cells HERV-E transcript specifically expressed by renal cell
presenting the corresponding peptide. If HIV-1 infected carcinoma tissue and cell lines encoded a peptide that
cells that present HERV peptides are subsequently lysed was recognized by CD8+ T-cells after allogeneic hemato-
by HERV-specific CD8+ T-cells, a decrease in HIV-1 poietic stem cell transplantation [82]. Recognition
pVL would be the result, explaining the observations in resulted in tumour regression in vivo, an example of the
vanderKuylRetrovirology2012,9:6 Page8of10
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