Human Endogenous Retrovirus K Gag Coassembles with HIV-1 Gag and Reduces the Release Efficiency and Infectivity of HIV-1

Monde, Kazuaki; Contreras-Galindo, Rafael; Kaplan, Mark H.; Markovitz, David M.; Ono, Akira

doi:10.1128/jvi.00301-12

Cited by 59 publications

(65 citation statements)

References 56 publications

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“…Such interactions could, however, profoundly impact HIV properties such as infectivity, the range of tissues it can infect, and the cytopathic damage caused to the host cells. A recent report described that the expression of a consensus sequence HERV-K Gag had a negative influence on HIV-1 particle release and infectivity caused by the coassembly of HERV-K gag with HIV-1 gag (20).…”

mentioning

confidence: 99%

HIV-1 Interacts with Human Endogenous Retrovirus K (HML-2) Envelopes Derived from Human Primary Lymphocytes

Brinzevich

Young²,

Sebra

et al. 2014

J Virol

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Human endogenous retroviruses (HERVs) are viruses that have colonized the germ line and spread through vertical passage. Only the more recently acquired HERVs, such as the HERV-K (HML-2) group, maintain coding open reading frames. Expression of HERV-Ks has been linked to different pathological conditions, including HIV infection, but our knowledge on which specific HERV-Ks are expressed in primary lymphocytes currently is very limited. To identify the most expressed HERV-Ks in an unbiased manner, we analyzed their expression patterns in peripheral blood lymphocytes using Pacific Biosciences (PacBio) singlemolecule real-time (SMRT) sequencing. We observe that three HERV-Ks (KII, K102, and K18) constitute over 90% of the total HERV-K expression in primary human lymphocytes of five different donors. We also show experimentally that two of these HERV-K env sequences (K18 and K102) retain their ability to produce full-length and posttranslationally processed envelope proteins in cell culture. We show that HERV-K18 Env can be incorporated into HIV-1 but not simian immunodeficiency virus (SIV) particles. Moreover, HERV-K18 Env incorporation into HIV-1 virions is dependent on HIV-1 matrix. Taken together, we generated high-resolution HERV-K expression profiles specific for activated human lymphocytes. We found that one of the most abundantly expressed HERV-K envelopes not only makes a full-length protein but also specifically interacts with HIV-1. Our findings raise the possibility that these endogenous retroviral Env proteins could directly influence HIV-1 replication. IMPORTANCEHere, we report the HERV-K expression profile of primary lymphocytes from 5 different healthy donors. We used a novel deepsequencing technology (PacBio SMRT) that produces the long reads necessary to discriminate the complexity of HERV-K expression. We find that primary lymphocytes express up to 32 different HERV-K envelopes, and that at least two of the most expressed Env proteins retain their ability to make a protein. Importantly, one of them, the envelope glycoprotein of HERV-K18, is incorporated into HIV-1 in an HIV matrix-specific fashion. The ramifications of such interactions are discussed, as the possibility of HIV-1 target tissue broadening and immune evasion are considered.

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confidence: 99%

HIV-1 Interacts with Human Endogenous Retrovirus K (HML-2) Envelopes Derived from Human Primary Lymphocytes

Brinzevich

Young²,

Sebra

et al. 2014

J Virol

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“…Sometimes these interactions are lethal for the invading retrovirus, as in the case of Fv1 or consensus Gag of HERV-Kcon [15,16]. It is clear though that we have not fully grasped the extent of the impact of these resident endogenous retroviruses on the life cycle of exogenous viruses.…”

Section: Discussionmentioning

confidence: 99%

“…The protein Fv1, derived from the gag region of MuERV-L (a murine endogenous retrovirus with high similarity to the human HERV-L) [13,14], interferes with the formation of exogenous Murine Leukemia Virus (MLV) proviruses in the target cell [15]. Furthermore, the HERV-K Gag consensus sequence protein co-assembles with HIV-1 Gag and negatively affects the late phase of HIV-1 replication, indicating that co-expression of HERV-K with HIV-1 could impact the HIV lifecycle [16]. ERV envelopes also can hinder retroviral infections.…”

Section: Introductionmentioning

confidence: 99%

Expression of HERV-K108 envelope interferes with HIV-1 production

et al. 2017

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The human endogenous retroviruses (HERV)-K of the HML-2 group include full-length or near full-length elements encoding functional proteins, and are classified as type-1 or type-2 (type-1 has a deletion in the 5′ end of the env gene). Because proteins of different retroviruses can interact, we hypothesized that HERV-K envelope (Env) could influence HIV-1 replication. Here we describe the negative effect of envelope expression of certain type-2 HERV-Ks on HIV-1 production. All HIV-1 and SIV strains tested were susceptible to various degrees to inhibition by the HERV-K108 envelope. We identified four residues within HERV-K108 Env as being critical to inhibit HIV-1 production. No inhibition was observed on EGFP expression, indicating that HERV-K Env does not affect general protein production. These findings demonstrate that envelope proteins from some endogenous retroviruses can limit production of exogenous lentiviruses such as HIV-1. Future studies will elucidate the mechanism mediating HIV-1 inhibition by HERV Envs.

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“…Human endogenous retrovirus (HERV) sequences are upregulated in neoplastic tissues due to genomic instability and epigenetic changes during transformation [33–35] and a similar phenomenon occurs in HIV-infected cells [36]. Furthermore, HERV-K (a member of the Betaretrovirus genus) Gag can co-assemble and co-package with HIV-1 Gag [37]. Similarly, it has been shown that endogenous JSRV Gag can co-assemble with exogenous JSRV Gag and, in the presence of a particular mutation (R21W), restrict the release of exogenous JSRV particles in a transdominant fashion [38, 39].…”

Section: Discussionmentioning

confidence: 99%

Construction of a molecular clone of ovine enzootic nasal tumor virus

Walsh

Gerpe

Wootton

2016

Virol J

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BackgroundEnzootic nasal tumor virus (ENTV-1) is an ovine betaretrovirus that has been linked to enzootic nasal adenocarcinoma (ENA), a contagious tumor of the ethmoid turbinates of sheep. Transmission experiments performed using virus isolated from cell free nasal tumor homogenates suggest that ENTV-1 is the causative agent of ENA; however, this etiological relationship has not been conclusively proven due to the fact that the virus cannot be propagated in vitro nor is there an infectious molecular clone of the virus.MethodsHere we report construction of a molecular clone of ENTV-1 and demonstrate that transfection of this molecular clone into HEK 293T cells produces mature virus particles.ResultsAnalysis of recombinant virus particles derived from the initial molecular clone revealed a defect in the proteolytic processing of Gag; however, this defect could be corrected by co-expression of the Gag-Pro-Pol polyprotein from the highly related Jaagsiekte sheep retrovirus (JSRV) suggesting that the polyprotein cleavage sites in the ENTV-1 molecular clone were functional. Mutagenesis of the molecular clone to correct amino acid variants identified within the pro gene did not restore proteolytic processing; whereas deletion of one proline residue from a polyproline tract located in variable region 1 (VR1) of the matrix resulted in production of CA protein of the mature (cleaved) size strongly suggesting that normal virion morphogenesis and polyprotein cleavage took place. Finally, electron microscopy revealed the presence of spherical virus particles with an eccentric capsid and an average diameter of about 100 nm.ConclusionIn summary, we have constructed the first molecular clone of ENTV-1 from which mature virus particles can be produced. Future experiments using virus produced from this molecular clone can now be conducted to fulfill Koch’s postulates and demonstrate that ENTV-1 is necessary and sufficient to induce ENA in sheep.

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Human Endogenous Retrovirus K Gag Coassembles with HIV-1 Gag and Reduces the Release Efficiency and Infectivity of HIV-1

Cited by 59 publications

References 56 publications

HIV-1 Interacts with Human Endogenous Retrovirus K (HML-2) Envelopes Derived from Human Primary Lymphocytes

HIV-1 Interacts with Human Endogenous Retrovirus K (HML-2) Envelopes Derived from Human Primary Lymphocytes

Expression of HERV-K108 envelope interferes with HIV-1 production

Construction of a molecular clone of ovine enzootic nasal tumor virus

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