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

Abstract

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.

Molecular functions of human endogenous retroviruses in health and disease

“…For example, the primate lentiviruses HIV and simian immunodeficiency virus (SIV) do not express their own dUTPase, and it is believed that a host cell endogenous retroviral enzyme (Prot) provides this activity during reverse transcription [70][71][72], in line with the recent observations that HIV-1 infection may increase the expression of HERV-K/HML-2 (ERVK) proviruses in vitro [185] and in vivo [185,186]. The envelope glycoprotein of one of HERV-K/HML-2 (ERVK) members, HERV-K18 (ERVK-18), is incorporated into HIV-1 in an HIV matrix-specific fashion [78]. In HIV patients, HERV-K/HML-2 (ERVK) proviruses are expressed at significantly higher levels in peripheral blood mononuclear cells than in those from uninfected individuals [187].…”

“…This may be functionally linked to an increased HERV expression in some tumors [37,77]. Of note, human primary lymphocytes express up to 32 different HERV-K/HML-2 (ERVK) envelopes, and at least two of the most highly expressed Env genes retain the protein-coding capacity [78].…”

Endogenous retroviruses mobilized during friend murine leukemia virus infection

“…HERV K virions are not thought to be infectious; however, it is possible that transcriptional activation of the proviruses in HIV-infected cells might facilitate pseudotyping of the transcripts within HIV virions and subsequent infectious spread/mobilization of the proviruses. In this regard, although there is no evidence for pseudotyping between HERV K and HIV-1, it has recently been reported that an HERV K Env can be incorporated into HIV-1 virions (Brinzevich, Young et al, 2014). The consequences of transcriptional activation are quite distinct from those of mobilization of the proviruses.…”

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

“…All env PCR products were cloned using HinDIII-SmaI restriction sites and either T4 ligase or In-fusion technology (Clontech Laboratories, Inc.) into a derivative of vector pTR600 [27] containing the HERV-K RcRe (Rec response element) segment, for RNA nuclear export [22]. All HERV-K env mutants where obtained by PCR mediated site directed mutagenesis, using as template HERV-Kcon env encoding plasmid pCRV1/ env and verified by sequencing.…”

“…Envelope sequences belonging to members of both types retain their ability to generate a processed protein, although type-1 Envs often show inefficient glycosylation [22], and some (both type-1 and type-2) can be incorporated into HIV particles [22–24]. HERV-K108 is among the best studied HERV-Ks and its expression is prevalent in transformed tissues such as melanomas [25].…”