HIV-1 interacts with human endogenous retrovirus K (HML-2) envelopes derived from human primary lymphocytes

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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 is currently 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) single-molecule 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 post-translationally processed envelope proteins in cell culture. We show that HERV-K18 Env can be incorporated into HIV-1 but not 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-Ks envelopes not only makes full-length a protein but also specifically interacts with HIV-1. Our findings raise the possibility that these endogenous retroviral Envs could directly influence HIV-1 replication.Importance Here we report the HERV-K expression profile of primary lymphocytes from 5 different healthy donors. We used a novel deep sequencing 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 envelops, and that at least two of the most expressed Envs retain their ability to make a protein. Importantly one of them, the envelope glycoprotein of HERV-K18, is incorporated into HIV-1 in a HIV-Matrix specific fashion. The ramifications of such interactions are discussed in the last part of the manuscript as the possibility of HIV-1 target tissue broadening and immune evasion are considered.