Susceptibility of Human Endogenous Retrovirus Type K to Reverse Transcriptase Inhibitors

Abstract

Human endogenous retroviruses (HERVs) make up 8% of the human genome. The HERV type K (HERV-K) HML-2 (HK2) family contains proviruses that are the most recent entrants into the human germ line and are transcriptionally active. In HIV-1 infection and cancer, HK2 genes produce retroviral particles that appear to be infectious, yet the replication capacity of these viruses and potential pathogenicity has been difficult to ascertain. In this report, we screened the efficacy of commercially available reverse transcriptase inhibitors (RTIs) at inhibiting the enzymatic activity of HK2 RT and HK2 genomic replication. Interestingly, only one provirus, K103, was found to encode a functional RT among those examined. Several nucleoside analogue RTIs (NRTIs) blocked K103 RT activity and consistently inhibited the replication of HK2 genomes. The NRTIs zidovudine (AZT), stavudine (d4T), didanosine (ddI), and lamivudine (3TC), and the nucleotide RTI inhibitor tenofovir (TDF), show efficacy in blocking K103 RT. HIV-1-specific nonnucleoside RTIs (NNRTIs), protease inhibitors (PIs), and integrase inhibitors (IIs) did not affect HK2, except for the NNRTI etravirine (ETV). The inhibition of HK2 infectivity by NRTIs appears to take place at either the reverse transcription step of the viral genome prior to HK2 viral particle formation and/or in the infected cells. Inhibition of HK2 by these drugs will be useful in suppressing HK2 infectivity if these viruses prove to be pathogenic in cancer, neurological disorders, or other diseases associated with HK2. The present studies also elucidate a key aspect of the life cycle of HK2, specifically addressing how they do, and/or did, replicate. Endogenous retroviruses are relics of ancestral virus infections in the human genome. The most recent of these infections was caused by HK2. While HK2 often remains silent in the genome, this group of viruses is activated in HIV-1-infected and cancer cells. Recent evidence suggests that these viruses are infectious, and the potential exists for HK2 to contribute to disease. We show that HK2, and specifically the enzyme that mediates virus replication, can be inhibited by a panel of drugs that are commercially available. We show that several drugs block HK2 with different efficacies. The inhibition of HK2 replication by antiretroviral drugs appears to occur in the virus itself as well as after infection of cells. Therefore, these drugs might prove to be an effective treatment by suppressing HK2 infectivity in diseases where these viruses have been implicated, such as cancer and neurological syndromes.

Exosomes transmit retroelement RNAs to drive inflammation and immunosuppression in Ewing Sarcoma

“…Strand-specific accumulation of pericentromeric transcripts in MRC5 cells prompted us to examine their potential amplification, which could be driven by Pol II 29,31,32 or by RTs of either cellular (such as TERT, shown for HSAT2 40 ) or retroviral 41,42 origin. We found that Pol II inhibitor DRB and, to a lesser extent, actinomycin D (ActD; a pleiotropic polymerase inhibitor) strongly blocked accumulation of HSAT2, ACRO1 and HERV-Kenv, along with IFNβ mRNA used as an internal control (Fig.…”

“…5c). The RT inhibitors 3'-Azido-3'-deoxythymidine (AZT/zidovudine; an inhibitor of HIV, HERV-K and L1-encoded RT activities 42,43 ) and nevirapine (NVP) had moderate effects, with AZT being more efficient in reducing levels of HSAT2, HERV-Kenv and ACRO1 by ~1.6 and 2.5-fold, respectively ( Fig. 5c); the observed reduction in IFNβ mRNA levels could be due to a decrease in repeat RNAs and diminished antiviral response under these conditions.…”

ALSUntangled 45: Antiretrovirals

“…The current evidence, taken from in vitro studies, suggests that HERV type K is susceptible to most members of a class of ARVs called nucleoside reverse transcriptase inhibitors (NRTIs; 38,39), but is relatively resistant to ARVs from the class protease inhibitors (PIs; [38][39][40][41]. Evidence for in vitro efficacy of non-nucleoside reverse transcriptase inhibitors (NNRTIs) and integrase inhibitors (INSTIs) is mixed (38,39).…”

“…While serum creatine kinase (total CK) levels dropped coincident with treatment, ''clinical courses were not significantly altered'' (48). This trial utilized an ARV that has excellent penetrance into the CNS (49) and has been reported to be active in vitro against HERV (38,39); however, the trial design was flawed in that it enrolled a very small number of PALS, followed them for variable amounts of time, and used unclear clinical outcome measures. The second ARV trial was a double-blind trial that randomized 46 PALS to either the protease inhibitor indinavir or placebo for 9 months.…”

“…Additionally, the specific ARV used would need to have activity against the retrovirus targeted and the retrovirus would need to be actively producing infectious viral particles. If targeting HERV type K would be beneficial in PALS, which is still unknown, then a reasonable regimen might consist of two NRTIs and one INSTI given the data above (38)(39)(40)(41). The cost of the specific ARV regimen would depend on the drug(s) selected.…”