HIV Tat acts on endogenous retroviruses of the W family and this occurs via Toll-like receptor 4

Abstract

In-vivo consequence of the study could be that, through increase of CD16 and CCR2, Tat promotes neuroinvasion not only by HIV-infected monocytes/macrophages but also by the HERV-Ws, with their neuropathogenic potential. Also, the novel finding of TLR4 stimulation by Tat may be of relevance, as TLR4 is critical in neuroinflammation. Within central nervous system (CNS), Tat-induced TNFα could induce high levels of the HERV-Ws, in both macrophages and astrocytes, also without HIV replication. The indirect mechanism by which Tat activates the HERV-Ws through induction of TNFα could add a new piece to the puzzle of CNS pathogenesis, that is the HERV-Wenv contribute to the HIV-related neurodegeneration.

The aliens inside human DNA: HERV-W/MSRV/syncytin-1 endogenous retroviruses and neurodegeneration

“…A major difference is that only MSRV is found as complete extracellular virus, while syncytin-1 is found only intracellularly or on the plasma membrane [16]. At the protein level, no antibodies discriminating MSRVenv and syncytin-1 are yet available [28]. At the RNA level, MSRVenv and syncytin-1 have 94% similarity; we observed that MSRVenv sequences have a 12-nucleotide insertion in the trans-membrane moiety [29].…”

“…Since 10% of healthy Caucasian release MSRV in the blood [16], we wondered whether MSRV and syncytin-1 are activated by HIV and thus whether their neuropathogenic and immunopathogenic properties could contribute to HIV-related neurodegeneration [28]. In fact, rather than HIV itself, as the virus production is too low to explain the extensive CNS disease often observed, mechanisms of amplification of toxicity and inflammation in response to HIV infection were suggested as a major cause of neurological disease [64].…”

“…The mechanisms by which HIV causes neurodegeneration are not fully elucidated, and include both host and viral mechanisms [28,63]. Additional relevant contributions to neuroAIDS are caused by reactivation of bystander latent/persistent viruses with neurotropic potential such as EBV, cytomegalovirus, and JC polyomavirus, which can result in life-threatening CNS infections in immunocompromised hosts [28].…”

“…In fact, rather than HIV itself, as the virus production is too low to explain the extensive CNS disease often observed, mechanisms of amplification of toxicity and inflammation in response to HIV infection were suggested as a major cause of neurological disease [64]. To this end, we exposed to HIV, or to its transactivator of transcription (Tat) protein, monocytes/macrophages and astrocytes, i.e., the cells that are thought to be more relevant for HIVrelated neurodegeneration [28].…”

“…However, due to the sequence similarities, effective distinction between the two elements by discriminatory quantitative real-time reverse transcription (RT)-PCR assays was carried out only by our group [24,[28][29]36] and later on, with the same assay, by Perron et al [37]. With the aid of these realtime PCR assays, which can amplify selectively either MSRVenv or syncytin-1 [29], we found that the DNA of MS patients had increased MSRVenv copies (sixfold mean increase, p = 0.02), while the syncytin-1-specific assay gave almost identical mean values for both patients and controls [29].…”