Abstract
In the past decade, studies of innate immune activity against HIV-1 and other retroviruses have revealed a powerful array of host factors that can attack the virus at various stages of its life cycle in human and primate cells, raising the prospect that these antiviral factors could be manipulated in immunotherapeutic strategies for HIV infection. This has not proved straightforward: while HIV accessory genes encode proteins that subvert or destroy many of these restriction factors, others, such as human TRIM5α show limited potency against HIV-1. However, HIV-1 is much more susceptible to simian versions of TRIM5α: could this information be translated into the development of an effective gene therapy for HIV infection? Reigniting research into the restriction factor TRIM5α in the era of superior gene editing technology such as CRISPR-Cas9 presents an exciting opportunity to revisit this prospect.
Highlights
The HIV/AIDS epidemic continues to present a humanitarian crisis for the world’s most disadvantaged communities
Human TRIM5α has limited efficacy against HIV-1 in vivo, whereas the rhesus macaque TRIM5α and TRIM5-CypA fusion are highly effective against primate lentiviruses [2]. huTRIM5α potently restricts another retrovirus, N-tropic murine leukemia virus (N-MLV) and appears to moderate HIV-2 infection, potentially contributing to an attenuated disease course [3, 4]
It was shown that SCID-X1 mice could undergo lymphoid reconstitution with transgenic hematopoietic stem cells (HSCs) generated by homology-directed repair-mediated gene editing methods, including CRISPR-Cas9, following immunotoxin-based selective depletion of hematopoietic cells [60]
Summary
The HIV/AIDS epidemic continues to present a humanitarian crisis for the world’s most disadvantaged communities. The Pan troglodytes endogenous retrovirus (PtERV1), active 3–4 million years ago, was shown to be one of the likely culprits for this change as efficient restriction of chimeric PtERV was abrogated in the presence of a hominid R332Q mutation but restriction of HIV-1 was improved [20]. Taken together, this points to a situation of evolutionary “trade-off,” where fixation of R332 in the human lineage conferred resistance to PtERV1 but in combination with other antiretroviral factors rendered us poorly suited to the challenge of HIV infection. While HIV-1 infection is globally distributed and continues to increase in numbers, HIV-2 is endemic to West Africa and appears
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