Molecular Therapy: Methods & Clinical Development (Jun 2021)

HIV-based lentiviral vectors: Origin and sequence differences

  • Nathan M. Johnson,
  • Anna Francesca Alvarado,
  • Trey N. Moffatt,
  • Joshua M. Edavettal,
  • Tarun A. Swaminathan,
  • Stephen E. Braun

Journal volume & issue
Vol. 21
pp. 451 – 465

Abstract

Read online

Three gene therapy strategies have received US Food and Drug Administration (FDA) approval; one includes HIV-1-based lentiviral vectors. These vectors incorporate features to provide long-term gene transfer and expression while minimizing generation of a replication-competent virus or pathogenicity. Importantly, the coding regions of viral proteins were deleted, and the cis-acting regulatory elements were retained. With the use of representative vectors developed for clinical/commercial applications, we compared the vector backbone sequences to the initial sources of the HIV-1. All vectors included required elements: 5′ long terminal repeat (LTR) through the Ψ packaging signal, central polypurine tract/chain termination sequence (cPPT/CTS), Rev responsive element (RRE), and 3′ LTR, including a poly(A) signal. The Ψ signaling sequence demonstrated the greatest similarity between all vectors with only minor changes. The 3′ LTR was the most divergent sequence with a range of deletions. The RRE length varied between vectors. Phylogenetic analysis of the cPPT/CTS indicated multiple sources, perhaps because of its later inclusion into lentiviral vector systems, whereas other regions revealed node clusters around the HIV-1 reference genomes HXB2 and NL4-3. We examine the function of each region in a lentiviral vector, the molecular differences between vectors, and where optimization may guide development of the lentiviral delivery systems.

Keywords