Nonhuman Primates and Humanized Mice for Studies of HIV-1 Integrase Inhibitors: A Review

Abstract

Since the discovery of the first inhibitors of HIV replication, drug resistance has been a major problem in HIV therapy due in part to the high mutation rate of HIV. Therefore, the development of a predictive animal model is important to identify impending resistance mutations and to possibly inform treatment decisions. Significant advances have been made possible through use of nonhuman primates infected by SIV, SHIV, and simian-tropic HIV-1 (stHIV-1), and use of humanized mouse models of HIV-1 infections. In this review, we describe some of the findings from animal models used for the preclinical testing of integrase strand transfer inhibitors. These models have led to important findings about the potential role of integrase strand transfer inhibitors in both the prevention and treatment of HIV-1 infection.

Keywords: drug resistance mutations; integrase; integrase strand transfer inhibitors; nonhuman primates; simian immunodeficiency virus (SIV); simian-human immunodeficiency virus (SHIV); simian-tropic human immunodeficiency virus (stHIV-1).

Figure 1.

Multiple amino acid sequence alignment of HIV-1 subtype B and different SIV integrases. The HIV-1 subtype B integrase sequence is provided as a reference. Identical amino acid residues that are conserved across all six proteins are marked with an asterisk (*); residues similar to each other are marked with a colon (:); those that are less similar are marked with a period (.); and those that are not similar are not marked. Catalytic triad residues (D64, D116, and E152) and residues involved in main resistance pathways against integrase inhibitors (T66, E92, T97, G118, F121 G140, Y143, S147, Q148, N155, and R263) are shaded in gray. The GenBank accession numbers for the sequences used in this alignment are DQ676870 (HIV-1 subtype B), DQ307022 (HIV-2) FJ424864 (SIV_gorCP2139.1con), EF394356.1 (SIV_cpzTan1.910), M33262 (SIVmac239), and U58991 (SIV_agmTan-1). The multiple sequence alignment was performed using Clustal Omega software [–29].

Figure 2.

Schematic diagram of the genomic organization of HIV-1, HIV-2, SIV, stHIV-1 and SHIV viral genomes. HIV-1/SIVcpz encodes the vpu gene but lacks the vpx gene. HIV-2/SIVmac encodes vpx but not vpu. The gag polyprotein encodes matrix (MA), capsid (CA), and nucleocapsid (NC). The pol genomic region encodes the viral enzymes protease (PR), reverse transcriptase (RT), and integrase (IN). Gray- and black-shaded boxes indicate SIV- and HIV-derived sequences, respectively. Abbreviations: SIV, simian immunodeficiency virus; stHIV-1, simian-tropic human immunodeficiency virus; SHIV, simian-human immunodeficiency virus; SIVcpz, chimpanzee-derived; SIVmac, macaque-derived; RT, reverse transcriptase; LTR, long-terminal repeat; env, envelope glycoprotein.