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.
Highlights
Simian immunodeficiency virus (SIV) is naturally endemic to a wide variety of African nonhuman primates (NHPs)
Following an accidental cross-species transmission of a variant of SIV termed SIVsm to rhesus macaques, a lethal disease was observed in these hosts with symptoms similar to AIDS [3,4,5,6,7,8]; this has given rise to the pathogenic SIVmac strain [5, 9]
simian AIDS (SAIDS) and human AIDS share similar symptoms that include acute and progressive loss of CD4+ T cells followed by immunodeficiency, opportunistic infections, and development of tumors [14]
Summary
Simian immunodeficiency virus (SIV) is naturally endemic to a wide variety of African nonhuman primates (NHPs). SAIDS and human AIDS share similar symptoms that include acute and progressive loss of CD4+ T cells followed by immunodeficiency, opportunistic infections, and development of tumors [14]. Integration into host cell DNA is the last step performed by the HIV and SIV integrase proteins before an irreversible infection takes place in a cell. Several key factors must be taken into account when choosing an animal model for the study of HIV-1 pathogenesis (Table 1) These include the use of the CD4 receptor and the use of either the CC-chemokine receptor 5 (CCR5) or the CXC-chemokine receptor 4 (CXCR4) as co-receptors, nuclear export factors, transcription factors, and cellular host factors [31]. Following infection with CCR5- or CXCR4-tropic HIV, successful reproduction of HIV-1 pathogenesis in humanized mice with substantial plasma viremia and systemic depletion of human CD4+ T cells was observed [41, 42]
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