Use of Inhibitors To Evaluate Coreceptor Usage by Simian and Simian/Human Immunodeficiency Viruses and Human Immunodeficiency Virus Type 2 in Primary Cells

Like human immunodeficiency virus type 1 (HIV-1), simian immunodeficiency viruses (SIV) and human immunodeficiency virus type 2 (HIV-2) use seven-transmembrane receptors as coreceptors during the process of virus-cell fusion (reviewed in references 6, 8, 9, 25, 74, and 87). Usually, this process requires an initial interaction of the viral envelope glycoproteins with CD4 (48, 107, 114). However, rare examples of CD4-independent HIV-1 isolates have been described (29, 47), and several HIV-2 and SIV strains can interact with coreceptors quite efficiently in the absence of CD4 (14, 30, 33, 35, 65, 89, 97). The first coreceptor described for HIV-1 was CXCR4, which serves to mediate the entry of the so-called T-cell line-tropic or syncytium-inducing (SI) viruses (39), now designated X4 isolates (7). The major coreceptor for the macrophage-tropic, non-syncytium-inducing (NSI) viruses, now designated R5 isolates, was found to be CCR5 (2, 20, 22, 27, 28). A plethora of other coreceptors has also been described to function for HIV-1 entry, especially for SI viruses, at least in the context of coreceptor-transfected cells in vitro (5, 19, 20, 22, 27, 31, 32, 38, 40, 50, 60, 62, 84, 85, 92, 93, 96, 102, 104, 105, 116). HIV-2 isolates can also use CCR5 and CXCR4 for entry into coreceptor-transfected cells in vitro. In general, coreceptor usage by HIV-2 is broader than that for HIV-1, in that many seven-transmembrane receptors have been reported to support HIV-2 entry when transfected into cell lines (10, 14, 22, 35, 45, 48, 52, 68, 77, 80, 89, 106). The first coreceptor to be identified as supporting SIV entry was CCR5, which was shown to function with SIVmac isolates soon after it was found to be an HIV-1 coreceptor (12, 18, 38). The use of CCR5 by several other SIV strains, including primary isolates from the natural host, has since been documented (14, 22, 30, 31, 33, 48, 53, 54, 64, 65, 93). CXCR4 usage by SIV strains is, however, very rare, although an example of SIV entry via CXCR4 is known, albeit for an isolate obtained from mandrills (SIVmnd) (98). However, the initial reports of SIVmac entry via CCR5 concluded that additional coreceptors used by SIV may be substitutes for CXCR4 (12, 18, 38). Since then, several seven-transmembrane receptors have been reported to support SIV entry in vitro, often with an efficiency comparable to that of CCR5 (3, 22, 31, 32, 38, 93, 96). Arguably, the most efficient among these SIV coreceptors are the ones variously designated BOB/GPR15 and Bonzo/STRL33/TYMSTR (3, 22, 31, 62). The question arises, however, as to whether these other coreceptors are as important as CCR5 and (for HIV-1 and HIV-2) CXCR4 for viral replication in vivo. There is mounting evidence that many, if not all, of the other coreceptors have only limited, if any, relevance to viral replication in primary cells and hence in vivo, except perhaps in specialized tissues and cell types (13, 31, 43, 70, 81, 86, 101, 102, 117). Care must always be taken when evaluating viral entry mediated via transfected seven-transmembrane receptors (66). We have continued to address this issue here using inhibitors targeted at CCR5 and CXCR4 (117). Our conclusion is that CCR5 is the most important SIVmac coreceptor in primary CD4+ T cells but that an alternative coreceptor(s) may indeed be relevant, at least in cells from some macaques. SIVrcm, however, uses CCR2 and not CCR5. These observations may be useful in studies of SIV-infected nonhuman primates as model systems for the development of HIV-1 vaccines (23, 57, 73). For the same reason, we have also studied the coreceptor usage of selected simian/human immunodeficiency viruses (SHIV).