During the course of HIV-1 infection, viruses emerge that use a broader range of coreceptors (6
), including CXCR4, CCR3, CCR2b, and, as shown here, Apj. These dualtropic and primary T-tropic viruses probably infect a broader range of target cells, and their emergence may coincide with an accelerated disease progression. The ability of SIVmac316, but not SIVmac239, to use Apj as a coreceptor demonstrates that this expansion of receptor use may occur within SIV-infected rhesus macaques as well. SIVmac316 is derived from a macaque infected with SIVmac239 that had developed AIDS-like symptoms (25
). The relative efficiency with which Apj is used as a coreceptor by primary viruses and its expression on activated PBMC suggest that it may play a role in viral dissemination in HIV-infected individuals. Moreover, the lower efficiency of Apj use by laboratory-adapted viruses, compared with primary T-tropic viruses, may suggest that Apj-using viruses are selected in vivo but not in vitro in humans as well as in macaques.
M-tropic HIV-1 isolates that have been isolated from the central nervous system have been shown to use CCR3, as well as CCR5, as a coreceptor (5
). Both CCR3 and CCR5 are present on the surface of brain microglia, and infection of fetal brain cultures by these isolates has been demonstrated (19
). Apj is also expressed in brain tissue and has sequence similarity to CCR5 and CCR3 in an N-terminal region of these molecules that has been shown to be important for coreceptor function (14
). However, neither of the tested central nervous system-derived M-tropic viruses, JR-FL or YU2, can use Apj as a coreceptor, although both use CCR3. It remains to be determined whether there is a specific role for Apj as a coreceptor in the central nervous system following the emergence of dualtropic or T-tropic viruses.
The identification of Apj and CCR9 as HIV-1 coreceptors supports earlier observations indicating that a specific array of tyrosines and acidic amino acids in the N termini of these molecules plays a critical role in infection by HIV-1 and SIV (14
). Single-amino-acid changes in this region of CCR5 interfere with the ability of primary M-tropic and dualtropic HIV-1 and with SIVmac239 to infect cells expressing these mutants. The amino termini of three alternate SIV coreceptors, Strl33, gpr15, and gpr1, exhibit sequence similarity to this region of CCR5. The results described above suggest that primary T-tropic HIV-1 isolates may also require the presence of specific N-terminal tyrosines in their coreceptors. The tyrosine-rich, acidic motif is less well developed in CXCR4 than in CCR5, with the Apj N terminus sharing characteristics of both sequences (Fig. a). Apj and CCR3 could facilitate the adaptation of CCR5-using viruses to CXCR4 by providing an N terminus that diverges from that of CCR5 and possesses similarity to that of CXCR4. Further adaptation to CXCR4 could require increased dependence on other regions of the molecule, including the second extracellular loop (29
). Figure b summarizes coreceptor usage data for CCR5, CCR3, Apj, and CXCR4.
FIG. 5 7TMS receptor sequences and coreceptor function. (a) Alignment of CCR5, Apj, and CXCR4 N-terminal sequences. The sequences of the N termini, beginning with the initiator methiones, of CCR5, Apj, and CXCR4 are shown. Tyrosines 10, 14, and 15, aspartic (more ...)
CCR9 also possesses a prominent array of tyrosines in its N terminus (Fig. a) yet supports the entry of only a single virus of 10 tested. Whether subtleties in the arrangement of these tyrosines, or other properties of the molecule, limit its ability to function as an efficient coreceptor remains to be demonstrated.
The contribution of HIV-1 coreceptors other than CCR5, CXCR4, and perhaps, CCR3 to natural infection and pathogenesis remains unclear. The efficiency of Apj coreceptor function relative to that of most of the other reported HIV-1 coreceptors, its use by a range of dualtropic and primary T-tropic viruses, and its presence in activated PBMC and in the central nervous system suggest that further examination of its role is warranted.