We have studied the in vivo distribution of the chemokine receptors CXCR4, CCR3, and CCR5, which are the major coreceptors for HIV/SIV infection. Although we did not evaluate the distribution pattern of other chemokine receptors in this study, the future availability of reagents such as high-quality antibodies specific for other chemokine receptors will certainly make this type of study possible. It should be emphasized that other chemokine receptors such as CCR1, CCR2b, Bonzo (STRL33), BOB (GPR15), GPR1, and US28 may also play some roles in HIV/SIV pathogenesis.
In this study, we found that T lymphocytes and macrophages in both lymphoid and nonlymphoid tissues represent the majority of the coreceptor-positive cells, reaffirming that these cells are the major targets for HIV/SIV infection in vivo and therefore are potentially subject to viral cytopathic consequences. The high level of coreceptor expression may also explain the initial and persistent viral (HIV/SIV) infection of lymphoid tissues throughout the course of infection (21
). In addition, the high level of CXCR4 expression on both immature and mature thymocytes is likely to render these cells particularly susceptible to the SI isolates. Our finding is consistent with reports that SI isolates are relatively thymocyte tropic and replicate faster than NSI isolates both in vitro and in SCID-hu mice (30
). Therefore, HIV/SIV can mediate lymphocyte depletion by directly infecting and replicating in thymocytes in vivo during all stages of T-lymphocyte maturation. The phenotypic switch from NSI to SI during infection is also likely to trigger more severe cytopathic effects in the thymus. Furthermore, the failure to detect coreceptor expression on FDC despite the presence of an intact FDC network suggests that the trapping and presentation of viral particles to target T lymphocytes in germinal centers is independent of coreceptors.
Coreceptor-positive cells are frequently identified in both the GI and GU tracts. However, the level of expression is generally higher in the proximal than the distal parts of the GI and GU tracts, suggesting that the expression may be differentially regulated. Since only a small proportion of the macrophages and the T lymphocytes express the coreceptors, a strict regulatory mechanism may govern the timing, the location, and the level of coreceptor expression. Although the exact mechanism is currently unknown, we believe that the degree of cellular maturation, the level of activation, and the concentration of the coreceptor-specific chemokines (e.g., SDF-1 and β-chemokine within the tissue environment are all likely to affect the level of coreceptor expression.
The coreceptor-positive T lymphocytes and macrophages in the distal portion of the GI and GU tracts may serve as a portal of viral entry as well as a source of viral dissemination. Based on our current knowledge, NSI rather than SI viruses are predominantly transmitted through the GI and GU tracts (59
), which suggests the existence of selective pressure in favor of NSI isolates during sexual contact. Is this selective pressure imposed on the viral replication rate, the preferential usage of certain coreceptors, or the degree of cytopathicity? In the rectum, since numerous CCR5- and CCR3-positive cells are readily detected in the lamina propria whereas the CXCR4-positive cells are barely visible, the coreceptor expression pattern may serve as one selective pressure for initial infection by NSI isolates. In contrast, the expression pattern of coreceptors in the GU tract is quite different. Although we did not detect coreceptor expression in the vagina, a large number of CXCR4- and CCR3-positive, but not CCR5-positive, cells are frequently identified in the cervix. Coreceptor expression in the GU tract is therefore not necessarily in favor of CCR5-using or NSI viruses. One intriguing question raised from this observation is whether the coreceptor CXCR4 can be utilized initially if SI isolates are present in the inoculum. That individuals who have homozygous defective CCR5 are indeed infectable by an SI isolate may indicate that CXCR4 can actually be used during the sexual transmission (43
). A simian/human immunodeficiency virus strain which uses exclusively CXCR4 in vitro can also penetrate the GU mucosal barrier and establish infection in a rhesus macaque (6a
). Collectively, these findings suggest that not only CCR5 but also CXCR4 can be used during sexual transmission. Both host factors and the phenotypic composition of the infecting virus will influence coreceptor selection during this process. The delineation of the selection process will require further investigation.
Consistent with previous reports, a high level of CXCR4 was found on the neurons in both the CNS and the peripheral nervous system (28
). In addition, we found a high level of CCR3 in neuronal tissues. Other chemokine receptors such as CXCR2 and the Duffy antigen are also expressed in neurons, but the biological function of these chemokine receptors in neuronal development, function, and disease remains to be determined (28
). The level of expression may also promote the entry of CD4-independent viral isolates, found primarily among HIV-2 strains (18
). An intriguing finding, however, is that the macrophages located primarily in the walls of small blood vessels are also positive for CXCR4 and CCR3. These perivascular macrophages or microglia, previously shown to be the targets of HIV/SIV infection (34
), can therefore serve as a mechanism for viral dissemination to the CNS.