In Vivo Distribution of the Human Immunodeficiency Virus/Simian Immunodeficiency Virus Coreceptors: CXCR4, CCR3, and CCR5

Abstract

We have evaluated the in vivo distribution of the major human immunodeficiency virus/simian immunodeficiency virus (HIV/SIV) coreceptors, CXCR4, CCR3, and CCR5, in both rhesus macaques and humans. T lymphocytes and macrophages in both lymphoid and nonlymphoid tissues are the major cell populations expressing HIV/SIV coreceptors, reaffirming that these cells are the major targets of HIV/SIV infection in vivo. In lymphoid tissues such as the lymph node and the thymus, approximately 1 to 10% of the T lymphocytes and macrophages are coreceptor positive. However, coreceptor expression was not detected on follicular dendritic cells (FDC) in lymph nodes, suggesting that the ability of FDC to trap extracellular virions is unlikely to be mediated by a coreceptor-specific mechanism. In the thymus, a large number of immature and mature T lymphocytes express CXCR4, which may render these cells susceptible to infection by syncytium-inducing viral variants that use this coreceptor for entry. In addition, various degrees of coreceptor expression are found among different tissues and also among different cells within the same tissues. Coreceptor-positive cells are more frequently identified in the colon than in the rectum and more frequently identified in the cervix than in the vagina, suggesting that the expression levels of coreceptors are differentially regulated at different anatomic sites. Furthermore, extremely high levels of CXCR4 and CCR3 expression are found on the neurons from both the central and peripheral nervous systems. These findings may be helpful in understanding certain aspects of HIV and SIV pathogenesis and transmission.

Definition of the Stage of Host Cell Genetic Restriction of Replication of Human Immunodeficiency Virus Type 1 in Monocytes and Monocyte-Derived Macrophages by Using Twins

“…Therefore, HIV infection of primary T lymphocytes by M-tropic, T-tropic, and dualtropic isolates may be mediated either by CCR5, by CXCR4, or by both (2,17,24). CXCR4-utilizing strains often appear during advanced HIV disease, but at other times CCR5utilizing HIV strains comprise the majority of transmitted strains (70,76,83,84). The viral determinants which influence binding to either of these two major coreceptors are found mainly within the V3 region, as originally predicted from biological studies of tropism (4,8,10,34,78,81).…”

V3 Recombinants Indicate a Central Role for CCR5 as a Coreceptor in Tissue Infection by Human Immunodeficiency Virus Type 1

“…For our analyses, we used the best-reported expression construct (pcDNA3-CCR3p) (82) and a sensitive enzymatic readout to increase our ability to detect CCR3-dependent entry. Conceivably, the presence of at least some degree of CCR3 recognition in nearly all tested recombinants may point to a positive selective pressure in the brain and colon in light of recent evidence of high expression levels in vivo of CCR3 in the CNS and lamina propria of the colon (109). Nonetheless, the global efficiency of CCR5 utilization strongly highlights CCR5 as a predominant coreceptor in mediating tissue-specific infections.…”

“…The nearly absent usage of CXCR4, BOB/GPR15, and Bonzo/STRL33 suggests the inability of these coreceptors to mediate tissue infection despite their expression on certain tissue-resident cell types (22,57,109). While no evidence has directly demonstrated the in vivo importance of BOB/GPR15 and Bonzo/STRL33, the role of CXCR4 in pathogenesis has been described for certain viruses residing in the blood (41,71).…”

Assessing the Relationship Between Cervical Ectopy and HIV Susceptibility: Implications for HIV Prevention in Women

“…Among HIV‐infected women, cervical ectopy has been shown to be associated with detectable levels of HIV RNA in cervicovaginal secretions . Other immunological factors that may facilitate HIV infection, including CD4 positive T‐helper cells and the expression of the chemokine receptor CCR5, are also found more frequently with columnar epithelium of the endocervical mucosa compared with the squamous epithelium of the ectocervix and vagina . The spermicide Nonoxynol‐9, which was investigated as a potential microbicide to prevent HIV infection, was found to contribute to the development of epithelial lesions .…”