| Excluding parenteral infections, human immunodeficiency virus (HIV-1) infection occurs almost exclusively through mucosal surfaces. Once the mucosa is crossed, the underlying mucosal mononuclear cells (MMCs) exhibit heightened susceptibility to the virus. I undertook these studies to examine mechanisms by which HIV-1 crosses mucosal epithelial cells and explanations for increased HIV infection and replication in this compartment. Utilizing HIV-1 vectors that expressed the enhanced green fluorescent protein as a reporter gene and either did, or did not, express the X4-tropic HIVNL4-3 envelope, I have shown that HIV-1 can infect colonic epithelial cells in both an envelope-dependent and independent manner. Utilizing monoclonal antibodies against gp120 and GalC I show that envelope-dependent infection is partially dependent upon binding to GalC, but envelope independent infection occurs independently of GalC binding. Based on these findings I conclude that HIV-1 infects mucosal epithelial cells by mechanisms both dependent and independent of viral gp120 and GalC. Envelope-independent infection of colonic mucosal epithelial cells may represent an alternative pathway of mucosal HIV-1 infection. In order to examine whether differences in chemokine receptor expression renders MMCs more susceptible to HIV-1 infection than are peripheral blood mononuclear cells (PBMCs) I performed infected MMCs and PBMCs with R5-tropic and X4-tropic HIV-1, engineered to express murine CD24 on the infected cell's surface. I have shown that both viruses infect a greater percentage of MMCs, compared to PBMCs. There are significant differences in chemokine receptor expression in the blood and gastrointestinal mucosa; mucosal cells are predominantly CCR5+ CXCR4+, while these cells make up less than 20% of PBMCs. It is this cell population that is most susceptible to both R5- and X4-tropic HIV-1 in both compartments. Regardless of whether viral isolates were derived from the blood or mucosa of HIV-1 infected patients, HIV-1 p24 production was greater in MMCs compared to PBMCs. Further, the chemokine receptor tropism of patient-derived viral isolates did not differ between compartments. Based on these findings I conclude that the gastrointestinal mucosa represents a favored target for HIV-1, in part due to its large population of CXCR4+, CCR5+ target cells, and not due to differences in the virus that it contains. |
