It has been more than 20 years since the original descriptions of AIDS were first reported in 1981.1-3 In the years since the initial discovery, HIV, its pathogenesis, and AIDS have been among the most intensely studied pathogens and diseases in the history of medical science. However, we are no closer now than we were back in the early 1980s to finding a cure, and although there has been significant progress in treatment, there continues to be dramatic increases in the numbers of infected people throughout the world.4 One fascinating aspect of the pathogenesis of HIV-1 is that despite the enormous amount of studies that have been undertaken during the past 20 years, we continue to discover new and surprising aspects of the pathogenesis of this particular virus that have eluded previous investigations. In other words, we still do not know the entire story of how HIV infects cells and produces disease. Sadly, the fact that researchers have not completely understood the viral pathogenesis over the years may have, at least in part, been responsible for keeping the most efficacious treatments, and perhaps even a cure, elusive. Pathogenesis of HIV-1 HIV-1 productively infects activated immune cells such as T lymphocytes, monocytes, macrophages, and dendritic cells.5 It also infects nonreplicating resting CD4+ T lymphocytes and macrophages in the lungs, brain, and possibly the gut, where it may establish latent viral reservoirs. The tropism of HIV for immune cells is mediated by the viral envelope protein gp 120. Originally it was shown that HIV-1, through its gp 120 loop, recognizes and binds to the CD4 molecule.6 The virus binding to CD4 would then send a biochemical signal into the cell through the CD4-associated tyrosine kinase, Lck, and this, somehow, resulted in viral entry and productive infection7 [F1A]. For more than a decade, this paradigm insisted that CD4 was the only cellular receptor required for HIV to infect cells. However, in 1996 it was discovered that CD4 does not act alone. What changed the model was the identification of another family of cell-surface receptors, the chemokine receptors, that were shown to be required in conjunction with CD4 for infection with HIV-1.8,9 Initially, only 3 different chemokine receptors were thought necessary for successful infection with HIV-1. These receptors were important for the tropism of the virus. Thus, the a-chemokine receptor, CXCR4, directed infection of T cells by T cell-tropic HIV-1, while the bchemokine receptors, CCR5 and CCR3, were responsible for infection of monocytes with monocyte-tropic HIV-1 virions [F1B]. As more studies were undertaken, however, it became clear that many other chemokine receptors could support HIV-1 infection. This led, once again, to a change in the paradigm as to how HIV-1 can infect cells. Currently, the accepted model for successful HIV-1 infection states that it was necessary for cells to express both a primary receptor, CD4, and a chemokine co-receptor that could be any of the a-chemokine receptors, CXCR4 and V28/CXCR3, or the bchemokine receptors, CCR5, CCR3, CCR8, CCR2b, APJ, Bonzo/STRL33/TYMSTR, and BOB/GPR-15.5,10-12 Unfortunately, this paradigm is insufficient to completely explain the pathogenesis of HIV-1. This is because there are many instances of HIV-1 infection where either the primary and/or co-receptors are missing from the infected cell. Indeed, HIV-1-infected CD4-negative cells have been identified in vivo, including various brain cells, epithelial cells, cardiomyocytes, CD4 negative lymphocytes, and thymocytes.13-17 The virus has also been shown to infect CD4-negative neural and epithelial cells in vitro, although not productively.18-20 However, it has been shown that HIV-1 can productively infect CD4-CD8+ T lymphocytes in vitro.21