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EDITORIAL |
*
Department of Microbiology and Immunology, Weill Medical College of
Cornell University, New York, New York
Department of Pathology and Laboratory Medicine, University of
Pennsylvania, Philadelphia, Pennsylvania.
A report in this issue of the Journal of the American Society of Nephrology demonstrates that the kidney can be a site of HIV-1 replication in vivo (1). This finding will interest both clinicians who care for HIV-1—infected individuals and researchers who specialize in the normal and abnormal functioning of the kidney. It will also—perhaps surprisingly to those who fall into the previous two categories—intrigue and conceivably confuse researchers, activists, and journalists who have been debating the origins of the AIDS epidemic.
HIV-associated nephropathy (HIVAN) is now the third most common cause of severe renal disease in adult African Americans, a reflection of the ever-increasing prevalence of HIV-1 infection in this racial group. However, detailed information on the proportion of HIV-1—infected people of whatever background who develop HIVAN is not yet available, from either America or Africa, and there have been no detailed studies of the relationship between HIVAN development and HIV viral load, viral phenotype, CD4 count, and the general clinical condition. Viral nephropathy in nonhuman primate models is also an understudied area, yet detailed animal studies could reveal considerable useful information on the disease process and its causes. These lacunae should be addressed by the nephrology research community and the funding agencies before HIVAN becomes even more common than it already is.
The present study demonstrates that 16 of 21 HIV-1—infected individuals who presented with renal disease were diagnosed with HIVAN, of whom all but one were African American or Hispanic (1). Those who were not diagnosed with HIVAN had other clinical conditions known to be associated with renal disease in the absence of HIV-1 infection: diabetic nephropathy, hypertensive nephropathy, nephrosclerosis, and allergic interstitial nephritis. Fourteen of the study subjects were receiving antiviral drugs (usually combination therapy) for their HIV-1 infection, but only 3 had "undetectable" viral loads. This is perhaps indicative of a relatively advanced state of HIV-1 disease in the study cohort as a whole.
Several assays were used to detect and quantify the presence of HIV-1 genetic material in kidney biopsy or autopsy samples, an important point given the highly sensitive (and prone to contamination) nature of PCR-based techniques. These included tests for the circularized, nonintegrated form of viral DNA, the presence of which is diagnostic of fairly recent infection of the cells and active viral replication (2). The DNA circles were found in 14 of the 21 HIV-1—infected cohort members with renal disease, including 2 who did not have HIVAN, and also in 2 more infected subjects who did not have kidney disease. Thus, although there is a strong association between HIVAN and the presence of nonintegrated HIV-1 DNA in kidney tissue samples, the relationship is not absolute. Of note are the four patients who were positive for nonintegrated HIV-1 DNA in the kidney without also having HIVAN (with plasma viral loads ranging from 490,000 RNA copies/ml to undetectable, i.e., <50 copies/ml). Furthermore, four HIVAN patients lacked integrated HIV-1 DNA, one of which had a plasma viral load as high as 750,000 RNA copies/ml. Of course, the failure to detect nonintegrated DNA may sometimes be artifactual, perhaps because of genetic differences between the infecting virus and the PCR probes used in the assay or because biopsies remove only very small samples of kidney tissue and thus may yield false negatives. It is also possible that HIVAN could sometimes be caused by HIV-1 replication that occurred in the kidneys months or years before the patient presented with renal symptoms but that is no longer occurring in that organ at the time of the biopsy.
A subset of the cohort was also studied for the presence of HIV-1 mRNA and/or DNA by in situ hybridization techniques (1). By and large, the results of these assays tracked those derived from the analyses of nonintegrated DNA, although there were some exceptions. The most useful information derived from these assays is the identity of the cells in which HIV-1 sequences can be detected. In general, tubular epithelial cells were the most commonly identified cells that expressed HIV-1 mRNA; the infection tended to be focal in that nearby tubules were often negative, and evidence was found for HIV-1 infection in association with tubular cell damage, probably caused by apoptosis. Whether the apoptotic cells were the direct result of virus infection or innocent bystanders killed by an indirect mechanism remains to be determined. In several patients with severe interstitial disease, there was clear evidence of a heavy infiltration of HIV-1—infected leukocytes that had formed microabscesses. In these microabscesses—and indeed in general—the level of HIV-1 mRNA expression in leukocytes exceeded that found in renal epithelial cells, indicating that leukocytic cells are probably the source of most but not all of the nonintegrated HIV-1 DNA in the biopsy and autopsy samples (1).
Although renal epithelial cells seem not to be the dominant site of HIV-1 infection in the kidney, it is now clear that they can be infected (1). But how? The mechanism by which HIV-1 enters these cells is not obvious. For fusion of the virus with any target cells to occur at high efficiency, the cells must usually express the CD4 antigen and a co-receptor (3). Of the known HIV-1 co-receptors, the chemokine receptors CCR5 and CXCR4 are the most important (4,5). There is a single report that PCR-based assays can detect mRNA for CD4 and CXCR4 (but not CCR5) in up to 25% of renal epithelial cells when the cells are cultured in vitro (6). However, it is not known whether these cells actually express these receptors on their surface in sufficient quantities for HIV-1 fusion to occur, either in vitro or in vivo. It is possible that the virus has evolved, in the environment of the kidney, to use a co-receptor other than CXCR4 and CCR5, perhaps even in a manner that is independent of the CD4 receptor. The in vitro use of alternative entry pathways is rare but not unprecedented, especially for HIV-2 and some simian immunodeficiency viruses (SIV) (7,8). Sorting out what is actually going on in living kidneys will probably require the isolation of replication-competent viruses from kidney cells or, perhaps more feasible, the cloning of full-length env genes directly from individual cell types, followed by characterization of the properties of the envelope glycoproteins that they encode. Easier—but much less definitive—is to study the properties of viruses isolated from the peripheral blood from individuals with HIVAN to see whether, for example, they have some unusual abilities to use co-receptors other than CCR5 and CXCR4. It will also be interesting to determine whether tubular epithelial cells express molecules involved in HIV-1 attachment to the cell surface, such as the recently identified type C lectin DC-SIGN (9,10). Such a mechanism might provide a means to concentrate virus on the plasma membrane and thereby increase the probability of infection of the cells via unconventional routes.
The work by Bruggeman et al. (1) is highly germane to understanding the pathology of HIV-1 infection of the kidneys and to generating future treatments for HIVAN. But why should it be remotely relevant to the origin of the AIDS epidemic? There is almost no argument, within or outside the HIV research community, with the view that HIV-1 entered the human race as a zoonotic transmission from chimpanzees infected with a precursor virus, known as SIVcpz, sometime during the past century, somewhere in central Africa (11,12,13). Where there is some dissent is in regard to the mechanism by which this occurred. Most professional scientists believe that a viral transmission from chimpanzees to humans most likely occurred when an SIVcpz-infected animal was hunted for food; biting and scratching are known routes of retrovirus transmission, and of course cutting up a dead animal for cooking involves significant exposure to blood (11). However, there has been speculation, mostly by journalists and some laymen on the fringes of AIDS activism, of a more sinister route of transmission: the contamination of oral polio vaccines (OPV) by an HIV-1 precursor virus during the production of these vaccines for clinical trials in central Africa during the late 1950s (14). The present article is relevant to this argument because the OPV were prepared in kidney cell cultures. Hence, those who believe in this iatrogenic origin of the AIDS epidemic will no doubt cite this article as being supportive of their argument. And so it is, but only to a certain extent. Most HIV virologists have, in fact, always considered it possible that kidneys could be a source of virus, if only as a result of the infiltration of infected macrophages and lymphocytes. The present results, of course, confirm that such infiltration does indeed occur and in addition demonstrate that cells endogenous to the kidney can harbor viral sequences (1). However, OPV was prepared using monkey kidneys, not chimpanzee kidneys, and it is chimpanzees, not monkeys, that harbored the HIV-1 precursor virus (15,16). The OPV theorists speculate that chimpanzee kidneys might have been used to make polio vaccines, but there is no hard evidence to support this. Indeed, the living scientists who were involved in the OPV trials flatly deny that the vaccine was ever cultured in chimpanzee kidneys (15). Unless scientific evidence—and not just opinions—to the contrary is obtained, the relevance of HIV-1 replication in kidneys to the origin of the AIDS pandemic is moot.
The key point about the OPV hypothesis is not that these events actually happened—they didn't—but that they could have happened. Cross-species virus transmission (zoonosis) is a regular occurrence in the animal world, and humans are far from immune. A simian DNA virus, SV-40, was probably transmitted to some recipients of polio vaccines prepared in monkey kidney cells during the 1950s and early 1960s, fortunately without widespread consequences (14). But when cross-species transmissions do successfully occur, the consequences can be devastating: the 1918 influenza pandemic and the present-day AIDS pandemic are two obvious examples. It is reasonable to say that, other than a collision with a large asteroid or man's own folly with nuclear weapons, no process is more likely to wipe out a significant fraction of the human race than a viral zoonosis. Yet we continue to take chances with virology, and the nephrology community is no exception. Kidney transplants are now, fortunately, almost a routine, life-saving procedure, yet the shortage of donor kidneys is serious. One possible solution to this problem is the use of animals, notably pigs, as a source of transplantable kidneys. This seems to us to be playing with fire, from the virology perspective, because of the dangers of a zoonosis (17,18,19). True, all possible precautions are being taken to screen pig kidneys for known viral pathogens. But it is the unknown we should fear most, and we can only screen for what we know exists; there is no such thing as a pan-reactive PCR primer. There seems little doubt that pig kidneys could save human lives, yet if the potential cost is the transmission of a new virus that could, in principle, decimate the human population, is that a risk we should be taking? The risk of a zoonosis from any one transplanted animal kidney may well be extremely low, but then so is the risk that an asteroid will strike the earth in any given year. The dinosaurs suffered the consequences of an improbable event, but at least that was an event that they could neither foresee nor avoid. Are we willing to risk our future when the risks are both foreseeable and avoidable?
References
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