Where the AIDS virus hides away

NEWS AND VIEWS Where the AIDS virus hides away Two research groups have independently shown that the long and variable latency period between HIV infection and overt AIDS is explained by replication of virus in the lymph nodes. Even Duesberg must pay attention. EvEN when walking in the dark, it helps to have a map. Then at least it may be possible to identify obstacles accidentally encountered. That is the spirit in which the two articles on the pathogenesis of AIDS in this week's issue (pp 355 & 359) should be welcomed. Neither can be counted as a step towards the more effective treatment of the disease; indeed, each tends to emphasize that the difficulties that lie ahead are formidable. But the two papers do explain why the time-lag between infection by HIV and the appearance of overt AIDS is both long and variable. In due course, this insight and the knowledge of how and where HIV is sequestered while its effects are latent cannot but be important. The belief that AIDS is caused by the retrovirus called HIV (for human immunodeficiency virus) is widely but not generally accepted. Some, who usually refer to that proposition as the 'HIV hypothesis', hold that other agents are responsible. Professor Peter Duesberg, from the University of California at Berkeley, has been the cheer-leader of that group, first by drawing attention to some surprising anomalies of infection by HIV, such as the difficulty, early in infection, of recovering virus from the T lymphocytes whose decline usually accompanies the onset of AIDS, more recently by arguing (with little justification) that drugtaking is responsible for AIDS (see Nature 362, 103; 1993). His more cogent objections have now been incidentally answered. That the natural history of a retrovirus should differ from that of the viruses most commonly infecting people is not, or should not have been, surprising. They are mostly DNA viruses, which ordinarily replicate within cells by hijacking the prexisting machinery of DNA transcription and translation. Then, the course of infection may be as predictable as with, for example, that by the measles or influenza viruses. The production of new virus particles depends on the activity of cells already infected; the proportion of susceptible cells infected then increases steadily as virus particles spread out from the foci of infection as, with a timelag, does the proportion of lymphocytes carrying neutralizing antibodies. The genomes of retroviruses, by contrast, consist of RNA. Those of the lentiviruses, of which HIV is one, come equipped with a gene specifying a reverse transcriptase (for converting RNA into the complementary DNA). Although the RNA genome may be used, as if it were one of the infected cell's own messenger molecules, to generate the proteins that would allow an intact virus particle to be regenerated, by far the more efficient means of replication is that DNA complemetary to the viral RNA should be incorporated in the genome ofthe cell, where it will indefinitely serve as a template for the production of its own genomic RNA and thus for intact viral particles. Apart from AIDS, the only human disease unambiguously known to be caused by a retrovirus is adult T-cell leukaemia, common in southwest Japan, but it will be surprising if there are not others. It is also relevant to this thumbnail sketch of what textbooks now say about the mechanism of viral infection that some DNA viruses (hepatitis-Band Epstein-Barr, for example) also appear to be integrated in the genome of the cells they affect, even if perhaps only rarely. Dues berg's puzzle about the pathogenesis of AIDS is that it is difficult to recover from 'helper' T lymphocytes, whose attrition for many patients signals the onset of overt AIDS, virus particles that might plausibly infect others. What kind of a virus is it that seems not to affect its chief targets? That has been the question. The answer, now made plain, is that the virus is alive and well in the lymph nodes, among other sites, of those infected with HIV. The two groups which have independently demonstrated this have used the polymerase chain reaction (PCR) to look for signs of the presence ofHIV in various types of cells of the lymphatic system of people infected with HIV. They have searched separately for the RNA and DNA forms of the viral genome. Bolognesi and Temin explain, on page 292, that such a search would not have been successful even ten years ago; the present applications of the technique make it possible to distinguish cells carrying HIV in its RNA or DNA forms from those that do not carry traces of the virus. Bolognesi and Temin also suggest how the strategy of AIDS research should be amended, in the light of the new findings, to yield a better understanding of the pathogenesis of AIDS. With hindsight, it is not surprising that the lymph nodes (but also the spleen, adenoid glands and tonsils) should be sites at which the presence of HIV is most readily demonstrated; that, after all, is where most helper T cells usually reside. In the lymph nodes just as in the peripheral blood, cells carrying the DNA form of the HIV genome are more common than those marked by RNA; true latency seems to be the rule. The NATURE · VOL 362 · 25 MARCH 1993 © 1993 Nature Publishing Group big surprise is the degree to which virus seems to multiply in these organs. But it is also striking that there are heavy concentra· tions of viral particles in the spaces between the cells of some structures in the lymph nodes. Does their location there allow them to infect T cells in their passage through the glandular structures of the immune system? Whatever the answer, the conclusion must be that the apparently latent period between ·infection with HIV and the overt symptoms of AIDS is not clinical latency at all, but rather a period in which the replication of the virus proceeds apace in the lymph nodes and some other tissues of the immune system. The suggestion by Bolognesi and Temin that there should now be more systematic investigations of the degree to which the RNA and DNA versions of the HIV genome occur in the various cells of the immune system at different stages in the development of the disease is plainly an important way of building on these discoveries. It may even suggest ways in which latency might be prolonged, in tum a better approximation to the notion of a cure for AIDS than anything else in sight. These developments will be a conundrum for Duesberg and his disciples. Will they now abandon their opinion that the 'HIV hypothesis' is an insubstantial hypothesis, less plausible than others, that AIDS is caused by drug-taking for example? Duesberg's advocacy of his cause, and in particular the manner ofhis advocacy, has maddened the AIDS research community. So too has this journal, by occasionally venturing to suggest that the more cogent of Duesberg's objections deserved to be taken seriously, if only because his reputation in other aspects of virology d (...truncated)