HIV

J.K. Wong, M. Hezareh, H.F. Gunthard, D.V. Havlir, C.C. Ignacio, C.A. Spina, D.D. Richman, "Recovery of replication-competent HIV despite prolonged suppression of plasma viremia," Science, 278:1291-5, 1997. (Cited in more than 215 papers since publication) Comments by Douglas D. Richman, professor of pathology and medicine, University of California, San Diego, and San Diego VA Healthcare System D. Finzi, M. Hermankova, T. Pierson, L.M. Carruth, C. Buck, R.E. Chaisson, T.C. Quinn, K. Chadwick, J. Margolick, R. Brookmeyer, J. Gallant, M. Markowitz, D.D. Ho, D.D. Richman, R.F. Siliciano, "Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy," Science, 278:1295-1300, 1997. (Cited in more than 250 papers since publication) Comments by Robert F. Siliciano, associate professor of rheumatology and of molecular biology and genetics, Johns Hopkins University School of Medicine Everyone beamed a couple of years ago when the drug cocktail of highly active antiretroviral therapy (HAART) proved capable of reducing plasma HIV RNA to levels so low they couldn't be detected by the most sensitive assays. Then these two papers appeared, supplemented by another shortly afterward,1 establishing that reservoirs of latent virus persist despite combination therapy. Scientists are still grappling with the questions raised by this sobering discovery. Robert F. Siliciano "... essentially ..., antiretroviral therapy as we use it today will not be able to cure anybody."--Robert F. Siliciano In 1995, Robert Siliciano and colleagues were the first to show that resting CD4+ T cells harboring integrated provirus were present in some infected individuals.2 Of course, that was prior to the introduction of HAART, a regimen combining at least three antiretroviral drugs including a protease inhibitor. Based on the evidence of the three 1997 papers, Siliciano notes, "The conclusion was that latent virus was present in all patients on antiretroviral therapy." It's a cruel irony that the virus lies latent in CD4+ T cells, which normally are the immune system's primary coordinators of response by killer CD8+ T cells to invasion by a pathogen. Latent virus was found to reside in a certain subset of CD4 cells. These are "memory" cells, cloned in huge volumes, each capable of recognizing a specific previously encountered antigen. Memory cells derive from "naive" CD4 cells that can launch an immune response against new pathogens and then return to a quiescent state. The advantage to HIV of favoring memory cells over naive cells is that the former are long lived in their resting state, waiting for the return of whatever specific antigen each one recognizes. The virus enters activated rather than resting CD4 cells, but sometimes those cells become dormant until awakened by immune system signals. Within the resting host, the inactive HIV genome does not issue viral products, and thus no antigen rises to the cell surface for recognition and attack by killer T cells. This latently infected cell has become a reservoir for the virus, shielding it from both the immune system and therapeutic drugs. "You can find virus all over the place in people with untreated HIV infection, but the question is, where does it persist in people on combination therapy?" Siliciano comments. The answer, he says, is in latently infected cells in the blood, lymph nodes, the spleen, and probably in the gastrointestinal tract. Douglas D. Richman "One of the problems in this field is that there's so much hope and so much desperation. Everyone wants a final solution."--Douglas D. Richman Can these reservoirs somehow be purged, and the virion flushed out where HAART can get at it? The lab of Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases (NIAID), has attempted to do just that, using an immune system regulatory protein, interleukin-2 (IL-2).3 It activates resting CD4 cells, which then eject the latent virus. A five-year, $43 million trial has been funded by NIAID, but even Fauci has acknowledged it is likely that the virus exists in compartments not accessible to IL-2.4 Another question arises: How long will HIV persist in these various compartments? Will the reservoirs eventually decay? Siliciano's group provided the answer in a 1998 paper calculating that with only one latently infected cell per million T cells, eradication would take 60 years.5 "Basically, you're never going to be rid of these cells," he says. "What that essentially means is, antiretroviral therapy as we use it today will not be able to cure anybody." Latently infected cells may be present in very small numbers, yet they represent the potential for a deadly "viral rebound" with discontinuation of HAART. But combination therapy is both expensive and difficult to endure physically for many years. Side effects affecting lipid metabolism, the pancreas, and the liver can range from a redistribution of body fat to insulin-dependent diabetes. Recently there has been hope that it might be possible, in some cases, to boost the immune system sufficiently to stop HAART and still contain the disease. This would involve "structured therapeutic interruption" of HAART when the immune system looks capable of keeping viral replication to very low levels. "It's a little bit of a dangerous concept," Siliciano acknowledges, "but there are not many other options." Among the few other options are new drugs that will attack both conventional and new targets, hopefully with less severe side effects. Also, a therapeutic vaccine might boost the immune system enough to permit safe cessation of HAART. "The question is, what kind of immunity is it appropriate to induce?" Douglas Richman asks. He says "evidence is mounting" that cytotoxic CD8 T cells affect the natural history of the virus, which may mean they are critical to control of viral replication. But even if proliferation of active CD8 cells becomes the key objective, he lists three other questions that await answers. First, what artificial means can induce an immune response that the virus itself is not inducing? Second, what type of vaccine might be useful? And third, how could the effectiveness of methods aimed at reducing an already virtually undetectable level of virus be measured? "The quantitative assays for these cells are incredibly cumbersome and imprecise," he says. The two papers used a similar method to find latent virus. They combined blood cells from patients on retroviral therapy, blood cells from HIV-negative donors, and reagents that would immunologically activate the memory T cells. Then they observed the latent virus as it quickly replicated and infected the HIV-negative cells. "We're trying now to better quantify these cells and characterize what's going on," Richman reports. Another big challenge his lab is tackling is to define the mechanism that establishes and maintains latency. Siliciano's team is on the same scent. "We're trying to define the biology of these latently infected cells and learn how to get rid of them, although I think that's going to be very hard to do," he says. The cells not only occur extremely infrequently, but the viral DNA enmeshed in the host DNA is only about 10,000 base pairs, and, of course, the HIV is latent. "It's a nightmare of a problem." "One of the problems in this field is that there's so much hope and so much desperation. Everyone wants a final solution," Richman observes. "But the reality is, it's complex, with one step back for every two steps forward." References 1. T.W. Chun et al., "Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy," Proceedings of the National Academy of Sciences, 94:13193-7, 1997. 2. T.W. Chun et al., "In vivo fate of HIV-1-infected T cells: quantitative analysis of the transition to stable latency," Nature Medicine, 1:1284-90, 1995. 3. T.W. Chun et al., "Effect of interleukin-2 on the pool of latently infected, resting CD4+ T cells in HIV-1-infected patients receiving highly active antiretroviral therapy," Nature Medicine, 5:651-5, June 1999. 4. S. Bunk, "New weapon attacks latent HIV reservoirs," The Scientist, 12 [24]:5, Dec. 7, 1998. 5. D. Finzi et al., "Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy," Nature Medicine, 5:512-7, May 1999.

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