July 1, 1998
Considerable optimism has been generated as a result of advances in HIV therapeutics. The use of combinations of potent antiretroviral agents capable of long-term, profound suppression of plasma viremia has been shown to prolong survival for individuals infected with HIV.[2,3,4] Consensus guidelines have been created for the optimal use of the increasingly complex armamentarium of antiretroviral drugs; 11 antiretroviral agents are now licensed for use in HIV infection, and this number is likely to increase in the near future.[5,6] Appropriate application of these guidelines has dramatically altered the prognosis for patients with late-stage HIV disease, and it is likely that treatment of individuals during the acute stage of HIV infection will dramatically lower the viral load set point and thereby significantly alter the natural history of the disease process.
These dramatic improvements in prognosis achieved with potent antiretroviral therapy are tempered by the many challenges that remain. Although the mortality rate due to HIV infection has decreased significantly in the era of potent antiretroviral therapy, the incidence of new infections has not seen such a dramatic downturn in the United States, and indeed the epidemic rages virtually out of control in parts of the world such as Southeast Asia and the Indian Subcontinent. Access to potent antiretroviral therapy is extremely limited in the developing world and in many segments of the developed world. These potent regimens are expensive and complex, with high pill burdens, numerous adverse effects, and myriad drug interactions. All of these factors raise quality-of-life issues with attendant challenges for adherence to the drug regimen. Emergence of a drug-resistant virus is a serious consequence of imperfect drug regimens and/or suboptimal compliance. In this regard, the success rate for potent antiretroviral regimens in reducing plasma viral load to undetectable levels is considerably lower in an urban clinic setting compared with a clinical trial setting, and is lower when drugs are added sequentially rather than simultaneously.
The existence of latently infected CD4+ T cells poses perhaps the greatest challenge to the long-term control of HIV infection in persons receiving potent antiretroviral therapy. Latently infected cells cannot be eliminated by the host immune response because of the absence of expression of viral antigens on the cell surface; furthermore, integrated proviral DNA cannot be targeted by currently available antiretroviral agents. Therefore, the natural half-life of latently infected resting CD4+ T cells appears to be the rate-limiting step in eradicating HIV infection. In fact, recent studies have established that replication-competent HIV can be recovered from cells of patients receiving potent antiretroviral therapy with undetectable levels of plasma virus for prolonged periods.[12,13,14] Taken together, these studies suggest that the half-life of latently infected resting CD4+ T cells may be very long, and that many years of complete suppression of virus replication may be required before elimination of HIV infection is feasible. Efforts are currently under way to combine potent antiretroviral therapy with interventions aimed at activating latently infected cells. In this situation, latently infected cells might be driven to a state of productive infection and die, while infectious virus released from these cells would be unable to infect new cells under the cover of potent therapy.
The feasibility of immune reconstitution following successful suppression of virus replication by potent antiretroviral therapy remains a topic of considerable interest and debate. It has recently become clear that in the first weeks following initiation of potent antiretroviral therapy, most of the sharp rise in the CD4+ cell count occurs as a result of redistribution of memory cells.[16,17] However, the mechanisms involved in the subsequent slow increase that is observed in the number of naive CD4+ cells remain enigmatic. The depletion of cell populations with certain immunologic specificities during the course of HIV infection creates "holes" in the immunologic repertoire that result in increased susceptibility to opportunistic infections. Therefore, the appearance of naive cells with specificities that had previously been lost would constitute true immune reconstitution. The interpretation of some data would suggest that such reconstitution can indeed occur during potent therapy; however, many questions concerning immune reconstitution remain unanswered. In this regard, the contribution, if any, of the thymus in immune reconstitution in HIV disease remains unclear. Immune-based therapies directed toward boosting production of naive CD4+ cells will be an important adjunct to potent antiretroviral therapy.
New avenues in potential therapies for HIV infection have been opened by the discovery that certain chemokine receptors can serve as coreceptors for HIV entry into CD4+ cells. Molecular epidemiologic data linking mutations in genes for HIV coreceptors with reduced susceptibility to HIV infection or with attenuated rates of disease progression in infected individuals highlight the importance of these receptors in the pathogenesis of HIV infection. In addition, polymorphisms in the genes for the ligands to the HIV coreceptors, modulation of expression of these genes, or both may hinder access of HIV to potential target cells, resulting in delayed progression of HIV disease.[23,24,25] Strategies aimed at blocking access of HIV to its coreceptors attempt to recapitulate the scenarios resulting from polymorphisms or down-regulation of these receptors. Several agents have already been identified that are capable of binding to CCR5 or CXCR4, the major coreceptors for macrophage- and T-cell-tropic strains of HIV, respectively. As is the case with the immunoregulatory network in general, caution is clearly warranted in manipulating the chemokine-chemokine receptor axis. Of note, unanticipated results of coreceptor blockade have been observed in vitro, including enhancement of replication of T-cell-tropic strains of HIV following blockade of CCR5 (the coreceptor for macrophage-tropic strains) (A. Kinter and A. S. Fauci, MD, unpublished data, 1997). Such observations highlight the importance of gaining a fuller understanding of the intracellular signaling events initiated by ligation of chemokine receptors.
Pathogenic events surrounding primary HIV infection are being actively studied by several groups throughout the world. An intervention that prevents establishment of a reservoir of latently infected cells following primary HIV infection would be invaluable. Such a goal will be a great challenge, given the rapidity with which a latent reservoir is established in primary HIV infection. Exhaustion of clones of HIV-specific CD8+ cytolytic T cells following primary HIV infection is another key event in the early pathogenesis of HIV disease that may represent a target for intervention. Persistently high levels of viral antigen, as well as the early loss of HIV-specific CD4+ cell proliferative responses, likely contribute to this CD8+ cell clonal exhaustion. It may be possible to prevent the loss of these CD4+ cell responses with early treatment of primary HIV infection by using potent antiretroviral therapy. The long-term impact of maintaining these cellular responses remains to be seen, but will likely be favorable.
Development of a safe and effective vaccine for HIV infection remains the "holy grail" of AIDS research. The grim global statistics of the HIV epidemic are potent reminders of the pressing need for such a vaccine. In 1997, nearly 6 million people became infected with HIV, and more than 90% of these new infections occurred in developing countries. In these countries, where annual per capita health care expenditures may total only a few dollars, access to potent antiretroviral therapy is essentially nonexistent. The development of a safe and effective vaccine continues to encounter a host of sobering challenges, including geographic variability of HIV subtypes, and the lack of correlates of protective immunity in HIV infection. Clinical trials of several vaccine candidates are currently in progress. Studies of experimental vaccines that are protective in the simian immunodeficiency virus model, and of immune responses in long-term nonprogressors with HIV infection continue to provide clues regarding immune responses that may be particularly beneficial. New concepts in vaccine design, such as vaccination with DNA and the use of cytokines to elicit a "custom-made" immune response, are also being applied to the search for an HIV vaccine.
Finally, are we, as the scientific community, now poised to gain the upper hand against HIV infection? In settings where access to potent antiretroviral therapy and to experienced care providers is possible, where conditions are amenable to adherence to a complicated medical regimen, and where drug adverse effects and quality-of-life issues are manageable, the answer is that long-term control of viral replication is quite likely. However, of the more than 30 million people worldwide who are living with HIV infection, only a tiny proportion has access to the conditions mentioned above. Gaining the upper hand against HIV infection will require a deeper understanding of the pathogenic events that cause HIV-induced disease, wider access to medical care and potent antiretroviral regimens, education about prevention (such as strategies to reduce high-risk behavior), access to interventions aimed at prevention, and the development and worldwide dissemination of a safe and effective HIV vaccine.
Oren J. Cohen, MD
Anthony S. Fauci, MD
From the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
Reprints: Anthony S. Fauci, MD, 31 Center Dr, MSC 2520, Bldg 31, Room 7A03, Bethesda, MD 20892-2520.
Editorials represent the opinions of the authors and THE JOURNAL and not those of the American Medical Association.
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