aDivision of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA
bHopital Pitie-Salpetriere, Laboratorie d’Immunologie Cellulaire, URA CNRS 625, Paris, France
cUtrecht University, Utrecht, The Netherlands
dDepartment of Medicine, Northwestern University Medical School, Chicago, Illinois, USA.
Correspondence to Jay A. Levy, MD, Division of Hematology/Oncology, Department of Medicine, University of California, 513 Parnassus, Box 1270, San Francisco, CA 94143-1270, USA. Tel: +415 476 4071; fax: +415 476 8365; e-mail: email@example.com
It is with great pleasure and a feeling of achievement that we celebrate this milestone in the history of the journal, AIDS. This leading publication in HIV/AIDS has had an extraordinary evolutionary course that has involved three publishers and 12 editors. We are pleased to have commentaries from each of the former editors. They helped build the journal into its present outstanding reputation for publishing the highest quality articles on HIV/AIDS, in basic science; clinical science; epidemiology and social science. We now have an impact level close to 6.4 and are the premier journal in HIV/AIDS as well as a leading journal in infectious diseases, virology, immunology and epidemiology. We are also the official journal of the International AIDS Society.
The invited reviews for this issue are written by pioneers in the fields of fundamental and clinical research as well as in global issues dealing with epidemiology, education and prevention. The articles cite the progress made in our understanding of these various facets of HIV/AIDS and highlight the accomplishments and, notably, the future challenges. We all recognize that researchers, physicians and other public health participants must continue to look for a long-term solution to this devastating epidemic.
Certain contributions ([1–3], this issue) focus on the long-term efforts and the accomplishments in approaching this global public health problem. Emphasis was placed on past and current programs in epidemiology, education, prevention and care. Unfortunately, in the beginning, HIV/AIDS was not given appropriate attention. As more information came forward, this viral infection was finally recognized as a major pandemic. Today, HIV has affected over 60 million people worldwide, making it probably the worst pandemic for humankind.
Anti-HIV therapy has certainly brought a great advancement in controlling the virus to avoid disease and perhaps in limiting its transmission (, this issue). However, we need therapies that are less toxic and do not require daily administration. In this regard, the enticing discoveries on natural intracellular anti-HIV factors are encouraging (, this issue). Approaches to use the knowledge on these intrinsic proteins, made specific for HIV, could open up strategies for novel anti-HIV treatments. Moreover, work on these factors could provide important information on the general functions of cellular processes, which have relevance to other human conditions.
In this regard, the challenge of the diversity of HIV isolates infecting world populations must be appreciated (, this issue) and the ability of the virus to remain latent or silent within cells as viral reservoirs must be considered (, this issue). Similar to the challenge of cancer – if only one latently infected cell survives – the disease threatens to re-emerge if the antiviral immune responses are not maintained or the anti-HIV therapy is not continued.
Importantly, anti-HIV therapies that harness the immune system would provide a welcomed increase in our armamentarium against the virus. This approach would mimic what is observed in long-term nonprogressors (a.k.a. long-term survivors) and, particularly, elite controllers. These infected individuals do not need antiretroviral drugs but control the infection with their immune system. The secret to this control still needs to be fully defined so that appropriate strategies can be found. In this regard, approaches to reduce immune activation deserve recognition. This process appears to be an important participant in HIV pathogenesis.
The innate, as well as the adaptive immune system, needs to be appreciated in the potential development of new anti-HIV therapies. Of the innate cells, the plasmacytoid dendritic cells (major producers of interferon-α) and natural killer cells merit close attention (, this issue). Other notable activities of this arm of the immune system include soluble factor(s) mediating the anti-HIV activity of CD8+ cells and the anti-HIV activities of circulating innate factors such as complement and mannose-binding lectins.
Within adaptive immunity (, this issue), both the HIV-specific antibodies and the CD8+ cell anti-HIV memory responses are important. They participate in preventing the progression to disease and, via effective vaccines, the transmission of HIV ([9,10], this issue). Notably, whether the CD8+ cell activity reflects primarily a cytotoxic activity or one mediated by soluble factors is not yet clear. Furthermore, although certain HLA haplotypes (e.g. B57, B27) correlate with long-term survival with HIV infection, evidence has indicated that the same MHC subtypes can also be associated with progression to AIDS. As we have learned throughout all the studies of HIV, the infection pattern is complex and the host antiviral response is more diversified than perhaps initially anticipated.
For prevention, a great deal of attention has been given to the behavioral approaches as well as interventions that might limit the spread of HIV (, this issue). Success has been observed with male circumcision and, to some extent, the use of microbicides containing antiretroviral drugs. Also, the important role of education toward HIV prevention and treatment as well as the reduction in HIV-related stigma should be fully recognized (, this issue). Therapy for prevention has recently become part of a strategy to ‘test and treat’ all infected individuals (, this issue). The anticipated result would be a reduction in the viral load in infected individuals that would lead to decreased transmission of the virus at the population level. This approach is based on the successful use of antiretroviral therapy (ART) to prevent mother-to-child transmission of the virus. Importantly, this strategy requires very high testing coverage, no delay in treatment after the diagnosis and the constant adherence to the daily administration of drugs. Another major concern is that the widespread distribution of these medicines, particularly when they are not needed, can bring about resistance to the drugs. Even after a short-term course of nevirapine (NVP), NVP-resistant viruses have emerged. Such a result has been observed with the use of antibiotics for prevention of bacterial infection. The feasibility, cost, toxicity (e.g. renal disease with tenofovir) and the occurrence of drug resistance are important concerns with this ‘test and treat’ strategy.
Ultimately, an AIDS vaccine is the most desirable objective for arresting this epidemic. Many trials have been reported but with very limited achievements in HIV prevention. However, the knowledge gained on what does not succeed is very helpful (, this issue) and there are some promising avenues. For example, studies based on the Thai RV144 trial could lead to improved approaches in vaccines. Moreover, studies on high-risk HIV-exposed seronegative individuals could provide insights into vaccine strategies.
The most recent notable long-term goal for HIV/AIDS is complete elimination of the virus from the body as has been suggested with observations on the ‘Berlin patient.’ Following treatment for leukemia with two stem cell transplant from a CCR5− donor, the recipient is off therapy for several years with no evidence of leukemia or HIV. Conceivably, this individual still has some cells carrying latent virus but they are under the control of the immune system and any residual virus would have limited target cells (CCR5+) available for infection and spread.
Approaches to ‘flush out’ these cellular reservoirs of HIV (, this issue) with certain compounds are being considered to effect a ‘cure.’ That strategy, however, is compromised by the large number of tissues that harbor HIV besides the immune system. These include cells of the intestine, the testes, the kidney and the brain. Furthermore, this approach is based on the assumption that HIV replication kills the cell infected. That is not always the case, particularly with non-CD4+ cells. And, as ART must be continued during these approaches, this treatment that reduces the anti-HIV immune responses can curtail an immunologic attack on the virus-producing cells. Other strategies being evaluated involve genetic manipulation of hematopoietic stem cells to delete CCR5 gene expression.
This anniversary issue focuses on the prominent AIDS virus in the world, HIV-1. Notably, much can also be gained from studies of HIV-2 in which the clinical course can be slow and in some cases nonpathogenic. It resembles to some extent the nonpathogenic clinical findings in natural SIV infection in which a low level of immune activation may be responsible for the beneficial outcome. Thus, studies of HIV-2 as well as the primate lentiviruses could provide important information for control of HIV-1.
The knowledge on HIV/AIDS gained in the past 25 years of study and covered by our journal, AIDS, has been remarkable. There have been over 400 000 articles published in this field since this disease and its causative virus were uncovered over 30 years ago. We are pleased to say that many of the important articles, well cited in the literature, were first published in AIDS. At least 10 000 articles have been published in this journal over the past 25 years.
By reporting important novel observations in the field, we look forward to continual service to the scientific, clinical, public health and other communities addressing the challenge of HIV/AIDS. Our ultimate goal, via effective communication, is to help bring about the long-term control and eventual elimination of this worldwide epidemic. Then, the journal AIDS can take pride in its place in history.
Conflicts of interest
There are no conflicts of interest.