Towards a world free from HIV and AIDS?

Abstract

Approximately 30 years ago, in June 1981, it was reported from the Center for Disease Control and Prevention (CDC) that five, otherwise healthy, homosexual men in California had presented with pneumonia caused by Pneumocystis jiroveci pneumonia, a rare disease seen exclusively in individuals with a severely suppressed immune system. Several reports confirmed the initial observation and lent support to the possibility that a new sexually transmitted, infectious agent was circulating within the gay community in the United States. The clinical condition was named acquired immunodeficiency syndrome (AIDS). Two years later, a research team at the Institut Pasteur under the guidance of Françoise Barré-Sinoussi and Luc Montagnier isolated human immunodeficiency virus (HIV), the causative agent of AIDS, from a lymph node biopsy of a French patient. The isolation and characterization of HIV paved the way for the design of diagnostic methods to identify the virus in blood and blood products and towards the development of novel antiretroviral treatment (ART) to control HIV replication in infected patients. For their discoveries, Barré-Sinoussi and Montagnier were awarded the Nobel Prize in Physiology and Medicine in 2008. In the last 30 years, an estimated 60 million people have been infected with HIV worldwide and 30 million people have died. The ultimate goal of the fight against HIV and AIDS is the global eradication of the virus and the disease that it causes. Needless to say, there are many serious obstacles that need to be overcome before such a goal can be achieved. A conference entitled 30 years of AIDS – memories, achievements and future perspectives was held on 3 May 2011 in Stockholm, Sweden. This conference gathered Swedish and international keynote speakers from a broad range of backgrounds. It provided a forum to summarize the important achievements obtained in the field of HIV research during the last 30 years, to review the current status of research and prevention and to discuss the progress towards a future world free from HIV and AIDS. The Karolinska Institutet was the main organizer of the conference, and support was also provided by the Swedish Medical Research Council, the Swedish International Development Cooperation Agency, the Swedish Institute for Communicable Disease Control, the EU-funded network of excellence Europrise and the Journal of Internal Medicine. Five reviews on topics relevant to the HIV epidemic are presented in the current issue of the Journal of Internal Medicine. The first review summarizes the current understanding of HIV biological variation and its significance for variations in clinical progression during HIV infection. The other four reviews focus on prevention, treatment and possible cure of HIV infection: (i) successes and controversies in the prevention of HIV transmission from infected mothers to their children; (ii) impact of antiretroviral drug resistance to ‘test and treat’ strategies; (iii) microbicides for HIV prevention at the mucosal site; and (iv) HIV reservoirs and the possibility of a cure for HIV infection. The HIV research field has been a very good example of how basic research can be rapidly implemented in clinical practice, for example the introduction of diagnostic tests and ART. In addition, HIV research has contributed to the understanding of the basic mechanisms of immunology and host–virus interaction. In spite of all the research efforts and knowledge generated in this field, we are still far from a cure and functional vaccines. In addition, although generous donors have provided increased economic support during the last decade for the distribution of ART to highly affected, resource-poor countries, the proportion of patients in need who receive ART is still low. However, many positive and inspiring steps have been taken by the HIV/AIDS community, represented by the speakers and participants at the Stockholm conference, towards the possibility of combating the HIV epidemic by a combination of strategies aimed at successful prevention and a possible cure. Research in the field of HIV/AIDS has become an important example of translational medicine, moving fast from basic research discoveries to innovation and intervention in clinical practice. The prevention of HIV transmission through blood testing and the development of ART are concrete examples that have saved and improved the lives of many millions of individuals around the world. These areas were reviewed at the conference by Barré-Sinoussi who remains one of the most active scientists in this field. Another feature, which has been quite unique to the HIV epidemic, is that basic research scientists and patient organizations have been very involved in affecting the decisions of politicians and healthcare leaders in the areas of clinical care and treatment access. A remarkable aspect of the first 30 years of the HIV epidemic is that the whole process has been documented on film. In 1986, the Swedish documentary film producer Staffan Hildebrand began documenting global aspects of the fight against HIV/AIDS on film: the film documentation is still ongoing led by Hildebrand. No other film producer operating internationally has focused this long on capturing the spread of HIV/AIDS and the unprecedented global response to the pandemic. The result of this work is the Face of AIDS film archive, currently based in Stockholm, containing more than 1000 h of unedited film sequences, shot in 45 countries between 1986 and 2010. Hildebrand has produced more than 70 short documentaries, which have been edited from the film archive and shown at international AIDS conferences and other AIDS-related international events. Since its start, the film archive has been owned and controlled by the nonprofit organization the Face of AIDS Foundation, which is based in Stockholm. The Face of AIDS Foundation has close ties with the Karolinska Institutet. During the past 25 years, a network of renowned world AIDS experts, activists and advocates has developed in support of the documentation. This network includes scientific leaders from the AIDS arena such as Anthony Fauci from the National Institutes of Health and Bruce Walker from Harvard Medical School, who have supported the project from the start. The vision for the archive is the development of a digitally accessible, online film archive of HIV/AIDS. The archive represents a unique visual education, research and information tool, which documents how the AIDS pandemic and the response to it have evolved over time around the world. During the late 1980s, research focussed on characterizing the biological features of primary HIV isolates obtained from biological fluids of HIV-infected patients. One of the research groups that pioneered the work in this field was lead by Eva-Maria Fenyö who has contributed to the current issue of the Journal of Internal Medicine, together with collaborators Joakim Esbjörnsson, Patrik Medstrand and Marianne Jansson [1]. In 1986, Åsjöet al. [2] characterized biological isolates from HIV-infected patients and classified them into two groups according to the extent of replication in peripheral blood mononuclear cells and the capacity to induce cell fusion (syncytia) in primary cells and cell lines. The classification of HIV isolates according to well-defined and distinct biological properties continued in the following years. The discovery of HIV co-receptors was an important step. Thus, for entry into cells, HIV uses the chemokine receptors CCR5 and/or CXCR4, in addition to its main receptor CD4. Accordingly, HIV isolates can be distinguished into those that use CCR5 (R5) or CXCR4 (X4). Of importance, the co-receptor usage affects not only the cell tropism of the virus but also its pathogenicity. The presence of X4 variants is associated with faster disease progression, and approximately 50% of patients progressing to AIDS carry X4 variants although progression to AIDS can also occur in presence of CCR5 variants [3]. Patients in the initial phase of HIV infection usually carry R5 variants. In their review, Fenyö and collaborators discuss the factors and molecular events leading to HIV co-receptor switch from CCR5 to CXCR4 usage and the broadening of cell tropism for HIV isolates that preferentially bind to CCR5. It is interesting that the increased emergence of isolates with the capacity to use CXCR4 may indicate an evolving HIV epidemic worldwide, and the authors review what is known in terms of co-receptor usage for isolates classified into different HIV genetic groups. Understanding of the molecular details dictating co-receptor use has led to the development and registration of drugs that block the CCR5 receptor, such as maraviroc. Thus, studies on co-receptor usage represent another example of how basic research can be translated into new principles for therapeutical intervention during HIV infection. Mother-to-child transmission (MTCT) of HIV remains an important component of the HIV epidemic in developing countries. The World Health Organization (WHO) and United Nations Programme on HIV/AIDS (UNAIDS) estimate that there are 2.5 million children amongst the 33 million people living with HIV globally. In addition, 370 000 new HIV infections occurred in children in 2009. Transmission mainly takes place at the time of delivery, but pregnancy and breastfeeding also account for up to 30% of transmissions. MTCT of HIV can be prevented, as demonstrated by a large number of clinical trials in which ART was administered at delivery or in the weeks prior to delivery. These therapeutic approaches for MTCT prevention are reviewed in this issue of the Journal of Internal Medicine by Gabriella Scarlatti and Mariangela Cavarelli [4]. In the article, they present the global epidemiology of MTCT emphasizing that MTCT is still a very important problem in developing countries in which many infected mothers are not identified prior to delivery and/or do not receive treatment with antiretroviral drugs (ARVs). The definition of the time of infection of the child by the mother, as well as the routes of transmission, has been pivotal for developing therapeutic strategies for MTCT. The authors summarize 25 years of research in this field, with HIV properties discussed in relation to the cell biology of the female reproductive tract. The impact on infection of breastfeeding, which is vital if alternative means of feeding (e.g. surrogate milk products) are not available, is reviewed in the context of infrastructural organization. Many years of research have been devoted to the identification of biomarkers in the mother to predict the risk of MTCT; amongst them, the most valuable are the plasma virus levels, CD4+ T cell counts and detection of virus in vaginal secretions [5]. No difference in preferential transmission of R5 or X4 variants has been reported [6, 7]. A prognostic biomarker for MTCT has emerged when measuring the levels of abnormal immune activation caused by microbial translocation [8]. The role of components of the humoral and cellular immune responses in MTCT prevention is extensively discussed in the article. The review ends by presenting the current recommendation from the WHO for avoiding MTCT and the possible consequences for transmission if the mother carries a virus resistant to ART. Two major achievements are required to eradicate HIV infection. The first is effective prevention against HIV infection, which ideally would be achieved by an effective HIV vaccine. The second is a strategy to cure the approximately 30 million people worldwide who currently are estimated to be living with HIV infection. Even though some progress has been made in the HIV vaccine field, there is still uncertainty about whether and when we may have access to a vaccine. In the absence of such a vaccine, other approaches towards improved HIV prevention are needed. These approaches involve improved surveillance and ‘traditional’ HIV prevention, the concept of ‘test and treat’, and novel biomedical prevention strategies. At the conference, Johan Giesecke from the European Centre for Disease Prevention and Control attempted to envision the HIV epidemic in Europe in 2020. He predicted that we would have a better understanding of the epidemic, including real HIV incidence, by improved epidemiology and laboratory methods to access recency of infection in newly diagnosed patients. He also predicted that increased HIV testing and increased and earlier access to ART would decrease HIV transmission within Europe. The effect of ART on rate of transmission and the prospect of reducing HIV transmission is reviewed by Brooke Nichols and colleagues in this issue. Viveca Urwitz of the Swedish Institute for Communicable Disease Control also discussed at the conference how HIV prevention could be improved by better incorporation of evidence-based methods, such as motivational interviewing. Despite extensive prevention efforts, in 2009 there were 2.6 million new HIV infections worldwide. Most of these new infections occurred in sub-Saharan Africa. For every two patients who start ART, five individuals become newly infected showing the growing need for more effective methods to curb the epidemic. In the absence of effective HIV vaccines or other novel methods for biomedical prevention of HIV infection, there has been a strong recent interest in and debate about the possibility of using ART to reduce HIV transmission, with the so-called test and treat strategies. In this issue, Nichols et al. [9] review the test and treat concept, including the epidemiological evidence of its potential benefits and the potential negative consequences of ARV resistance on the effectiveness of this strategy. The authors explain that test and treat consists of universal HIV testing combined with immediate ART for those individuals found to be infected. Universal testing may be able to prevent new infections as individuals who become aware of their HIV status could reduce their risk behaviour. In addition, immediate ART for infected individuals can prevent new infections as ARVs suppress viral replication and thereby the HIV RNA load, which is a key factor in determining transmissibility of HIV. Montaner et al. [10] were amongst the first to propose the ‘test and treat’ approach. Granich et al. [11] then further explored the benefits of this approach in a mathematical modelling study. Based on their model, they predicted that annual voluntary HIV screening followed by immediate start of ARVs for those individuals who tested positive, regardless of their CD4 count, could reduce the HIV pandemic to one incident case of HIV per 1000 people by 2016. However, they made several assumptions, which may not be easily implemented in daily practice, and therefore received some criticism. Nichols et al. point out that development of drug-resistant viruses is a specific concern of test and treat. Thus, expanded access to drugs in a test and treat programme will increase the number of individuals taking ARVs and as such may lead to an increased rate of emergence of drug resistance. As a consequence, more people may need expensive second-line treatment. An additional problem is that drug-resistant viruses may be transmitted to others. Transmitted drug resistance has clinical significance as it is associated with virological failure in patients who receive at least one ARV to which the virus has lost susceptibility [12]. In addition, drug resistance can have important implications for public health as it leads to a rebound in viral load, which increases transmissibility of the virus. The authors review the mathematical models that have been used to study the potential impact of test and treat, and consider how they have evolved from simple, unrealistic models into more complex models. Mathematical models are inherently limited by the assumptions that are used to construct them; the authors discuss some problems with the models that have been used to investigate the possible impact of test and treat such as the feasibility of universal HIV testing and the possibility of providing unlimited HIV treatment and care. The authors conclude that test and treat is a promising prevention strategy, but its benefits have only been shown in mathematical models and ecological studies. Test and treat should therefore be evaluated in large-scale epidemiological studies. Emergence and transmission of drug resistance is currently not a major problem, but more patients will receive treatment in a test and treat programme. In addition, ARVs used in test and treat programmes may also be used for prevention as pre-exposure prophylaxis and as microbicides. Therefore, surveillance of drug resistance is recommended in areas in which test and treat is introduced to confirm that drug resistance levels remain low. Microbicides are products that are designed for vaginal or rectal application to inhibit or block early events in HIV infection and thereby prevent transmission of the virus. In this issue, Kelly and Shattock [13] review recent advances towards the development of effective microbicides. They examine the rationale for investigating highly active ARVs and other compounds as vaginal or rectal microbicides, as well as approaches, to improve efficacy through the development of combination microbicides and new formulations that may increase user acceptance. The aim of first-generation microbicides was to disrupt HIV virions or prevent fusion and cell entry. Despite promising data from in vitro studies and, in some cases, nonhuman primate models of infection, these early-generation microbicides failed to demonstrate efficacy in clinical trials. Currently, the most advanced microbicides in the development pipeline are based on ARVs. The CAPRISA 004 trial was a major breakthrough because it provided proof-of-concept evidence that microbicides can be effective [14]. The microbicide that was evaluated in the CAPRISA 004 trial was based on a vaginally applied gel that contained the registered ARV, tenofovir. The gel provided significant protection from HIV infection in women. If the ongoing Vaginal and Oral Interventions to Control the Epidemic (VOICE) is able to demonstrate a similar level of protection, it is likely that tenofovir will be advanced as a microbicide product. The authors explain that the challenge will be to increase efficacy. Compliance with microbicide protocols is clearly a crucial aspect of clinical trials but equally clearly is considered by some to be a factor difficult to control and prone to overestimation. Kelly and Shattock highlight recent data indicating that HIV infection through genital or rectal mucosal barriers may, in most cases, be established by a single isolate. Although some spread of infection to lymphatic tissue is detectable at the time of initial exposure to the virus, it may be at too low a level to establish productive infection at these sites. Expansion of the original foci of infection results in further seeding of lymphatic tissue leading to self-sustaining propagation and systemic infection from day 6 after infection [15]. Thus, the mucosal barriers appear to be effective in limiting entry of virus, which means that ‘modest improvements in barrier integrity’ could be sufficient to prevent infection. Clearly, such improvements could be provided by microbicides. In addition, the delay before a sustainable infection is established provides a potential opportunity for interventions, such as treatment with microbicides, that could prevent expansion of the initial founder population and thereby prevent the establishment of systemic infection. Early-generation microbicides were developed to prevent HIV fusion because it was believed that complete blockade at the initial stage of infection would be necessary to prevent infection. However, these agents lacked sufficient potency to prevent HIV infection. Nevertheless, in view of the delay before an infection becomes self-sustaining, Kelly and Shattock point out that inhibitors that act postentry have become an additional focus for investigation as microbicides. This may explain why single-agent tenofovir, which acts postentry to block reverse transcription of the viral genome, was found to be 39% effective in reducing a woman’s risk of becoming infected with HIV during sex [14]. It is hoped that new microbicides may offer an even higher level of protection. Modern ART is a great success and has impacted considerably on morbidity and mortality amongst HIV-infected patients, as discussed at the conference from the perspective of clinicians, represented by Eric Sandström (Stockholm South Hospital), and the pharmaceutical industry, represented by Daria Hazuda (vice president of virus and cell biology at Merck Research Laboratories). In this issue, Sarah Palmer and John Coffin [16] review the current knowledge of HIV reservoirs and discuss the possibility of a cure for HIV infection. During the first years after the introduction of ART in 1996, it was hoped that successful therapy might eradicate the infection and thereby cure patients. Unfortunately, this has not been the case because the virus infects and remains in long-lived cellular reservoirs [17]. Successful therapy usually drives plasma HIV RNA levels to ‘undetectable levels’, that is <40–50 copies mL−1 which is the limit of the detection of standard assays. Yet, ultrasensitive assays show that most patients continue to harbour low-level persistent viraemia [18]. Palmer and Coffin review the results of treatment-intensification studies, which indicate that low-level viraemia could arise from several different sources. These sources include the following: (i) long-lived HIV-infected cells that replicate and produce virus; (ii) ongoing replication cycles in cells located in sanctuary sites in which drug levels are suboptimal; and/or (iii) proliferation of latently infected cells with regeneration of a stable reservoir of slowly dividing infected cells. They point out that the memory CD4+ T cell is a well-defined latent reservoir of HIV, where latency is established when an activated CD4+ T cell becomes infected by HIV, but it transitions to a terminally differentiated memory cell before it is eliminated. Palmer and Coffin also examine the dynamics and possible reservoirs of persistent HIV in patients on suppressive therapy and the complex mechanisms promoting viral latency. The best-defined HIV reservoir is a small pool of latently infected resting memory CD4+ T cells carrying an integrated form of the viral genome [19]. The precise molecular mechanisms contributing to the generation and maintenance of this reservoir remain to be elucidated. However, available data indicate that the chromatin environment influences HIV expression. Thus, mechanisms that promote HIV latency in infected CD4+ T cells include histone and DNA modification in the HIV long terminal repeat (LTR). The recruitment of cellular histone deacetylases (HDACs) and CpG (CG-rich DNA) methylation, which closes the LTR chromatin structure, prevents HIV transcription and expression. In the last part of their review, Palmer and Coffin examine possible strategies to purge latent viral reservoirs. The aim is to find ways of reactivating latent HIV proviruses in resting memory CD4+ T cells and other possible cellular reservoirs, whilst providing ART to prevent infection of new cells by the virus that is released from the latent reservoirs. They describe recent promising research that has begun to seriously address HIV remission and/or eradication. Thus, attempts are being made to use cocktails of cytokines or small molecules that may upregulate cellular transcription to induce HIV gene expression. The latter approach includes inhibiting class I HDACs because these enzymes promote latency by regulating genome structure and transcriptional activity. Other potential targets are regulators of DNA methylation. Palmer and Coffin conclude that although further research is needed, recent studies have provided new insights into the mechanisms of latency and persistent HIV reservoirs. Considerable effort is now underway to apply the findings of these mechanistic studies to the extremely difficult but important clinical problem of HIV remission and/or eradication from an infected patient. The presentations given at the conference 30 years of AIDS – memories, achievements and future perspectives and the reviews in the present issue of the Journal of Internal Medicine have demonstrated the possibility that eventually HIV can be eliminated. Prevention, improved treatment, cure and development of effective HIV vaccines are the key strategies for HIV elimination worldwide. These goals can only be achieved through the awareness of the lessons learned during the first 30 years of the HIV epidemic, as summarized at the conference by Peter Piot from the London School of Hygiene and Tropical Medicine. Amongst the topics to consider, Piot discussed the need for specific funding mechanisms, global engagement as the key for local action and the combination of emergency response with long-term strategy. A point of discussion at the conference in Stockholm was how Sweden, which is a country with a few HIV-infected patients, should participate in the global fight against HIV. This question is not unique to Sweden, and many countries with modest HIV prevalence rates in Europe and other parts of the world face the question of how to contribute towards ending to the HIV epidemic. Many researchers in European countries and the United States have been pivotal for capacity building in the field of HIV and AIDS and for creating a generation of scientific leaders in developing countries. HIV research contributions from richer countries should not be terminated now when solutions in the form of improved cure and vaccines are possibly at reach. It is worrisome that the medical consequences of HIV infection are very different at the moment in the northern and southern hemispheres, as discussed at the Stockholm meeting by Francoise Barre-Sinoussi. In resource-rich countries, HIV has become a chronic infection and patients have a life expectancy that is not dramatically different from that of the general population. In developing countries, AIDS mortality is still very high, and up to 25% of HIV-infected individuals die during the first year after treatment initiation. Crucial issues in highly affected countries in the southern hemisphere are general access to ART, prevention of MTCT and treatment of co-infections. Another important point of discussion regarding the issue of research funds for poverty-related diseases is whether HIV research in Europe and countries with a low prevalence of HIV should become a priority only of international research funding agencies or whether national agencies should participate in creating a strong platform for research support and continuity in such countries. Basic scientific research in the field of HIV and AIDS is about to be translated into products for prevention, treatment and cure. This has been possible through a global effort for the last 30 years, an effort which needs to be continued towards a world free from HIV and AIDS. No conflicts of interest to declare.