Chemokines and immunomodulation: applications for HIV infections

The genetic control of HIV infection by the host involves a certain number of genes, among which those which code for chemokines/chemokines receptors, cytokines, MHC. Genes such as CCR5, CCR2, SDF1, and more recently CX3CR1 received great attention from several laboratories including ours, since they play a role as HIV coreceptor and, as such, on the infectivity of the host. In addition, it was shown that the polymorphism of these genes influences the evolution of infection, whether they have a protective or deleterious effect. Results obtained by our laboratory on the genetic polymorphism and its implication in HIV infection will be reported herein. Furthermore, to better understand their role, we looked for the capacities that the chemokines may have to play an immunomodulatory function, independently of their chemoattractive effect. In two examples, we showed that chemokines influence notably the cellular immune functions, such as CD8 cytotoxicity (Rantes/CCR3) and gamma interferon production (fractalkine/CX3CR1). Globally, the results indicate that chemokines/chemokines receptors polymorphism represent important epidemiological factors, but also contributes to evaluate the prognosis of HIV infection, through a better understanding of the disease physiopathology.     

Apoptotic cell death and cytokine dysregulation in human immunodeficiency virus infection: pivotal factors in disease progression

The progressive loss of CD4 T lymphocyte is patognomonic of Human Immunodeficiency Virus (HIV) infection and results in immunodeficiency and the appearance of acquired immunodeficiency syndrome (AIDS)-defining pathologies. Although a percentage of CD4 T lymphocytes is destroyed directly by HIV infection, a much higher proportion of lymphocytes remains uninfected and therefore must be destroyed by mechanisms not directly involving viral infection. One such mechanism is apoptotic T cell death (ATCD). ATCD in HIV infection has been shown to be: 1) secondary to cross-linking of CD4 by viral proteins; 2) mediated by both APO-1/Fas and lymphotoxin (LT); and 3) differentially modulated by type 1 and type 2 cytokines. We will briefly analyze the experimental evidences suggesting that ATCD contributes significantly to the immunopathogenesis of HIV/AIDS via depletion of CD4+ T cells.     

The AIDS epidemic: profiles of development

As all HIV-infected subjects become virus carriers, the epidemic will not attain a "steady state" until the number of deletions (from death and other factors) equals or outnumbers that of new cases, i.e. each HIV-infected subject transmits the infection to only one subject in the course of his lifespan. A full stop of all spreading of HIV will most likely require worldwide vaccination. By simple mathematical models it is shown that calculation of the number of HIV infected individuals based on the number of AIDS cases is very uncertain. The ratio of HIV infected subjects to AIDS cases is greatly influenced by the length of the incubation period and the case doubling time. Since the growth of the epidemic is exponential, all efforts to control the epidemic should be continuously intensified as single measures will only retard the rate of spread. The effect of saturation/deletion on the number of susceptible individuals is insignificant in this phase of the epidemic, except in small groups at special risk.     

Cytokines and HIV infection

Infection with the human immunodeficiency virus (HIV) results in the production of cytokines by cells that comprise the immune system. Such cytokines regulate both immune function and viral replication, and thereby complicate their contribution to the progression to AIDS. Certain cytokines that regulate immune function exert opposing effects, such that some promote mainly cellular immune function, whereas others enhance antibody production. It has been suggested that an imbalance in cytokine production is responsible in part for the immune dysregulation characteristic of progression to AIDS. Different cytokines can also have different effects on HIV expression and replication. Cytokine-based therapy has been suggested for preventing or delaying progression to AIDS. If such therapy is to be successful, it will be necessary to identify the correlate of immune protection, as well as to determine which cytokines enhance or suppress protective immunity, and the effects of these cytokines on viral replication.     

HIV infection in India: Epidemiology, molecular epidemiology and pathogenesis

The year 1986 saw first case of HIV infection as well as first report of AIDS case in India. Since then the epidemic has spread throughout the country. In the recent years there is evidence of epidemic being stabilized with decrease in new infections reported from some parts of the country. The absolute number of HIV infections in the country is expected to be close to 2.5 million and National AIDS Control Programme, phase III is geared to contain the epidemic. HIV viruses circulating in India predominantly belong to HIV-1 subtype C. However, there have been occasional reports of HIV-1 subtype A and B. Matter of concern is reports of A/C and B/C mosaic viruses that are being reported from different parts of the country. The data on HIV drug resistance from India is rather limited. Most of the studies have shown that the virus strains from drug naïve patients do not show significant level of drug resistance mutations. The few immunological studies in Indian patients show that the Indian HIV infected patients show both HIV-specific CTL responses as well as neutralizing antibody response. Mapping of CTL epitopes showed that while Indian patients identify same regions of Gag antigen as recognized by South African subtype C infected patients, some regions are uniquely recognized by Indian patients. There are very few studies on host genetic factors in India in context with HIV infection. However there are evidences reported of association of host genetic factors such as HLA types and haplotypes and HIV disease.     

Retrovirally mediated IFN-beta transduction of macrophages induces resistance to HIV, correlated with up-regulation of RANTES production and down-regulation of C-C chemokine receptor-5 expression

Constitutive expression of IFN-beta by HIV target cells may be an alternative or complementary therapeutic approach for the treatment of AIDS. We show that macrophages derived from CD34+ cells from umbilical cord blood can be efficiently transduced by a retroviral vector carrying the IFN-beta coding sequence. This results in resistance to infection by a macrophage-tropic HIV type 1, as shown by the drastic reduction in the HIV DNA copy number per cell and in p24 release. Moreover, IFN-beta transduction totally blocked secretion of proinflammatory cytokines after HIV infection. The constitutive IFN-beta production also resulted in an increased production of IL-12 and IFN-gamma Th1-type cytokines and of the beta-chemokines macrophage-inflammatory protein-1alpha, macrophage-inflammatory protein-1beta, and RANTES. RANTES was found to be involved in the HIV resistance observed, and this was correlated with a down-regulation of the CCR-5 HIV entry coreceptor. These results demonstrate the feasibility and the efficacy of such IFN-beta-mediated gene therapy. In addition to inhibiting HIV replication, IFN-beta transduction could have beneficial immune effects in HIV-infected patients by favoring cellular immune responses.     

The growth in the role of social workers in measures tp prevent HIV/AIDS during the developing epidemic of drug abuse

In the presence of the developing epidemic of HIV infection and drug addiction the introduction of the post of the specialist on social work in the staff of AIDS centers is proposed. The principle of the primary training of such specialists permits their free orientation in the interests of a concrete group or individual. The first group of such specialists will be graduated from the Arkhangelsk Medical Academy in the year 2000.     

The UNAIDS strategy in the prevention of HIV/AIDS in the countries of Eastern Europe

Grounds for the necessity of the formation of effective approaches to the prevention of HIV epidemic with a view to counteract the rapid spread of infection in East European countries are presented. Attention is specially drawn to fact that the epidemic will not be limited by drug users, but will quickly cross the boundaries of this group. The development of preventive measures must be based on the use of the world experience. New effective approaches to work with vulnerable groups (the strategy of harm reduction, work in communities, consultations, etc.) must be widely used. The program of actions of the UNAIDS European Section, stipulating the strengthening and extension of the potential of the countries in the region for the effective counteraction to the epidemic, is formulated. As priority areas, activities covering vulnerable groups and with young people have been determined. The strategy of UNAIDS is realized through 20 UN theme groups on HIV/AIDS in the countries of Eastern Europe. Special attention is drawn to the creation of methodological networks. The creation of a unified strategic plan for counteraction the epidemic of HIV/AIDS is regarded by UNAIDS as its perspective for the future.     

Inferring the Source of Transmission with Phylogenetic Data

Identifying the source of transmission using pathogen genetic data is complicated by numerous biological, immunological, and behavioral factors. A large source of error arises when there is incomplete or sparse sampling of cases. Unsampled cases may act as either a common source of infection or as an intermediary in a transmission chain for hosts infected with genetically similar pathogens. It is difficult to quantify the probability of common source or intermediate transmission events, which has made it difficult to develop statistical tests to either confirm or deny putative transmission pairs with genetic data. We present a method to incorporate additional information about an infectious disease epidemic, such as incidence and prevalence of infection over time, to inform estimates of the probability that one sampled host is the direct source of infection of another host in a pathogen gene genealogy. These methods enable forensic applications, such as source-case attribution, for infectious disease epidemics with incomplete sampling, which is usually the case for high-morbidity community-acquired pathogens like HIV, Influenza and Dengue virus. These methods also enable epidemiological applications such as the identification of factors that increase the risk of transmission. We demonstrate these methods in the context of the HIV epidemic in Detroit, Michigan, and we evaluate the suitability of current sequence databases for forensic and epidemiological investigations. We find that currently available sequences collected for drug resistance testing of HIV are unlikely to be useful in most forensic investigations, but are useful for identifying transmission risk factors.     

A Screen-and-Treat Strategy Targeting Visceral Leishmaniasis in HIV-Infected Individuals in Endemic East African Countries: The Way Forward?

In the wake of the HIV epidemic, visceral leishmaniasis (VL), a disseminated protozoan infection caused by the Leishmania donovani complex, has been re-emerging, particularly in North Ethiopia where up to 40% of patients with VL are co-infected with HIV. Management of VL in HIV co-infection is complicated by increased drug toxicity, and high treatment failure and relapse rates with all currently available drugs, despite initiation of antiretroviral treatment. Tackling L. donovani infection before disease onset would thus be a logical approach. A screen-and-treat approach targeting latent or the early stage of infection has successfully been implemented in other HIV-associated opportunistic infections. While conceptually attractive in the context of VL–HIV, the basic understanding and evidence underpinning such an approach is currently lacking. Prospective cohort studies will have to be conducted to quantify the risk of VL in different risk groups and across CD4 cell count levels. This will allow developing clinical prognostic tools, integrating clinical, HIV and Leishmania infection markers. Interventional studies will be needed to evaluate prophylactic or pre-emptive treatment strategies for those at risk, ideally relying on an oral (combination) regimen. Issues like tolerability, emergence of resistance and drug interactions will require due attention. The need for maintenance therapy will have to be assessed. Based on the risk–benefit data, VL risk cut-offs will have to be identified to target treatment to those most likely to benefit. Such a strategy should be complemented with early initiation of antiretroviral treatment and other strategies to prevent HIV and Leishmania infection.     

The cytokine network of acute HIV infection: a promising target for vaccines and therapy to reduce viral set-point?

Cytokines play a central role in the pathogenesis of many diseases, including HIV infection. However, the role of the cytokine network in early HIV infection is only now starting to be elucidated. A number of studies conducted in recent years have indicated that cytokines of the acute/early stages of HIV and SIV infection can impact viral set-point months later, and this is of critical importance since viral set-point during chronic HIV infection affects virus transmission and disease progression. This raises the question whether modulating the cytokine environment during acute/early HIV infection can be a target for novel approaches to develop a vaccine and therapeutics. In this review we focus on the kinetics and function of cytokines during acute HIV and SIV infection and how these may impact viral set-point. We also discuss unresolved questions that are essential for our understanding of the role of acute infection cytokines in HIV infection and that, if answered, may suggest novel therapeutic and vaccine strategies to control the worldwide HIV pandemic.     

The epidemiology of human immunodeficiency virus in South Africa

We review the epidemiology of human immunodeficiency virus (HIV) in South Africa where the prevalence of HIV infection is among the highest in the world. The epidemic reached South Africa relatively recently but the prevalence of infection has increased rapidly and there are significant differences among provinces. Although few 15-year-old people are infected the prevalence increases rapidly with age thereafter, especially among women. The prevalence of herpes simplex virus type 2 exceeds that of HIV and curable sexually transmitted infections are common. 'Circular migration' may help to explain the high rates and rapid spread of HIV in the region. The incidence of tuberculosis has increased dramatically as a result of the HIV epidemic. Antiretroviral therapy for the prevention of vertical transmission has been shown to be effective in local conditions but transmission through breast-feeding remains problematical. While some epidemiological models have been developed, much more needs to be done in this regard in order to plan, coordinate and evaluate an effective response to the epidemic. We conclude by discussing some of the research that is needed and steps that could be taken to reduce the continued spread of the infection.     

我国男男性行为人群中人类免疫缺陷病毒感染疫情特点及防治策略

目前我国人类免疫缺陷病毒（HIV）感染疫情总体处于低流行水平,但男男性行为（MSM）人群中HIV感染呈现快速上升趋势,传播亚型呈现出新的特点,疾病进展较快。HIV核酸及抗原抗体检测等手段对早期发现MSM人群中HIV感染者具有重要意义。解析MSM人群艾滋病疾病进展的影响因素,发现新的生物学标记,可为早期评估HIV感染的预后提供创新性手段。早期发现我国MSM人群中HIV感染者和抗病毒治疗等综合干预,对我国艾滋病流行的控制具有重要意义。     

Tuberculosis and HIV: a deadly interaction.

The spread of the HIV epidemic has been one of the major factors contributing to the worldwide resurgence of the tuberculosis epidemic. It was estimated that in 1997 8% of global tuberculosis cases may be attributed to HIV infection. The highest burden of HIV-associated tuberculosis is concentrated in resource-poor countries. HIV infection increases the individual's susceptibility to tuberculosis by impairing immune response to mycobacterial infection. In addition, HIV-associated tuberculosis is more difficult both to diagnose and to treat. A strong international commitment to the development of innovative strategies of diagnosis, treatment, and the prevention and integration between tuberculosis and HIV prevention programs are urgently needed to face the threat of HIV-associated tuberculosis.     

Making the health care system 'safe' for persons with HIV infection or AIDS.

If health care reform is implemented in states and nationally, the safety of this process needs to be examined for persons with human immunodeficiency virus (HIV) infection or the acquired immunodeficiency syndrome (AIDS). Reform should assure ongoing prevention and transmission control of HIV and continuous coverage of medical costs for persons ill with HIV or AIDS. These persons currently benefit from various state and federal categoric programs designed to assure access to preventive and personal care services. Washington State has passed health care reform legislation that envisions integrating these programs to provide a system of population-based and personal health care. This legislation was analyzed using existing epidemiologic and entitlement information about persons with HIV infection or AIDS in the state to assess its effect. The relationship between public health and personal care services will be a central concern for those with HIV infection or AIDS, and complete coverage of this group may be achieved relatively late in the process of implementing health care reform. Health personnel planning under health care reform will affect the delivery of HIV- and AIDS-related services. Including treatment of AIDS in the basic benefit package merits particular attention. These issues parallel those being faced by the nation as a whole as it seeks to ensure epidemic disease control and compassionate care for long-term disabling illness if health care reform is implemented.     

HIV infection in Russia and Commonwealth of Independent States: current situation and prospective

The dynamics of the spread of HIV infection in Russia and the CIS countries is presented. The relationship between the spread of HIV infection and an increase in the number of injection drug users is substantiated. The factors inhibiting the spread of the epidemic of HIV/AIDS in Russia and the CIS countries are analyzed with due regard to the world experience. Attention is paid to the development of the epidemic situation in HIV infection due to, similarly to Russia and to more than 100 countries of the world, drug addiction. The effectiveness of the activity of the Russian health service organs in controlling this epidemic is emphasized. The prospects of prophylactic measures for controlling HIV infection in Russia and the CIS countries are determined.     

Target cells in vaginal HIV transmission

Understanding the mechanisms of HIV transmission to women will be crucial to the development of effective strategies to curb this epidemic. Current data suggest that HIV has at least two routes to penetrate the vaginal epithelium and reach lymphoid tissues, trans-epithelial migration of infected Langerhans cells or virus penetration into the lamina propria through loss of epithelial integrity resulting in direct infection of lymphocytes, dendritic cells and macrophages.     

Prevention and control of HIV infection in the Osh region of the Kyrgyz Republic

A total of 178 cases of HIV infection were diagnosed in the Osh region of the Kyrgyz Republic for January 1, 2003, the intensity of the prevalence of HIV infection being 14.5 per 100,000 of the population with this figure for the whole republic being equal to 5.9. In the dynamics of the HIV infection epidemic two periods were detected. During the first 3 years (1998-2000) a few individual imported cases of HIV infection were registered in the region. During the last 2 years (2001-2002) 98.8% of all cases of HIV infection registered in the region, as well as the presence of an epidemic outbreak among injection drug users (IDU), were detected. The risk factors of getting HIV infection were the intravenous use of drugs and a low level of information among young people concerning the routes of transmission of this infection and means of protection from HIV/AIDS: the promotion of healthy life style among young people, the introduction of the programs of "harm reduction" among IDU and the rules of safe sex.     

Prospects for new antitubercular drugs

The inexorable rise in cases of tuberculosis worldwide, fuelled by the HIV epidemic, highlights the need for new drugs and particularly those that can shorten the duration of treatment. Clinical trials of existing broad-spectrum agents such as the fluoroquinolone moxifloxacin are proceeding, on the basis of efficacy in models of infection and preliminary clinical data. These may provide a stopgap, but the real breakthrough will come when novel agents with potent sterilising activity are discovered. Few such novel pre-clinical drug candidates exist and therefore considerable effort is being exerted to employ new tools to identify drug targets essential for survival of Mycobacterium tuberculosis.