Concurrent infections and HIV pathogenesis

Introduction The progression towards AIDS in HIV-1-infected individuals appears to be directly related to CD4 cell count decline and HIV-1 viral loads in the plasma and lymphoid tissues [1]. Though several factors account for the wide variations in HIV-1 disease progression, immune activation is probably the most important determinant for these differences. Activation of host immune cells (primarily CD4 cells, macrophages and dendritic cells) facilitates multiple steps of the viral life cycle and cellular factors that are directly or indirectly connected with it. These include up-regulation of the viral co-receptors (CCR5 and CXCR4), decreased β-chemokine secretion [2], enhanced viral entry and integration as well as viral assembly and/or release [3]. Immune activation also leads to profound changes in the cytokine network, with increased secretion of tumor necrosis factor-alpha (TNF-α), interleukin (IL)-2, IL-4, IL-6 and IL-10, and affects the cell cycle [4,5]. Immune activation is also associated with various degrees of immune dysfunction, hyporesponsiveness and apoptosis, all leading to enhanced progression of immune deficiency and decreased survival [6–11]. Thus, since all concurrent infections, whether systemic or local, will lead to various degrees of immune activation in vivo, it is plausible that they may enhance HIV infection, increase HIV replication and viral load, and accelerate the progression of disease [12–14] (Fig. 1).Fig. 1.: Possible mechanisms for the effects of concurrent infections on susceptibility and progression of HIV infection. Numbers in brackets represent the reference number in the text.Several features of the AIDS epidemic in Africa mark it as a distinctive entity in comparison to that in other areas of the world. It seems that HIV is transmitted more easily, the clinical manifestations are quite different and its progression is faster, [15–19]. However, the issue of progression is not confirmed, due to lack of sufficient controlled studies [20,21]. The above-cited features are probably responsible for the catastrophic dimensions of the epidemic in Africa and Southeast Asia where the prevalence of the infection in adults has reached 30% or more [22]. We have suggested previously that chronic immune activation of the host, by helminthic and probably also by other infections, may account, at least in part, for these dramatic differences in the behavior of the epidemic [23,24]. The immune activation, we argued, makes the host more susceptible to HIV infection and less capable of handling the infection once it is acquired. We have accumulated several lines of evidence that lend support to these general ideas [25–31]. A large number of clinical observations have indicated that the presence of concurrent infections – sometimes preceding, and often following the infection with HIV, may influence the course of HIV infection, and concomitantly, HIV infection may alter the course and manifestations of other infections. It is the purpose of this article to review these observations, and particularly those that shed light on our understanding of the pathogenesis of HIV infection, and on possible implications for intervention therapy. It is especially distressing that in those regions where the spread and impact of the AIDS epidemic is the most alarming, antiretroviral therapy is not available. It is in these regions in particular, that treatment of concurrent infection may be feasible, and that such intervention may have substantial influence on the epidemic. This is also why we have limited ourselves in this review to the major bacterial and parasitic diseases and excluded viral infections, though the importance and potential role of viral infections in affecting host immunity is very significant. For similar reasons, we have also decided not to include in this review opportunistic infections such as toxoplasmosis, Pneumocystis carinii and oral candidiasis. Bacterial infection Sexually transmitted diseases There is strong epidemiological evidence that sexually transmitted diseases (STD), particularly those associated with genital ulceration, significantly increase the risk of acquiring HIV-1 infection (Table 1). The high prevalence of ulcerative STD may contribute to the rapid expansion of the HIV-1 epidemic in sub-Saharan Africa [32]. Common bacterial infections associated with genital ulcerative disease are Haemophilus ducreyi (chancroid) and Treponema pallidum (syphilis), while those associated with non-ulcerative diseases include Neisseria gonorrhea and Chlamydia trachomatis[33,34]. Several studies show that infection with chancroid and syphilis is associated with an increased relative risk of HIV infection and with increased HIV viral loads for both men and women [34,35]. In vitro studies have shown that T. pallidum as well as its associated lipoproteins, induce HIV gene expression in monocytes through a nuclear factor NF-κ B pathway [36].Table 1: Interaction of different concurrent infections and HIV. Infection with non-ulcerative agents such as N. gonorrhea and C. trachomatis is more prevalent among HIV-infected patients than genital ulcerative agents [37]. This finding brings into focus the question of the mechanisms by which STD enhance HIV transmission. While genital ulceration would make HIV transmission easier, it is evident that the inflammatory exudate, present at the site is probably the main cause for facilitation of HIV transmission, even within ulceration. Such exudates consist of CD4 cells, monocytes and Langerhans’ cells, many of them infected with the virus and also immune activated in response to the infection, which enhances viral replication in these cells. This observation has been made in women with non-ulcerative STD infection [38], as well as in HIV-infected men with urethritis caused by gonorrhea, Chlamydia and Trichomonas. Higher seminal HIV RNA levels have been found in men with urethritis than in men without it [39]. It is therefore expected that anti-microbial treatments will substantially decrease the HIV RNA levels in both ulcerative and non-ulcerative disease [35,39], and that successful treatment of STD, will greatly reduce the transmission of HIV. To further prove this possibility, two large community-based STD intervention studies were undertaken in Tanzania (Mwanza) [40] and Uganda (Rakai) [41]. While the Mwanza study revealed that almost 40% of HIV infections had been prevented in the communities receiving antibiotic intervention, the Rakai study found that no HIV infections were prevented in the intervention communities. The interpretation of this ‘unexpected’ discrepancy is not clear. One interpretation is that the AIDS epidemic was at different stages in the two areas [42]. The Mwanza results could reflect the short-term impact of STD prevention and control in an immature epidemic, whereas the Rakai project study reflects the short-term impact in a mature epidemic. Another interpretation, is that in the Rakai study the control arm received the antihelminthic agent albendazole and thus the eradication of the helminths in that arm had a similar effect on HIV viral load as the anti-microbial treatment, and therefore the lack of difference between the two arms (see below). In any case, the overall evidence that STD enhance HIV transmission is compelling, and suggests that prevention and control of STD before or early in an HIV epidemic will have a major impact on the spread of HIV. Mycobacterial tuberculosis Tuberculosis is the most common major opportunistic infection affecting HIV-infected individuals worldwide. In the last decade of the millennium it is estimated that 8 000 000 cases of tuberculosis attributable to HIV infection will occur with 2 900 000 deaths [43]. The main burden of HIV-associated tuberculosis is in Africa and Asia where access to antiretroviral therapy is extremely limited. It is in these areas that the natural history of HIV-associated tuberculosis is best studied and where potential interventions would have the greatest benefit. The normal host immune response to tuberculosis is characterized by vigorous cellular activation resulting in a Th1 cytokine response and granuloma formation [44]. The pro-inflammatory cytokine TNF-α plays a central role in granuloma formation and containment of infection [45]. In HIV-infected patients with tuberculosis, levels of TNF-α are considerably higher than in HIV seronegative patients [45,46]. Longitudinally, TNF-α remains elevated whereas levels of IL-6, soluble IL-2 receptor, interferon (IFN)-γ and TNF receptor decrease [45,46]. The levels of TNF-α remain persistently elevated despite a reduction in cellular activation markers indicative of probable dysregulation of cytokine production [46]. In vitro infection with Mycobacterium tuberculosis or exposure to purified protein derivative leads to cellular activation which induces viral replication [47]. Enhanced HIV replication is due largely to the effect of pro-inflammatory cytokines [48,49], particularly TNF-α and IL-6 [49]. The pro-inflammatory cytokines enhance HIV replication in part by activating the nuclear activating factor NF- κ B which in turn lead to transcriptional activation of the HIV-1 long terminal repeat gene [50]. Live M. tuberculosis and its products, purified protein derivative and lipoarabinomannan, have been shown to activate NF- κ B [50–52]. In addition, tuberculosis induces up-regulation of the chemokine receptor CCR5 which is an important co-receptor for HIV [53]. Enhanced local replication of HIV has been shown at the site of disease in patients with pulmonary tuberculosis [54]. Viral load increases during active tuberculosis and decreases with effective therapy in anecdotal cases from industrialized countries [47]. However data from African patients with no access to antiretroviral therapy indicates that viral load does not decrease despite effective therapy [46,55–58]. One study found that viral load reduction occurred with anti-tuberculous therapy only in patients with higher CD4 lymphocyte counts [59]. In the simian model of AIDS with SIV infection, Bacille Calmette–Guerin (BCG) infection resulted in T-cell activation, increased viral load and led to accelerated progression to AIDS [60]. Clinical studies assessing whether tuberculosis accelerates HIV are contradictory. Retrospective case–control studies in HIV-infected patients with tuberculosis show increased mortality [61,62] or increased occurrence of opportunistic infections [63]. However, studies that compared tuberculosis patients with patients with other AIDS-defining conditions found no evidence of disease acceleration by tuberculosis [64,65]. These studies were done in industrialized countries with access to antiretroviral therapy. We have recently completed a prospective cohort study in which we found increased mortality and opportunistic infections in HIV-infected patients with tuberculosis [66]. Notably, we found that the effect of tuberculosis on survival was lost in patients with AIDS or a CD4 lymphocyte count < 200 × 106/l presumably because these patients have advanced disease and further acceleration is difficult to detect. The strongest evidence that tuberculosis enhances the progression of HIV disease is the fact that effective preventive therapy for patients at risk of tuberculosis (those with a positive tuberculin skin test), confers a survival benefit [67]. Taken together, the in vitro evidence that tuberculosis leads to enhanced HIV replication is overwhelming, and the in vivo evidence, particularly from Africa (where most patients are antiretroviral-naive), strongly suggests that tuberculosis does lead to an accelerated course of HIV disease. This finding has important implications, especially for poor countries where access to antiretroviral therapy is extremely limited. Early recognition and treatment of tuberculosis are clearly important. Preventive therapy is effective and should be widely implemented. Immunomodulation of HIV-associated tuberculosis requires further study. Helminthic infections Helminthic infections are probably the most common and prevalent infections in most or all of the developing countries. Altogether, one-quarter of the world's population is infested with these infections. The total estimated number of infected people is over one and a half billion [68,69]. These are chronic infections acquired in early childhood, people are infected with more than one parasite, and many of them persist into old age unless cured. Epidemiologically, there is a remarkable similarity in the geographic distribution of the helminthic infections, particularly in Africa, to that of HIV and tuberculosis [70] (Fig. 2). This raises the question of whether there are possible causal links between these infections. In the following sections, we shall try to summarize the evidence in favour or against such links and especially on the effects of helminthic infections on the immune response of the infected host.Fig. 2.: The distribution of helminths (Ascariasis, Trichiuriasis and hookworm infections), HIV/AIDS cases and tuberculosis incidence in Africa. Data from [93].All helminthic infections are associated with strong chronic immune responses that have some common features to them. These are eosinophilia, high serum IgE, and a dominant Th2 cytokine profile with increased IL-4, IL-5 and IL-10 secretion [25,28,71,72]. This cytokine profile may, however, vary during the same infection, such as switch from Th1 to Th2 during Schistosoma infection, or in different helminthic infections, such as filariasis [71,72]. There are conflicting reports as to IL-2 and INF-γ secretion, though it seems that they are not increased above normal levels [71–73]. Most importantly, the chronic immune activation caused by the chronic infection, results in wide immune dysregulation that is manifested by: (i) changes in peripheral lymphocyte populations: decreased CD4 and CD4 : CD8 ratios with increased proportion of activated cells and apoptosis [25,28,74]; (ii) impaired immune response to recall antigens [75]; (iii) impaired signal transduction and anergy ([76], G. Borkow, L. Quibin, A. Kalinkovich, Z. Weisman and Z. Bentwich, unpublished data). These changes are related to helminth burden and duration of infection, are reversible and will disappear following the eradication of the geohelminthic infections. The rate of ‘normalization', however, differs for different elements of the immune response [78,79]. In more recent studies carried out in Israel on Ethiopian immigrants, the changes in the immune system were shown to be caused by the helminthic infections and not by other environmental influences, such as nutrition, hygiene, or other infections ([80], Z. Weisman, A. Kalinkovich, M. Stein and Z. Bentwich, unpublished data). The immune profile associated with the helminthic infections, may skew the host's immune response towards a Th2 type as has been shown in several studies (summarized in [23,71,72,81–86]): (i) in the presence of a dominant Th2 profile, the immune response to other antigens is skewed towards a Th2 type response; (ii) the ability to a cellular response will be impaired in (iii) of is impaired in immune response and anergy will chronic helminthic the immune response to with progression of the infection and with helminth Taken together, these clearly that the immune system of the host is and therefore is expected to quite from that of the is the of these to the between geohelminthic infections and HIV and (i) the occurrence of HIV and tuberculosis and of tuberculosis, are more in the poor where helminthic infections are prevalent (ii) chronic immune activation due to helminthic infections is associated with increased expression of HIV both CCR5 and as well as with increased susceptibility for HIV infection in vitro (iii) helminthic load of is with increased HIV plasma viral load eradication of helminthic infection may in relative reduction of HIV plasma viral load, though this probably on type and load of helminth infection unpublished HIV progression is in regions in Africa where helminthic infections are common and similar to rate helminthic infections are cellular immunity to tuberculin is impaired in areas for tuberculosis and infested with helminths and may be helminth eradication is against tuberculosis in most developing countries where helminthic infections are and the response to treatment is by a decrease in eosinophilia, the of successful treatment on a Th2 to Th1 and helminth eradication There however, some these observations, particularly since they have been made in poor that from to and not from helminthic infections Though our studies in Israel and have some of these Weisman, A. Kalinkovich, M. Stein and Z. Bentwich, unpublished there is a for and epidemiological and studies to them. It is important to show whether in where on a large has there is a decrease in HIV and tuberculosis infection also whether such is by decreased HIV viral load and progression of the and not less importantly, whether of immunity to HIV will be However, the for is well made because of its in the of large eradication of helminthic infections the poor in the of the AIDS epidemic, should be and even the are only probable or infections is as a it more often in HIV-infected even in areas The HIV-infected host not only is more susceptible to infection with present in the is also to of a infection It in the areas for also in the where may be present especially in and particularly in and It is of that some HIV-infected patients were found to of active antiretroviral therapy and of HIV replication Though the interpretation of this finding is not it would that immune and of anergy associated with contribute to the active similar to the activation of some diseases following it be due to the Th2 immune activation in the of cell following Several of the features of infection are of HIV infection. In there is a decrease of CD4 the immune activation profile is and a dominant Th2 profile is present HIV infection and both induce changes and these effects are they occur concomitantly, such as the Th1 to Th2 switch with HIV-infected patients without patients show a cytokine profile with in IL-4, IL-10 and and decreased production of CD4 cell count and high viral load are also features of this infection increases HIV probably due to a of immune activation antigens were found to HIV replication in peripheral cells and in cells infected in mechanisms were shown to be in this (i) cellular activation increases expression of cellular immune activation markers within the CD4 (ii) increased secretion of IL-2 and (iii) accelerated rate of apoptosis of CD4 cells with and by successful treatment of and is associated with a decrease in TNF-α levels antigens also induce natural cells and CD8 T-cell responses in resulting in or In those active natural cell is with enhanced CD4 cell which results in enhanced HIV viral replication the major the gene TNF-α which is enhanced by that results in leading to levels are at the of infection, is and this leads to of production has an ability to gene of and TNF-α In a model of L. by 8 infection a reduction of IL-2 was in of cells. The is both an impaired IL-2 production to cell activation and a in IL-2 The treatment of in HIV-infected patients may have dramatic effects on and mortality of the patients from the infection However, the rate of the is not since the treatment does not the infection, to the is also not of the in infected patients decreases HIV plasma viral load significantly as has been recently in These clearly that treatment of may decrease and reduce progression of HIV infection, and should be there is for active disease in HIV-infected patients of antiretroviral In Africa, HIV infection is the most and is one of the most prevalent a between and HIV has not been there is substantial evidence that these two may with and the pathogenesis of disease. have indicated that mortality is higher in to with and and that HIV-1 infection a ability to infection In vitro studies have shown that exposure of from to soluble antigens or from enhanced HIV-1 replication by The HIV-1 replication through of TNF-α and activation of long terminal viral recent studies with from individuals in indicated that recall immune responses by soluble increase HIV-1 replication L. A. A. unpublished data). studies that a widely in Africa for the treatment of and has an in vitro effect associated with and/or these data be confirmed, may be in the treatment of patients with HIV-1 infection. in the developing where the burden of both HIV-1 and it may be the most intervention There is some evidence that may HIV viral Several studies have that and its HIV-1 replication in In addition, the of HIV-1 an in HIV replication A prospective cohort study of adults with active and adults without in revealed that individuals with active had plasma HIV-1 viral load higher than individuals without with resulted in reduction in HIV-1 RNA load in individuals with HIV and at Thus, there is a potential for and intervention Several The between HIV-1 and in women has shown increased occurrence of in and and mortality in to with infection It is however, whether has increased HIV viral load in or caused to as a of of these would increase transmission of HIV. There is a to the effect of HIV infection on the of and on the and of in in and have transmitted HIV infection. The parasitic of the vary greatly in importance as potential opportunistic African is no more common or during AIDS however, data are extremely limited. A case–control study in Africa the between HIV virus infection and African and found no difference between the prevalence of HIV infection in patients and is characterized by major of the immune system with and as features In not cytokines such as and by activated macrophages has an effect induces The of the immune system leads to of and cytokine The with however, is different the is not clearly there appears to be a of infection, which lead to studies have immune by from chronic patients The between and cytokines may disease control or progression, as was shown in the in vivo model T. the expression of lymphocyte CD4 and in the between cells and as well as the expression of T-cell receptor and Taken together, it is that may be an opportunistic infection in HIV-infected and that it has profound effects on the immune system of the However, its role in or the infection and progression of HIV infection is not and epidemiological We have to present the of the major infections with HIV infection, and the results of the between them. A common to all these infections is the immune activation associated with which is an part of the immune response they Though the type and of such immune activation are not the same in the various infections, the is often of the infection and replication of the since immune activation probably plays a major role in the pathogenesis of HIV infection, its presence before or during entry of the virus to progression and of the immune Thus, the most important that be at this is that eradication or of concurrent infections may have a major impact on the spread and progression of HIV infection and as well as on the of HIV This particularly to the developing where these infections are common and where access to antiretroviral therapy is not available. studies are to and further (i) the of concurrent infections on the spread and progression of HIV and and (ii) the changes in the immune profile and in the immune response of the host infected with concurrent infections. The A. for the in and this