Neuroimmunomodulation by opiates: relationship to HIV-1 infection and AIDS

Advances in Neuroimmunology Vol. 3, pp. 31 46, 1993

0960 5428/93 $24.00 © 1993 Pergamon Press Ltd

Printed in Great Britain. All rights reserved

Neuroimmunomodulation by opiates: relationship to HIV-1 infection and AIDS Robert M. Donahoe Laboratory of Psychoimmunology, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Georgia Mental Health Institute, 1256 Briarcliff Road, Atlanta, GA 30306, USA

Summary Opiate addiction is a major risk factor for acquired immunodeficiency disease syndrome (AIDS). Since alkaloid opiates and endogenous opioid peptides have been shown to affect immune function, there is considerable interest in understanding whether opioids themselves play any direct or indirect role in modulating expression of HIV-1 and the development of AIDS in heroin addicts. This issue is difficult to address for two main reasons. The addictive liabilities of opiates prohibit direct controlled assessments of their effects in humans and epidemiological assessments of heroin addiction are compromised by the association of addiction with a variety of interdependent milieu cofactors, aside from opiates themselves, that have the independent potential to modulate immune function and viral expression. Accordingly, experimental evidence attained through in vitro and in vivo studies with animal models and human blood cells must supplement clinical observations to obtain the best possible estimate of the potential of opiates to modify host responses to HIV-1 infection and the development of AIDS. Reviewing current evidence from this perspective indicates that there is substantial support for the notion that opiates can affect both immunological and virological processes that dictate the pathogenesis of HIV-1 infections. However, the influence exerted by opiates appears to be conditionally dependent on the stage of opiate dependency. Thus, a wellmaintained opiate dependency can be ben-

eficial to host defense systems while poorly maintained dependencies can be quite disruptive. Such information has relevance, not only to the AIDS situation per se, but, also, to therapy of drug addiction and to the field of neuroimmunomodulation in general.

Discussion Introduction Not long after acquired immunodeficiency disease syndrome (AIDS) was described as a medical entity (Gottlieb et al., 1981; Masur et al., 1981; Siegal et al., 198 0 , it became evident that intravenous (i.v.) drug abusers constituted a major high-risk group for contraction and spread of this disease syndrome (Wormser et al., 1983). According to statistics from the Centers for Disease Control, over 30% of HIV-l-infected individuals in the United States currently have a history of i.v. drug abuse. In many of these cases, heroin is the predominant drug of abuse. Because of the association between opiates and AIDS, there has been intense interest in knowing whether opiates themselves modulate the expression of HIV-1 infection and development of AIDS. There is, in fact, considerable circumstantial evidence to support a role for opiates in this regard, including epidemiological evidence. However, a number of recent epidemiological studies have indicated that there is no direct connection between opiates and AIDS. 31

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Therefore, the current review is intended to survey selected evidence of relevance to this issue. Based on an interpretation of this evidence, a conceptual model of the potential connection between opiates and AIDS is also presented.

Evidence questioning a direct role o f opiates in A I D S

There are numerous data supporting the notion that opiates may influence the outcome of infection with HIV-1. Some of these data come from epidemiological studies of AIDS itself such as the studies of DesJarlais et al. (1987) and Stoneburner et al. (1988). However, several very recent epidemiological studies have concluded that opiate abuse is not likely to cause exacerbation of HIV-1 infection and development of AIDS in any direct way (Kaslow et al., 1989; Farizo et al., 1992; Zenilman et al., 1992). Thus, epidemiological assessments of the role of opiates in AIDS have resulted in equivocal findings that are not very satisfying from a public health standpoint. Therefore, to maintain a proper perspective on this issue, it is essential that the limitations of epidemiological assessments of addiction are thoroughly appreciated. Street heroin addiction is associated with complex psycho-social and biomedical dynamics. Besides opiates themselves, there are numerous interdependent factors in the typical heroin-addiction milieu with the independent potential to influence infectious and immunological processes of possible relevance to development of AIDS. To illustrate the importance of cofactors in this situation, one can point to the fact that most epidemiological studies of heroin addiction fail to adequately consider the confounding influence that cocaine use can have on study-outcome. This is an important consideration because cocaine abuse is prevalent

among heroin addicts and appears capable of countering immunodepressing effects of opiates (Donahoe et al., 1986, 1991). Similarly, most epidemiological studies of addiction ignore the effects of different styles and durations of drug abuse on study-outcome. This is an important consideration since duration of opiate-dependency and patency of that dependency are critical to the immunological status of addicts as documented by studies showing that very long-term addiction (>10 years) is more immunologically detrimental than relatively shorter-term addiction (Donahoe and Falek, 1988; DesJarlais et al., 1987) and by studies indicating that tolerance to the immunomodifying effects of opiates develops in parallel with classical pharmacological tolerance (Meisheri and Isom, 1978; Dafny, 1983; Shavit et al., 1986b; Bryant et al., 1990; Donahoe et al., 1991, manuscripts in preparation). Furthermore, the addiction milieu is characterized by factors with immunomodulatory potential that are likely to impact on expression of AIDS even though the extent and nature of their effects have never been defined in an addiction setting. The generally poor nutritional status of addicts as well as their frequent encounters with a variety of drugs, infections and foreign antigens and with stress are all relevant in this regard. Similarly, the illicit nature of drug abuse and the psychodynamics of addiction make unbiased subject selection and data collection in epidemiological studies of heroin addiction a very difficult task. In summary, the addiction milieu is notoriously complex. This complexity makes it impractical to expect epidemiological assessments to delineate effects of opiates alone in regard to specific biological consequences of addiction. This situation demands that more directed types of experimental approaches be considered in helping to estimate the potential of opiates to influence the course of AIDS.

AIDS and opiates Evidence which supports a direct role for opiates in A I D S

We (Donahoe and Falek, 1988; Donahoe, 1990) and others (e.g. Friedman et al., 1991) have reviewed the topic before, about whether opiates contribute to the process of HIV-1 infection and development of AIDS. Salient points of these reviews are presented here along with selected new data of relevance to the topic. Several distinct yet interdependent lines of evidence are presented in the ensuing discussion as support for the notion that opiates may participate directly in expression of HIV-1 infection and AIDS. One such body of evidence relates to clinical and epidemiological observations in the preAIDS era which suggest that opiates have immunomodulatory properties. There is also a large body of evidence that alkaloid opiates modulate immunity in both in vivo and in vitro experimental systems. In a similar vein, there is considerable experimental evidence that the endogenous opioid system is intimately involved in modulation of the immune system (the neuroimmunomodulation literature). Finally, there is an important, emerging literature indicating that opiates and opiate-dependency influence expression of HIV-1 virus and other viruses of relevance to AIDS.

Clinical and epidemiological evidence that support a role for opiates in modulating resistance to infectious disease

Epidemiological and clinical studies of heroin addiction conducted before the AIDS-era have certain advantages over those conducted afterward because HIV-1 infection and AIDS themselves serve as confounding variables and because studies in the pre-AIDS era often were conducted without the confounds of concomitant cocaine abuse. Accordingly, pre-AIDS epidemiological studies on heroin addiction offer valuable, possibly unique, perspec-

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tives on the potential of opiates to modulate immune functioning and resistance to opportunistic disease in heroin addicts. In 1950, Hussey and Katz reported that the frequency of infectious complications of opiate abuse had increased dramatically in the decade prior to their report. They noted that this increase was associated with a trend for heroin addicts to share drug paraphernalia, particularly drug-injection equipment. They also noted an increase in infectious complications in addicts to opportunistic diseases like tuberculosis and suggested that opiates themselves may have been involved. During this time, also, clinicians frequently observed that heroin addicts suffered from an enlargement of peripheral lymph glands, known as 'addict's nodes', that could have been suggestive of immune disturbance (and which are intriguingly akin to the lymphadenopathy of AIDS-related complex). Following the milestone report of Hussey and Katz (1950), the infectious complications of addiction continued to be documented consistently throughout the 1960s (Sapira, 1968) and 1970s (Louria, 1974). Then, in the 1970s, reports began to appear that heroin addicts frequently exhibit depressed and altered immune functions as analyzed by ex vivo types of studies. Falek, et al. (1972) reported that heroin addicts experience increased levels of chromosomal damage in leukocytes analyzed cytogenetically. Brown et al. (1974) showed that T-cell responsiveness to mitogenic stimulation is depressed with leukocyte preparations from heroin addicts and that immunoglobulin production was elevated in heroin addicts--the latter finding being attributed to the frequent bacterial infections encountered by addicts. Around this time, also, reports appeared that opiate abuse is associated with elevations in the incidence of several forms of cancer (Harris and Garret, 1972; Hewer et al., 1978; Sadeghi, et al., 1979). In the 1980s, specific T-cell deficits were recorded

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in heroin addicts related to their ability to form rosettes with sheep erythrocytes (E) (McDonough et al., 1980) and to depressed ratios between T-helper and T-suppressor lymphocytes (Layon et al., 1984; DesJarlais et al., 1985; Donahoe and Falek, 1988). It is particularly important to this discussion to recognize that the studies of heroin addiction reported by McDonough et al. (1979) were not confounded by the influence of concomitant cocaine abuse. Equally important is the fact that the major finding of this study, that the ability of T-cells to form rosettes with sheep erythrocytes (E) is depressed with lymphocytes from heroin addicts, corresponded with results of a study by Wybran et al. (1979) which showed that morphine depresses E-rosette formation in vitro. Thus, the absence of at least one known experimental confound in the study of McDonough et al. (1979) and the consistency between in vivo and in vitro effects of opiates that were identified by the studies of McDonough et al. (1980) and Wybran et al. (1979) lend support to the notion that depressed T-cell function in addicts is actually attributable to some direct effect of opiates on T-cells in vivo. During the years when immune deficiencies were first being described in heroin addicts, probably the most accepted prevailing hypothesis for these effects was that addicts suffer immunologically due to immune paralysis caused by antigenic overload. The logic of this hypothesis rests with the fact that addicts are almost constantly exposed to foreign substances as a result of their drug-injection practices and their frequent exposure to infections. This hypothesis remains viable today, but the works of Wybran et al. (1979) and McDonough et al. (1980) discussed above changed the perspective on how antigenic overload should be thought to influence immune function in addicts. That is, it is best to consider antigenic overload as a cofactor with opiates in modulating host immunity.

In 1985, Tubaro et al. published a report that is of particular relevance to consideration of the immunomodifying potential of opiates for man. They showed that morphine injected into opiate-addicts depresses phagocytic function but not T-cell E-rosette formation. The inability to find deficiencies in T-cell E-rosette formation in this study conflicts with the results of the study by McDonough et al. (1980) discussed above (and other similar studies). The reason for this difference appears to be related to differences in paradigms used for these two studies. The study by Tubaro et al. (1985) is, in fact, distinctive to the field of opiateimmunology research. In this study, controlled doses of morphine were given regularly to heroin addicts to maintain opiatedependence while immune function was assessed. In contrast, all other reported studies of the immune status of heroin addicts have used study-subiects recruited proximal to the time of their admission to addictiontreatment centers so that the addicts being studied are in varying states of opiatetolerance and opiate-withdrawal. Thus, it is distinctions in relative states of opiatetolerance that appear to be the main reason that the findings of Tubaro et al. (1985) differ in regard to T-cell E-rosette formation from those of McDonough et al. (1979). Such reasoning is supported by the findings of Shavit et al. (1986b), Bryant et al. (1990) and Donahoe et al. (manuscripts in preparation) who showed, using animal models of addiction, that opiate-tolerant animals do not exhibit cell-mediated immunological deficiencies while nontolerant animals, and, especially animals in the acute phases of opiate withdrawal (Donahoe et al., 1991, manuscripts in preparation), experience marked deficiencies in cell-mediated immune function. In conclusion, .data..from clinical studies of the immunological effects of opiates that were conducted before the AIDS era, or,

AIDS and opiates at least, without the complications of AIDS involvement, are suggestive that opiates do influence immune functions in heroin addicts. Whether this type of immunological influence is material to development of AIDS, however, has yet to be determined in any definitive way, although the suggestion is strong that it does.

E v i d e n c e f r o m experimental models that opiates are i m m u n o m o d u l a t o r s

Aside from clinical and epidemiological data, there are considerable experimental data to indicate that alkaloid opiate narcotics (opiates) modulate immune function. As long ago as 1898, Cantacuzene reported that morphine modulates the expression of chemotactic and phagocytic activity in in vitro and ex vivo experimental systems. This information was confirmed in 1909 by Archard et al. and substantiated much later, in the modern era, by Ruff et al. in 1985. The considerable gap between the earliest experimental descriptions of the immunological effects of opiates and more recent studies probably reflects a relative lack of clinical concern as well as a lack of understanding of basic immunological and pharmacological principles in earlier times. As discussed previously, it was not until 1950 when Hussey and Katz first reported the abnormal susceptibility of heroin addicts to infectious disease. At the basic scientific level, the association between immune dysfunction and opiates was not fully appreciated until the 1970s when a series of studies secured the notion that opiates can serve as immunomodulators. Among these studies, the ones listed below are probably most responsible for placing the thesis that opiates have immunomodulatory properties on sound scientific footing: (1) the definition of opiate receptors by Goldstein et al. (1971), Pert and Snyder (1973) and Simon et al. (1973);

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(2) the discovery by Hughes et al. (1975) of endogenous opioids; (3) the finding by Wybran et al. (1979) that the ability of T-cells to form E-rosettes was affected in a naloxone-reversible and stereospecific way by in vitro exposure of T-lymphocytes to morphine and to the endogenous opioid, met-enkephalin. Of course, it was the work of Wybran et al. (1979) which provided the key immunological piece of the puzzle. This work showed that Tcells themselves are likely to have cell-surface receptors for opiates that could directly mediate the immunomodifying properties of these drugs. In fact, in 1980, Lopker et al. reported that phagocytes have pharmacologically relevant opiate receptors and, since then, a number of studies have described opiate receptors on T-cells through the application of classical pharmacological procedures (reviewed by Madden and Donahoe, 1990). Following the seminal descriptions of in vitro immunological effects of opiates, a variety of reports corroborated these effects. Most recently, Taub et al. (1991) elegantly demonstrated that immune responses generated in vitro and characterized by antibody production are sensitive to the stereospecific effects of various types of opioid-receptor agonists. As well as effects of opiates on T-cells, a body of literature has also accumulated that monocyte/macrophage functions are altered by opiate exposure in vitro, although these effects appear to be T-cell mediated (Sharp et al., 1985; Peterson et al., 1987). Notably, NK-cell function, however, does not seem to be affected in in vitro paradigms of opiate exposure (Kreek, 1991), although this appears to be a controversial subject (Kay et al., 1984). At the same time that in vitro data regarding the immunomodulatory effects of opiates were accumulating, a number of in vivo experiments showed that administration of opiates to animals could cause measurable immunological changes. Indeed, immunological changes in response to opiate

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exposure have been identified in such varied experimental species as mice, rats, swine and monkeys--a fact which helps secure the relevancy of these findings to the human circumstance of opiate-dependency. The studies of Gungor et al. (1980) and Tubaro et al. (1983) were the first to substantiate the potential of opiates to modulate host resistance to opportunistic disease when they showed that mice injected with morphine experience immune changes and become abnormally susceptible to bacterial infection. Ex vivo analyses have also substantiated the immunomodifying effects of opiates in vivo. For example, in the studies of Tubaro et al. (1983), animals injected with morphine were shown to have deficient macrophage function. Ex vivo analyses have also shown that exposure of animals to opiates alters various T-cell functions (Weber et al., 1991) and NK-cell activity (Shavit et al., 1986a; Novick et al., 1989; Yeager et al., 1992). Furthermore, most studies of this type have indicated that celltrafficking within the circulatory system and within organs of the immune system is frequently and variably altered when animals are exposed to opiates. For example, the studies of Bryant (1988) and Sei et al. (1991) showed that mice implanted with cellulose-pellets containing morphine experience acute, severe thymic and splenic atrophy. Also, several studies on the effects of morphine in rhesus monkeys have shown that circulating levels of various T-cell subtypes and other leukocytes are altered by opiates (Donahoe et al., 1990, 1991, manuscripts in preparation; D. J. Carr, personal communication). Analyses of the in vivo effects of opiates in experimental animal systems revealed that the immunomodifying effects of opiates are related to centrally controlled responses to the opiates, bringing these observations into the realm of neuroimmunomodulatory phenomena. Shavit et al. (1986a) were the first to provide convincing evidence that opiates require central neurological mediation in

the expression of their immunomodifying effects. Their studies were concerned with NK-cell activity and were followed by experiments of Weber and Pert (1990) which showed that a primary target for the mediation of NK-cell function by opiates is the periaqueductal gray region of the brain. Recently, Bayer et al. (personal communication) and Fecho et al. (personal communication) have found that central neurological mechanisms are also involved in modulating host T-cell responses. In addition, studies by Bryant et al. (1988), Sei et al. (1991) and Donahoe et al. (manuscripts in preparation) have shown that the neuroendocrine system is involved in the immunomodifying effects of opiates in both mice and monkeys. A summary view of relevant experimental data tends to suggest that the immunomodifying effects of opiates are quite div e r s e - e v e n , in some instances, conflicting. Various studies have indicated, however, that it is normal for immunological effects of opioids to be expressed in diverse and seemingly conflicting ways. Several studies have shown that opioids modulate immune phenomena differently in different individuals (Murgo et al., 1986; Oleson and Johnson, 1988; Kavelaars et al., 1990a) and under varying exposure conditions (Rowland and Tokuda, 1989) indicating that interindividual variability is a contributing factor in such diversity. Also, as discussed before, the relative state of tolerance to opiates is a very important aspect of the immunological manifestations of opiate exposure and dependency. Thus, diverse immunological effects are likely to be seen in heroin addicts in relationship to the pharmacological and behavioral spectrum of the drug-tolerant state. Indeed, a major theme of this review is that the immune effects of opiates in heroin addicts are conditionally expressed in respect to a wide variety of milieu and genetic factors that differ on an interindividual basis. Accordingly, it is logical to expect situations where it is 'normal' for the immune effects

AIDS and opiates of opiates to be variably benign, detrimental and, even, facilitatory (also see later discussion). In conclusion, there is considerable in vitro and in vivo evidence from experimental model systems that opiates modulate immune function. Since in vitro studies indicate that opiates act directly on cells of the immune system while many in vivo studies indicate that the immunomodifying effects of opiates are controlled centrally, ambiguity currently exists as to the relative contribution of direct versus indirect effects of opiates in modulating immune functions. Despite this ambiguity, however, there is every reason to believe that both direct and indirect types of effects are relevant to modulation of immune function by opiates. This fact, along with the fact that immune effects of opiates are expressed relative to the state of physiological and behavioral dependence, supports the conclusion that the immunomodulatory properties of opiates are mediated through the complex interworkings of the neuroimmune network. This theme is developed further in the ensuing section of this review. Natural opioid peptides also modulate the immune response

As mentioned previously, Hughes et al. (1975) was the first to validate the concept that endogenous opioids are involved in neural regulation. Not long after the discovery of peptide opioids, Wybran et al. (1979) conducted an in vitro analysis of the effects of opioids on E-rosette formation showing that methionine-enkephalin enhances the formation of T-cell E-rosettes. Around this same time, Miller et al. (1983) corroborated the E-rosette-enhancing effects of enkephalins in in vivo studies with human T-cells. Currently, three major classes of opioid peptides are known: endorphins, enkephalins and dynorphins (Pasternak, 1988). In turn,

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these opioids serve as prototypical endogenous agonists for three distinctive classes of opiate receptor: tz, ~ and K receptors, respectively. Since the seminal studies of Wybran et al. (1979) concerning the immunological effects of enkephalins were carried out, a large body of information has accumulated that each of these three classes of opioid peptides and receptors influence various aspects of immune functioning. For the most part, the same types of immune responses as are affected by alkaloid opiates, as described previously, have also been shown to be affected by one or another of the major classes of opioid peptides (see reviews by Plotnikoff et al., 1986; Heijnen et al., 1991). As discussed previously, it is notable that endogenous opioids can have both immuno-enhancing and immuno-depressing effects. At present, such variable effects are hypothetically attributable to varied causes that relate to the pharmacology and pharmacokinetics of these agents and the receptor-systems that they stimulate, as well as the physiological state of the host. Adding to the complexity of understanding the role of the endogenous opioid system in immune regulation is the fact that numerous studies have indicated that T-lymphocytes produce their own endogenous endorphins and enkephalins when activated by mitogenic stimuli which serve as autocrine factors in immune regulation (Smith et al., 1985). Consideration of an autocrine network of this type identifies closely with the issue discussed previously of the nature and purpose of direct effects of alkaloid opiates on T-cell function. Thus, it is likely that immunoreactive opioids work in concert with neural and neuroendocrine signals to regulate neuroimmune processes and it is equally likely that these processes are responsive to exogenous alkaloid opiates. The work of Kavelaars et al. (1990b) which showed that in vitro stimulation of lymphocytes with [3-adrenergic

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agonists induces release of immunoreactive [3-endorphin, is particularly noteworthy in this regard. Such findings are also consistent with the recent work of Fecho et al. (personal communication) that immune effects of morphine are mediated in part by [3-adrenergic activity in vivo. These considerations provide a strong link between neuroimmunomodulatory theory and the role of opiate addiction in modulating immune function. In conclusion, the involvement of the endogenous opioid system in modulation of immune function indicates that the immunomodulatory effects of alkaloid opiates are most likely connected with the neurological and neuroendocrinological properties of these drugs. Because of the complexity of the neuroimmune network, it is obvious that considerably more research is needed to specify the ways that such effects lead to deficient immunocompetency in heroin addicts. Opiates as virological modulators and their potential role in HIV-1 infection and A I D S

Although the mechanisms involved are yet unclear, it is certain that infectious processes related to expression of HIV-1 virus are relevant to the development of immune deficiency and the ensuing infectious and oncogenic sequelae that characterize the AIDS syndrome. A likely scenario for expression of these processes (Ascher and Sheppard, 1991; Fauci et al., 1991) is that HIV-1 viral genomes are harbored in plasmids in quiescent CD4+ T-lymphocytes and are caused to be integrated into the DNA of these cells when the cells are activated through immunological recognition of antigen or other nonspecific means (Bukrinsky et al., 1991). Virus is then reactivated from the lymphocytes through various disturbances to T-cell homeostasis. At the same time, infectious particles are generated in macrophages and other cell types capable of harboring HIV-1 virus. Over time, it is felt

that more virulent virotypes are generated by these processes through a sequence of events related to viral mutation and natural selection. As time passes and viruses increase in virulence, the propensity of these virotypes for infecting CD4+ T-cells increases also. This infection causes the CD4+ T-cells to become increasingly susceptible to formation of immunodeficient intercellular syncytia and to cell death. Eventually, as CD4+ cells are destroyed, the balance between CD4+ T-cells and CD8+ T-cells collapses and the affected host suffers from a loss of immunocompetency. It is suspected, also, that autoimmunity plays a role in promoting the development of AIDS as does infection of the brain. Such considerations could be pertinent to development of AIDS in many unspecified ways. Several reports have recently identified a role or possible role for opiates in the types of virological processes that are likely to be involved in development of AIDS. Peterson et al. (1990) have shown that morphine can cause induction of HIV-1 in replicating cultures of HIV-l-infected T-cells. If such effects are relevant to in vivo circumstances of opiate-dependency, then it is logical to presume that they are connected with development of AIDS. Furthermore, studies from my own laboratory (manuscripts in press and in preparation) have indicated that opiates influence expression of the sooty mangabey strain of simian immunodeficiency virus (SIVsmm) in monkeys, while Risdahl et al. (personal communication) have made similar observations about expression of herpesvirus in a swine model. Consideration of the specifics of the monkey and swine studies of Donahoe et al. and Risdahl et al., respectively, are helpful in judging the potential of opiates to affect expression of AIDS. Perhaps the most notable, even surprising, observation from these studies relates to the fact that opiate-dependency protects animals from some of the pathological manifestations that

AIDS and opiates are usually associated with the respective viruses used in these studies, most especially their lethal effects. In contrast, when opiatedependent monkeys infected with SIVsmm were subject to opiate-withdrawal, latent SIVsmm virus was induced to a low-level of transient expression. Thus, these studies indicate that viral expression is variably suppressed or enhanced in opiate-dependent animals in respect to the status of the dependency (i.e. whether tolerance is maintained and withdrawal avoided). Furthermore, as shown by Cardan (1984) and Gierarts et al. (1987), latent herpesviruses also appear to be induced when opiate exposure is novel, in therapeutic settings. Such information identifies with findings discussed previously about how opiate-tolerant animals and humans generally seem to exhibit a lack of T-cell disturbances which are, otherwise, prominent in acute opiate exposure and during opiate withdrawal. Notably, also, the monkey and swine studies of Donahoe et al. (1991, manuscripts in preparation) and Risdahl et al. (personal communication), respectively, showed that opiate-dependent animals are more susceptible to bacterial infections at the same time that their susceptibility to viral infection is lessened. Such effects may be related to the observations of Tubaro et al. (1985) which indicated that opiate-tolerant humans are more susceptible to bacterial infections at the same time that they experience depressed macrophage function. Thus, the propensity of opiate-dependent monkeys and swine to develop bacterial infections may be due to depressed phagocytic capacity. On the other hand, repression of viral infections in opiate-dependent monkeys and swine may relate to findings that significant T-cell deficits are absent in opiate-tolerant heroin addicts (Tubaro et al., 1985), mice (Shavit et al., 1986b; Weber et al., 1991) and monkeys (Donahoe et al., manuscripts in preparation). Since lentiviruses like SIVsmm are known

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to require T-cell activation for expression of DNA-integrated viruses to occur, it is likely that disturbances of T-cell function during opiate-withdrawal and recovery from withdrawal (Donahoe et al., 1991, manuscripts in preparation) are involved in viral-induction processes. It is also likely that the stress-response is a critical component of such effects since withdrawal from opiates is a severely stressful event for opiate-dependent hosts and since stress is known to induce expression of latent retroviruses akin to HIV-1 (Riley, 1981). In this way, it is appropriate to conceptualize deleterious and protective effects of opiates as deriving from their role in promoting or limiting stress, respectively. Thus, when a host is stressed by initial exposure to opiates and during withdrawal from opiates, there is every likelihood that immunological processes will be subverted as virological processes are activated. In turn, when an opiate-dependent host is experiencing a state of well-maintained opiate-tolerance and stress is low, the deleterious consequences of ambient stress and the, otherwise, stressful effects of opiates themselves would be expected to be minimized. Indeed, when Donahoe et al. (manuscripts in preparation) stressed monkeys that had achieved a relatively complete state of opiate-tolerance, various immunological parameters were seen to differ for opiateexposed monkeys in comparison with control monkeys that experienced the same experimental stress but were not dependent on opiates. Conclusions

The inadequacies of epidemiological assessments of heroin addiction and the lack of understanding of the processes required for the development of AIDS continue to obscure the exact role of opiates in AIDS. Nonetheless, the evidence presented in this review amply documents the fact that opiates can modulate immunological and viro-

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logical processes of potential relevance to the development of AIDS. As such, this evidence encourages speculation about the nature of the AIDS-opiates connection. A prime consideration in judging the means by which opiate-addiction is likely to modulate expression of AIDS is an appreciation of the conditionality of the immunomodifying effects of opiate exposure. Current evidence suggests that opiateexposure can variably depress or enhance immune function, or cause no perceptible change. This evidence links the immune effects of exogenous opiates with the immunomodifying influences of the endogenous opioid system and the neuroimmune network as a component of stress-response systems. Thus, it appears that the immunomodifying effects of opiates are mediated through complex, dynamic influence over the functioning of the neuroimmune network in a way that is analogous, if not identical, to the de n o v o response of animals to stress. Therefore, ignoring the role of cofactors that also can influence immune function in a host receiving opiates, the immunological effects of opiates can be expected to be proportional to the homeostatic disruption mediated by opiate exposure, which, in turn, can be expected to vary in relation to the experience of the host with the drug and in relation to the stage of opiate-exposure at any given time. Thus, in opiate-naive animals and humans, initiation of opiate exposure activates the stress-axis causing homeostatic disruption and, subsequently, immunological disruption. If opiate exposure continues at appropriate levels, homeostatic and immunological stabilization can be expected to occur in a way that is dependent on opiates (i.e. opiate tolerance). Subsequently, when opiates are removed from an opiate-tolerant host, precipitating the opiate-withdrawal syndrome, homeostatic balance is again destabilized, including the ability to mount immune responses effectively. In this latter

instance, normalization of homeostasis will eventually take place if abstinence from opiates continues. The preceding conceptualizations fit well with observations about the incidence of infectious complications in users and abusers of opiates. In long-term street-heroin addicts where infectious disease is common, repeated episodes of opiate-use and opiatewithdrawal are also common, making it very likely that these two circumstances are connected by the ability of opiate-withdrawal and reinitiation of opiate use to disrupt homeostasis and increase host susceptibility to infection. Novel or infrequent use of opiates can also be expected to disrupt homeostasis and immune function. However, despite evidence that opiates used in these ways can exacerbate herpesvirus infections (Cardan, 1984; Gierarts et al., 1987), the opportunity for infection to develop under such circumstances is likely to be minimal compared with the situation of chronic heroin addiction. The situation for individuals regularly receiving opiates is more complex because of the temporal variability associated with establishment and maintenance of opiate-tolerance (e.g. monkeys become tolerant to some immunological changes precipitated by opiates in days to weeks while it takes months for tolerance to other types of immunological changes to occur (Donahoe et al., manuscripts in preparation)). Thus, it is difficult to project the exact consequences that such variable states of tolerance are liable to have on host susceptibility to infection, although it seems evident that they can result in both promotion and depression of host defenses against infection. Indeed, the most interesting aspect about the opiate-tolerant state is that it appears to be capable of promoting fidelity of immune functioning by normalizing homeostasis. These considerations indicate that the immune liabilities of opiate exposure are best judged according to considerations of the balance between po-

AIDS and opiates tentially deleterious homeostatic disruption by opiates versus potentially beneficial effects related to conditions that avoid opiatedirected stress as well as ambient stress, i.e. opiate tolerance. Considerations about the ability of opiates, opiate-dependency and opiate-withdrawal to affect stress and homeostasis are as relevant to expression of latent viruses as they are to immune function. This is an important point since the infectious cycles of HIV-1 and several other viruses identified as potential cofactors in AIDS, like herpesviruses and cytomegaloviruses, are characterized by stages of viral latency. In fact, stress has long been known to activate latent herpesviruses as well as retroviruses akin to HIV-1 (Riley, 1981). Therefore, the ability of opiates to participate in activation of latent viruses and, in circumstances of opiate-tolerance, to repress such induction, may be equally, or, even, more relevant to the relationship between opiates and AIDS than the immunomodifying consequences of opiate-exposure discussed above. Still, the mechanisms involved, whether directed toward viral or immune status, are likely to be closely related, if not identical. Therefore, it is reasonable to assume that modulation of expression of viruses and of immune functions are both relevant to the way opiates influence expression of AIDS, most probably in an interactive way. Evidence discussed in this review indicates that opiate-tolerant animals experience depressed macrophage function accompanied by increased susceptibility to bacterial infection at the same time that they express normal T-cell functions that may promote viral latency. This information indicates that, for individuals using opiates, protective responses to infectious agents are likely to differ by the nature of the infectious agent as well as the stage of opiate-dependency involved. Such issues are not well defined by present research but are of obvious relevance to considerations of

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the opiate-AIDS connection because of the variety of infectious microorganisms associated with this disease syndrome. In summary, a conceptualization is presented about the potential of opiates to modulate expression of HIV-1 and development of AIDS that rests on current understanding of the way opiates modulate immune function and viral expression. The central focus of this conceptualization is that the effects of opiate exposure on host defense mechanisms are conditionally dependent on the relative ability of these drugs to variably disturb or maintain homeostasis within the neuroimmune network in respect to the relative state of opiate tolerance at any given time during opiate exposure(s) (or lack of tolerance as the case may be). This concept includes the notion that control over host defense mechanisms by opiates is very dynamic and that the effects manifested by this control can range from enhancement to depression. Of course, in the real world of opiate addiction, the ultimate manifestation of the ability of opiates to modulate host defense systems is further directed by innate response characteristics of the host and by myriad defense-modifying cofactors that are variably present in addictive settings. Such complexity defies complete scientific understanding at the present time and as discussed in this review is the reason that epidemiological assessments of heroin addiction are limited in their ability to identify the unitary role of opiates in AIDS. Implicit in the concepts presented in this review is the notion that opiate addiction itself is a potential cause of immunodeficiency disease, even in the absence of HIV-1. The concepts described in this report also suggest ways to reduce the medical and publichealth risks of heroin addiction. Accordingly, it would seem wise to pursue therapeutic strategies for heroin addicts that reduce homeostatic imbalances that are caused by erratic use and abstinence from opiates. Of course, complete drug abstinence would be

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the ideal solution in this regard but for a variety of psycho-dynamic and economic reasons, complete abstinence is often unobtainable for street heroin addicts, leaving methadone maintenance as the preferred alternative as a means of stabilizing homeostasis. The foregoing considerations are also relevant to therapeutic uses of opiates. An ideal therapeutic application of opiates would appear to be one that aims at achieving the least amount of homeostatic disruption possible. When using opiates therapeutically, this objective would be met by establishing and maintaining opiate-tolerance as efficiently as possible (e.g. by patient-controlled release of opiates). When it is time for opiate therapy to be stopped, this objective would be met by minimizing the stresses inherent to drug withdrawal. Finally, it is important to recognize that the concepts expressed in this review are broadly relevant to the liabilities of stress to host defense systems and to the immunocompromising potential of all manner of behaviorally active substances with addictive liabilities. Many studies have shown that stress can have deleterious consequences for host defense against opportunistic disease (Keller et al., 1991). These consequences stem from the ability of stress to modulate host immune function and to induce latent viruses--consequences which, as developed in this review, are identical to those that accompany exposure to opiates. Since addictive substances in general share many properties with opiates, including the ability to induce tolerance and an alliance with stress events, it is reasonable to assume that the concepts expressed here have universal relevance to all addictive substances. Notably, these considerations suggest that stress-reduction is likely to be beneficial for all individuals with HIV-1 infections, not only addicts. In conclusion, the foregoing considerations indicate that more research into the

complexities that link opiates with stress and with modulation of host defenses against opportunistic disease should help achieve better basic understanding of host defense processes and better ways to deal with heroin addicts infected with HIV-1 and suffering from AIDS. Such information is also likely to provide clues to the best ways to treat heroin addiction and other opiatedependencies as well as the best ways to use opiates therapeutically. References

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