PARASITES As Cofactors For AIDS
Excerpts from the work of Dr. Richard Bowman Pearce
The growing body of evidence is supporting the idea that parasitic disease may be an essential factor for AIDS. The theory was based upon three lines of evidence :
all the risk groups for AIDS had evidence for chronic "pan-immunosuppression" prior to HIV/AIDS
the epidemic of parasites in homosexuals preceded AIDS by a few years. That was a common factor with African and Haitian risk Groups.
parasites exert immunosuppressive, antigenic and mitogenic effects on T cells.Between 80 and 100 percent of sexually active homosexual men worldwide are infected with one or more species of intestinal parasite.
The epidemic of parasites in gay men preceded AIDS by a few years.
In separate studies, the parasites gay men carry -- E. dispar (formerly E. histolytica), other so-called "nonpathological" amebae and Giardia -- have been shown to be specifically associated with a suppression of cell mediated immunity, elevation of IgM, depressed CD4:CD8 ratios, and increased risk for seroconversion to - and seropositivity for - HIV.
Parasites explain why AIDS develops among men and women alike in Africa and other tropical regions (Southeast Asia, the Caribbean, India) where parasites infect men and women indiscriminately. By contrast, in developed countries and urban settings, male homosexuals are the principal risk group for chronic parasite infection and AIDS.
Malaria appears to predispose to HIV in central and eastern Africa. Malaria has long been regarded as a co-factor for EBV-induced Burkitt's lymphoma.
E. histolytica extract activates latent HIV in T cells in culture. In mice, parasites activate HIV transgenes, depress anti-HIV and anti-adenoviral CTL activity, and promote a Th2 predominant state (which may favor retroviral replication). Mice with malaria are much more susceptible to leukemia caused by Moloney Murine Leukemia Virus than non-parasitized mice.
Logistic regression analyses of factors predisposing to KS in gay men show that the leading independent risk is exposure to feces. The intestinal parasites that colonize gay men are transmitted exclusively through the fecal-oral route. One early survey of Kaposi's Sarcoma in Africa showed an exact geographical confluence between KS and onchocerciasis, a chronic parasitic disease. Thus, the development of KS in gay men without HIV may be related to chronic immunodepression by parasites that permits the emergence of the KS associated herpes virus, HHV8.
Only feral cats that are parasitized naturally acquire FIV and develop feline AIDS. Pathogen-free cats do not transmit FIV when housed together, and when inoculated with FIV undergo an acute phase response but fail to develop feline AIDS characterized by severe CD4 depletion, opportunistic infection, and death.
Monkeys housed in the nation's primate centers, including those used in SIV studies, are universally infected with intestinal parasites and the animals in which the first reported cases of immunodeficiency appeared had been previously infected with malaria.
Cattle with trypanosomes are significantly more likely to be infected with Bovine Leukemia Virus (BLV) and to develop leukosis than parasite-free herds.
Progression to fulminant AIDS is more rare in groups such as sex partners of hemophiliacs and health care workers with occupational exposures to HIV than other risk groups whose immune systems are chronically activated. Such persons may seroconvert to HIV and/or develop anti-HIV cell-mediated activity, but lacking parasites or other chronic immune stimulus, do not progress to fulminant AIDS at the high rates observed in the major risk groups.
In 1987, it was predicted that HIV and AIDS would most likely spread by heterosexual transmission beyond Africa into other parasite endemic regions of the world, especially rural South America, Southeast Asia, and India. This, in fact, has occurred. If parasites were not an obligatory cofactor for AIDS, heterosexual transmission of HIV and AIDS would theoretically have occurred at an equally high rate in parasite-free regions of North America, Europe, and Australia. The comparatively low rate of HIV infection and AIDS progression among heterosexuals in these temperate regions is consistent with the idea that environmental cofactors are important determinants of HIV transmission and pathogenesis.
Not widely known is the fact that 80% or more of sexually active gay men currently carry Entamoeba dispar, E. coli, E. hartmanni, I. btschlii, D. fragilis, and Giardia intestinalis among other protozoa (compared to an incidence in the general population of a 1-3%). The epidemic of parasites in gay men began in the mid 1970s and grew exponentially becoming pandemic in this group by 1979, a year or two before AIDS began to take its toll. E histolytica lectin stimulates HIV production in vitro while E. dispar and other "non-pathogenic" amebae in HIV(-) gay men are independently associated with skin anergy, chronically elevated IgM, and an increased risk for seroconversion to HIV.
In gay men, oral-anal contact is an independent risk factor for KS. KS can develop in HIV negative homosexual men, suggesting that some other immunodepressing agent besides HIV-1 can predispose to the putative KS virus, HHV8. This other source of immunodepression could be parasites since, in Uganda, KS (but not other tumors) has been found to be in exact and narrow geographical confluence with the chronic parasitic disease onchocerciasis. In Africa and other tropical areas as well as in Belle Glade, Florida, AIDS affects women as frequently as men.
In the U.S., between 1 and 2 million gay men are currently multiply infected with protozoa, yet very few are even aware of the fact. No other putative cofactor for AIDS, (e.g. mycoplasma, alcohol and drug abuse, HHV-6A) has such a uniformly high incidence rate in the gay and tropical risk groups for AIDS.Epidemiological Association between Intestinal and Other Non-opportunistic Parasites and HIV/AIDS
Largely unappreciated, but by no means unknown, is the fact that 60% to 100% of sexually active gay men currently harbor one or more species of intestinal parasite, including Entamoeba dispar, E. coli, E. hartmanni, Iodamoeba butschlii, Dientamoeba fragilis, and Giardia intestinalis among others (Law et al, 1991, Esfandiari et al., 1995).
A recent surveillance for Giardia in New York City shows that the spread of this parasite through sexual means, i.e. as a STD among mostly gay men, continues to the present time. The highest rates are among hispanic children (mostly Dominican immigrants) and gay men, both HIV(+) and HIV(-) (NYC Department of Health, not allowed href="mailto:Ymilko@pppmail.nyser.net">Ymilko@pppmail.nyser.net).
Like sexually active gay men, the tropical risk groups for AIDS also have a high prevalence of non-opportunistic parasites. In addition to enteric infections by nematodes and protozoa, these include schistosomiasis, strongyloidiasis, onchocerciasis and malaria (Climent, et al., 1994; Moore and Buster, 1984; Bouree, et al., 1995; Plumelle and Edouard, 1996).
The triad of HIV, non-opportunistic parasites, and AIDS is now reported for Haiti, the Republic of Congo (formerly Zaire), Uganda, Rwanda, Tanzania, Ethiopia, Puerto Rico, Jamaica, Martinique, Papua New Guinea, India, Pakistan, Southeast Asia, Belle Glade, Florida and South Los Angeles. Indeed, lymphotropic retroviruses, which require immune activation to reproduce successfully, may have co-evolved with parasites in the tropical regions of the world whence HIV and HTLV emerged.Parasites Are Agents of Chronic Immunosuppression
Even the so-called "non-pathogenic" (i.e. non-invasive) ameba can depress cell-mediated immunity. They found that anergy significantly and independently associated with the presence of E. histolytica [now termed E. dispar], E. coli, and Iodamoeba btschlii but not with other parasites (P< 0.005). The authors concluded:
"Our main findings were that intestinal parasites and systemic deficiency of cell-mediated immunity correlate within the group of healthy homosexual men and that this correlation specifically involves the 3 amoebas, E. histolytica, E. coli, and I. btschlii. [O]ur data support the hypothesis that parasites may cause AIDS or act as a cofactor to facilitate HIV infection and/or its progression to AIDS."
For gay men, parasitic infections are multiple, repeated (weekly exposures are not uncommon), and encountered for the first time in the second and third decades of life. This sudden and sustained onslaught of antigens and protozoa may have considerable impact on immune responses and the state of immune activation not only in the gut, but systemically as well.
Bentwich and colleagues of the Weizman Institute in Rehovot Israel have reported that Ethiopian Jews with and without HIV-1 also carry several species of intestinal parasite including helminths (Kalinkovich et al., 1996 XI ICA). These patients are being followed for possible changes in the in rate of progression to AIDS but it is these authors' opinion that progression to AIDS is slower in Ethiopians treated for parasites. They have shown that lymphocytes from parasitized individuals are highly susceptible to HIV infection in vitro (persona lcommunication).
Speaking at a recent conference, Dr. Bentwich reported that in Africa, Ethiopians with HIV died two to three times more quickly than those infected in the West and who were without parasites. In an article appearing in the Jewish Bulletin of Northern California Bentwich was quoted as saying:The Epidemic of Parasites in Gay Men Preceded AIDS
The incidence of gastrointestinal parasites rose exponentially in gay men during 1977-1983 (Figure 2). The transmission of parasites was associated with sexual activity that exposed partners to feces, particularly oral-anal sex or "rimming." By 1980, the prevalence of parasites was 60% or greater for homosexual men attending STD clinics or private practice (Pearce, 1983; Markell and Kuritsubo, 1981; Phillips et al., 1981; William, et al., 1978; Schmerin, et al., 1977; Mildvan et al., 1977). HIV was apparently introduced into Western societies in the 1970s or even earlier.
One possible reason the virus didn't proliferate and produce fulminant disease until the early 1980s might be the absence of a suitable pool of parasitized hosts. By that time parasite epidemic in gay men had reached its height. Even well before 1980, clinicians had warned about the emerging parasite epidemic in gays. The first to report a homosexual case cluster of E. histolytica was Harry Most who dubbed Manhattan a "tropical isle" (Most, 1968). This concern was echoed by another leading infectious disease specialist who in in 1979 warned:
Evidence indicates that an epidemic of intestinal protozoan infection exists in the homosexual male population in New York City. The difficulty in making a diagnosis, inadequate therapy, failure to alert potential victims,and official neglect of the epidemic have combined to create a dangerous situation. (Kean et al., 1979)
The parasite theory led to the prediction that AIDS would spread beyond Africa and Haiti into other regions of the world where parasites are holoendemic (Pearce, 1986, 1989). In contrast, and contrary to the warnings of some researchers (Redfield, 1986), AIDS has not emerged as an overwhelming epidemic among heterosexuals in the developed (and largely parasite-free) countries of North America, Europe and Australia. This strongly suggests an environmental component to AIDS is present in the tropical regions of the world.
Unlike Other Putative Cofactors for HIV (e.g. HTLV-1, CMV, HHV-6A, Adenoviruses, Mycoplasma), Parasites Are Chronic, Multiple, Recurrent, Antigenically Highly Variable, and Present in 80-100% of the Gay and Tropical Risk Groups but Only 1-2% of the General Population
Table 2. Frequency of intestinal parasites in ARC patients with lymphadenopathy syndrome (LAS), thrombocytopenia (ITP) compared to healthy gay controls and mostly heterosexuals in the San Francisco Bay Area in 1982. [From Pearce and Abrams 1987].
Parasitism Has Been Etiologically Linked to Other Lymphotropic Retroviral Diseases Including ATLL, Burkitt's Lymphoma, and BLV-induced Bovine Leukemia, and Feline Immunodeficiency Virus (FIV) Induced AIDS in Cats and MAIDS in Mice.
Strongyloides, filaria, malaria and other parasites are thought by several researchers to predispose to adult T cell leukemia (ATLL) by chronically activating the HTLV-1 provirus (Nakada et al., 1983; Patey et al., 1992; Plumelle Y, et al. 1997).
Strongyloides has also been frequently observed in association with HTLV-1 and ATLL. Nakada et al. reported that 60% of 166 chronic Strongyloides sterocoralis carriers were HTLV-1 seropositive compared to only 20% of nearly 3000 controls consisting of persons not carrying the worm at the time of the study (Nakada et al., 1983).
Denis Burkitt originally postulated that malaria caused Bukitt's lymphoma by chronically activating B cells and depressing anti-EBV immune responses (Burkitt, 1969). If true, one would expect less lymphoma in Africans with sickle cell anemia since such individuals resist malaria.
A survey of the literature reveals one study, published in 1970, showing that Nigerians with the sickle cell trait were significantly (P<0.03) less likely to develop Burkitt's lymphoma than persons with wild type hemoglobin (Williams A, 1966).
Primates with SAIDS are also infected with parasites. According published reports and to James L. Blanchard, DVM Ph.D., Head Veterinarian at the Tulane Regional Primate Research Center, all new world and old world monkeys used in research, including those currently used in AIDS research, are infected with several species of intestinal protozoa including E. histolytica and Giardia (van Riper, et al., 1966; JLB, personal communication).
Cattle with trypanosomes are significantly (P<0.001) more likely to be infected with BLV, a virus related to HTLV-1, than non-parasitized herds (Hare et al., 1970). Previously, in a USDA study, it was observed that 100% of overtly leukemic cattle were trypanosomized (Malmquist, 1965).
In contrast to pathogen-free experimental cats, nearly all outdoor and feral cats carry parasites including Isospora felis, I. rivolta, Dupylidium canium, Toxocara cati, Toxascaris leonina, Ancylostoma sp and Toxoplasma gondii (Lin et al., 1990).
More recently, a group from the Colorado State University was able to induce AIDS in cats raised and housed under pathogen-free conditions. By infusing plasma pooled from cats with FIV infection, more than 50% of recipient kittens developed AIDS by 6-12 weeks (Diehl, et al., 1995). The model is reminiscent of transfusion cases of AIDS in humans where allogeneic proteins may stimulate the immune system and predispose to HIV infection and progression to AIDS.
These observations in cats, cattle, and mice merely reflect what veterinarians have long known: animals with intestinal parasites are much more susceptible to other infections, particularly viruses.Confluence of Onchocerciasis and KS in Uganda
In 1966, Williams and Williams reported a closely defined geographical confluence between KS and onchocerciasis (a filarial parasite) in the Western Nile District of Uganda (Williams and Williams 1966). In contrast, other tumors such as cervical and breast cancers were present throughout the entire district which is heavily populated. A second report on the distribution of onchocerciasis in Africa confirms the existence of specific foci for the parasite as reported by Williams and Williams (Oomen, 1969). It is possible that black flies (Simuliidae) that are the insect vector for onchocerciasis also transmits the viral agent of KS. However, HHV8, the probable agent of KS is readily transmitted by sexual contact so clearly an insect carrier is not obligatory for transmission. A more likely scenario is that the immunosuppression caused by chronic ochocerciasis allows for HHV8 expression just as all herpes viruses express during periods of protracted immunosuppresion.Based on the African Paradigm and Independent Risk Associated with Anilingus, Parasites Explain the "Mystery" of KS in HIV-negative Gays
HIV seronegative gay men with only slightly depressed or normal numbers of CD4 cells can develop KS (Chuck et al., 1996). The virus that most likely causes KS, HHV8, is easily transmitted sexually since up to 25% of random blood donors are seropositive for HHV8 (Lennette, et al., 1996). The KS virus apparently disseminated through the homosexual community by sexual contact. However, in several studies, anilingus ("rimming"), was found to be a strong and independent risk factor for KS (Beral et al., 1992).
Anilingus is also the most important factor for the transmission of intestinal parasites among adults in this country. It is certain, given the high prevalence of parasites in the homosexual risk group, that these HIV-negative patients with KS and reporting frequent oral-anal contact were heavily parasitized.
Thus, KS and lymphomas both may be present in HIV negative gay men immunosuppressed by parasites. Those more severely immunocompromised by the CD4 depleting effects of HIV may have more aggressive tumors. This appears to be the case as KS in HIV(-) patients runs a more indolent course than in HIV(+) patients.Parasites Explain the High Incidence of AIDS in Women in the Tropical Areas Compared to Developed Countries
Parasitic infection may be a primary contributing factor to AIDS in Africa where men and women alike are at risk (Quinn et al. 1987). Parasites are also endemic in Belle Glade, Florida (Moore and Buster, 1983), Ethiopia (Bentwich et al., 1995), and among the indigenous peoples of Papua New Guinea (Dwyer et al., 1997) and the Caribbean - all risk groups for AIDS. Activation of T cells, macrophages and other APC is necessary for HIV replication. This fact alone, may explain why lymphotropic and monocyte-tropic viruses originated in parasite endemic regions where suitable hosts reside. Indeed, HTLV-1, HIV-1, HIV2, and EBV - all lymphotropic viruses - are all found in close geographical relationship with parasite endemic regions (Tajima et al., 1981, 1985; Merino et al.; Pearce, 1989; Burkitt, 1969).
Women, especially in the devloping countries of the world, are also prone to harbor chronic vaginal infections such as trichomoniasis, or have other predisposing vaginal factors for HIV.(van de Wijgert, et al., 1996).
In 1982, the CDC and Several Clinical Researchers Recommended That Physicians Treat "Non-pathogenic" Amebae in Gay Men
In 1982, the CDC issued a recommendation that asymptomatic intestinal parasitic infections in persons "for whom anal-oral contact is a sexual practice should be treated in accordance with recommendations for symptomatic individuals" (CDC, 1982). With few exceptions, this recommendation has not been followed.
Unfortunately, most physicians caring for homosexual patients are unaware of the potential adverse consequences of chronic parasitism on the course of HIV infection and their patients are often not being provided with the option of treating these chronic infections. Since the infections are often aysmptomatic in terms of gastrontestinal criteria, infections often continue undiagnosed and untreated for months and longer.Safe Sex Guidelines Are Not Focused on Preventing Fecal Contamination
Although sexual behaviors in other areas have changed in response to safer sex campaigns, the practice of rimming (anilingus) has not diminished in recent years (Elford et al., 1992) nor is it adequately addressed in safer sex guidelines. Although some safe sex guidelines generally caution against oral-anal contact, the need to avoid fecal contamination during foreplay and when removing condoms is not emphasized.
Present-day gay erotic videos faithfully show condom use and avoidance of semen ingestion, but rimming is frequently featured. Men viewing these socially conscious videos may regard all activities portrayed as "safe."
Unfortunately, most gays are totally ignorant that they may be infected with parasites or that many AIDS researchers consider them possible cofactors for AIDS. The estimated 1/2 to 1 million HIV(+) gay men in this country who are also infected with parasites, and their physicians, ought to be informed that many leading researchers consider parasite treatment a prudent course of action. Most importantly, from a public health standpoint, studies of the possible exacerbating role of parasites in AIDS need to be conducted.Groups Without Activating Cofactors Appear to Have a Slower Progression to AIDS
Approximately 20% of wives or sex partners of HIV(+) hemophiliacs or HIV(+) transfusion recipients in this country have seroconverted to HIV (Kim et al., 1988; Chorba et al., 1993; Peterman et al., 1988), but the incidence of AIDS in these "at risk" individuals is remarkably low. This is in spite the probability that a sizeable fraction of them may be misclassified and are actually a part of other risk groups.
Low HIV infection and AIDS progression rates have been reported by others for heterosexual partners of hemophiliacs (Kamradt, 1990). If HIV alone were sufficient to cause disease, it is likely that a much higher percentage of sexual partners of hemophiliacs should have gotten AIDS by now.
Their progression rate may be low because they are one of a few groups with HIV-1 but without chronic immune activation.
The Parasite Cofactor Theory has Support from Many Top AIDS Researchers and has Appeared in Mainstream Journals Including Science, Nature, The New England Journal of Medicine, The Lancet, Immunology Today, and JAMA
The idea that parasites are possible cofactors for AIDS has been expressed by many researchers in reputable journals (Fauci 1988, 1993 ; Lange et al., 1983; Bentwich et al., 1995; Quinn et al. 1987; Stanley et al., 1996 ; Rene et al., 1984; Bergstrรยธm et al., 1986; Pearce, 1983, 1984, 1986; Pearce and Abrams 1984, 1987; Krogstadt et al., 1986; Cox, 1990; Archer and Glinsman 1985, Piot et al., 1988). However, neither the majority of gay men nor their physicians are aware of the possible consequences of enteric infections. Most are not even aware there is an epidemic of parasitic infections in gay men! As reviewed here, there is much circumstantial and some direct evidence to suggest that parasites are an important if not obligatory factor in AIDS.
The diagnosis of parasites in asymptomatic or mildly symptomatic gay men is rarely sought and, when parasites are disclosed, treatment for non-pathological amebae is seldom offered. Indeed, some have argued that because these parasites do not invade the bowel wall, they do not need to be treated (Allason-Jones E et al., 1986).
This argument has held sway among many public health officials and clinicians for several years but it has been countered by epidemiologists, immunologists, and retrovirologists. Parasites are likely to continue to be transmitted as an STD among individuals at risk for HIV until and unless studies show a direct and definitive role for non-opportunistic parasites in AIDS or KS (if any).
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