Has Gallo Proven The Role Of Hiv In Aids Essay Example For Students

Has Gallo Proven The Role Of Hiv In Aids? Essay Introduction In 1982, Robert Gallo from the National Cancer Institute in the USA, put forward the hypothesis that the cause of AIDS is a retrovirus. One year later, Myron Essex and his colleagues (1) found that AIDS patients had antibodies to the Human T-cell Leukemia virus Type-1 (HTLV-I), a virus discovered by Gallo a few years earlier. At the same time, Gallo and his colleagues (2) reported the isolation of HTLV-I from AIDS patients and advocated a role for this retrovirus in the pathogenesis of AIDS. This hypothesis however, was not without a few problems: 1. While HTLV-I was accepted to induce T4-cell proliferation and cause adult T-cell leukaemia,(3) the hallmark of AIDS was T4-cell depletion, and the incidence of leukaemia in AIDS patients was no higher than in the general population; 2. The highest frequency of antibodies to this virus was found in Japan, yet no AIDS cases had been reported from that country;(4) 3. In the same month in which Gallos and Essexs groups reported their data, Luc Montagnier and his colleagues from the Pasteur Institute, described the isolation of a retrovirus, later known as Lymphadenopathy Associated Virus (LAV), from the lymph nodes of a homosexual patient with lymphadenopathy.(5) Although this virus was similar to HTLV-I, one of its proteins, a protein with a molecular weight of 24,000 (p24), did not react with monoclonal antibodies to the HTLV-I p24 protein. Samples of this virus were, on several occasions, sent to Gallos laboratory. In May 1984, Gallo, Popovic and their colleagues published four papers in Science in which they claimed to have isolated from AIDS patients, another retrovirus, which they called HTLV-III.(6,7,8,9) On the 23rd of April 1984, before the Science papers were published, Gallo and Margaret Heckler, the then Health and Human Services Secretary called a press conference to announce that Gallo and his co-workers had found the cause of AIDS and had developed a sensitive test to show whether the AIDS virus is present in blood. In 1985, the Pasteur Institute alleged that Gallo had misappropriated LAV in developing the blood test. The ensuing conflict, which reached the American courts, was eventually settled by a negotiated agreement signed in 1987 by Gallo, Montagnier, US President Reagan and French Premier Chirac. The agreement declared Gallo and Montagnier to be co-discoverers of the AIDS virus, presently known as the Human Immunodeficiency Virus (HIV). Nevertheless, the misappropriation conflict drew the attention of John Crewdson, an investigative journalist, and US Senator John Dingell. In November 1989, Crewdson published a lengthy article in the Chicago Tribune newspaper, With allegations that Robert C. Gallo stole from French scientists the virus he discovered to be the cause of AIDS. (10) This led to a National Institute of Health (NIH) internal inquiry into the allegation with an outside committee of expert but disinterested parties led by Yale biochemist Frederic Richards to oversee the activity of the internal panel.(11) Following the inquiry, which was viewed as a fact-finding mission, the Richards committee insisted on a formal investigation on suspect data in one of four seminal papers published by Gallos lab in Science on 4 May 1984.(12) In this paper, the first of a series of four, with Mikulas Popovic the principal author, their appears to be differences between what was described in the paper and what was done. (10) A draft report of the formal investigation written by NIH Office of Scientific Integrity (OSI), was published in September 1991. In the draft report, Popovic is accused of misconduct for misstatements and inaccuracies that appeared in the paper, and that Gallo, as laboratory chief, created and fostered conditions that give rise to falsified/ fabricated data and falsified reports. However, Gallos actions were not considered to meet the formal definition of misconduct.(13) The final draft report of the OSI, completed in January 1992, was immediately criticised by the Richards Panel as well as Senator Dingell. This led to a review of the OSI report by the Office of Research Integrity (ORI), which found Gallo guilty of scientific misconduct. Nonetheless, the scientific misconduct is said not to negate the central findings of the 1984 Science paper. Asian Philosophies of Critical Thinking Essay Among the recipients of WBI blood, 36% were WBI 6 months after transfusion, but so were 42% of individuals who received WB-negative samples. Both donors and recipients of blood remained healthy. They concluded that WBI patterns are exceedingly common in randomly selected donors and recipients and such patterns do not correlate with the presence of HIV-1 or the transmission of HIV-1, most such reactions represent false- positive results; 3. Antibodies to p24 have been detected in 1 out of 150 healthy individuals, 13% of randomly selected otherwise healthy patients with generalised warts, 24% of patients with cutaneous T-cell lymphoma and prodrome and 41% of patients with multiple sclerosis;(52) 4. Ninety seven percent of sera from homosexuals with ITP and 94% of sera from homosexuals with lymphandenopathy or AIDS contain an antibody that reacts with a 25Kd membrane antigen found in platelets from healthy donors and AIDS patients, as well as a 25 Kd antigen found in green-monkey kidney cells, human skin fibroblasts, and herpes simplex cultured in monkey kidney cells. This reaction was absent in sera obtained from non-homosexual patients with ITP or non-immune thrombocytopenic purpura;(48) 5. Conversely, the p24 antigen is not found in all HIV positive or even AIDS patients. In one study, the polymerase chain reaction (PCR) and p24 were used to detect HIV in patients at various CDC stages from asymptomatic to AIDS. p24 was detected in 24% patients and HIV RNA in 50%;(53) 6. In another study, In half of the cases in which a subject had a positive p24 test, the subject later had a negative test without taking any medications that would be expected to affect p24 antigen levels the test is clinically erratic and should be interpreted very cautiously.(54) Thus the finding of viral particles in the AIDS cultures/co- cultures, RT and proteins which react with AIDS related sera in the material from the supernatant or cell lysates which in sucrose density gradients bands at 1.16 gm/ml, cannot be considered synonymous with the isolation or even the detection of a retrovirus. Even if a retrovirus is isolated from in vitro cultures/co-cultures from tissues from AIDS patients, this does not, by itself, constitute proof of the existence of the virus in vivo, (in AIDS patients), and even less that the retrovirus has been exogenously acquired. This is because: 1. At present, it is generally accepted that one of the most striking features that distinguish retroviruses from all other animal retroviruses is the presence, in the chromosomes of normal uninfected cells, of genomes closely related to, or identical with those of infectious viruses. The human genome, in addition to other proviral sequences, is known to contain both HTLV-I (55,56) and HIV (57) sequences. Depending on conditions, the proviral genome remains unexpressed or part or all of it may be expressed. The latter may or may not lead to the assembly of viral particles (endogenous retrovirus).(17) In animal cultures, healthy non-virus producing cells sooner or later spontaneously release retroviruses.(20) The appearance and yield can be increased by (i) mitogenic stimulation;(58) (ii) co-cultivation techniques;(59) (iii) cultivation of cells with supernatant from non-virus producing cultures.(60) According to one eminent retrovirologist, George Todaro, the failure to isolate endogenous viruses from certain species may reflect thelimitation of in vitro cocultivation techniques;(61) 2. Gallos team, like everybody else: (i) isolated HTLV-III (HIV) from cell cultures; (ii) isolated HTLV-III from mitogenically stimulated, activated cell cultures; 3. In addition, Gallo and his colleagues also used co-cultivation techniques; 4. The first HTLV-III isolation was from the HT (H4, H9, H17) cell line. Reading Gallo and his colleagues first paper, one surmises that the HT cell line was established in Gallos laboratory. The Gallo inquiry revealed that the HT cell line is in fact HUT78, a cell line established in another laboratory from a patient with mature T4-cell leukaemia, a disease which Gallo claims is caused by the exogenous retrovirus, HTLV-I.(3) If so, then all HT cell cultures, and the clones derived from it, infected with HTLV-III or non-infected, and the material from these cultures which bands at 1.16 gm/ml, should contain HTLV-I, and thus RT and retroviral particles. Furthermore, because about 25% of AIDS patients have antibodies to HTVL-I,(1) and the immunogenic proteins of HTLV-I and HIV have the same molecular weights, then approximately 25% of the non-infected HT (H4, H9, H17) cultures in addition to RT and particles, should have, in the Western blot, the same bands as those of the HTLV-III infected cultures. Thus, these WBs will erroneously appear positive for HTLV-III. Proof that HTLV-III (HIV) is causally linked to AIDS. Gallo claims, a claim accepted by the vast majority of AIDS researchers, that in the May 1984 Science papers he and his colleagues presented unambiguous evidence that this and this alone was the cause of AIDS.(62) A minimum requirement for making such a claim should be presentation of the following evidence: 1. That all AIDS patients are infected with HTLV-III; 2. Infection with HTLV-III leads to T4-cell depletion, given the assumption that HTLV-III leads to the clinical syndrome by its T4 cytotoxicity. The evidence for the existence of HTLV-III was viral isolation and ELISA antibody tests. Even if one assumes that the data presented represents true isolation, the virus was isolated from less that half (10/21) of AIDS patients with opportunistic infections, and in less than one third (13/43) with Kaposis sarcoma, then and now the two most characteristic AIDS diseases. Even if the virus could have been isolated from all patients, given the nature of retroviruses and the method used for HTLV-III isolation (cultures, mitogenic stimulation, co- cultivation) the possibility cannot be excluded that the virus did not exist in vivo (in AIDS patients), and that it was a provirus whose expression was facilitated by the culture conditions. The only method used to prove HIV infection in vivo was the antibody tests. Such a test can only be used only after its specificity has been proven by use of the only possible gold standard, the virus itself. This has not been done. Furthermore, the antibody test used by Gallo was ELISA, at present known to be non-reproducible and non-specific. In a study of 1.2 million healthy military applicants conducted by Colonel Donald Burke and his colleagues,(63) it was found that although approximately 1% of all individuals had an initial positive HIV ELISA, only 50% of repeat ELISAs were positive. Of the latter, only approximately one third were associated with two subsequent positive WBs. In Russia, in 1990, out of 20,000 positive ELISAs only 112 were confirmed using the WB as a gold standard. In 1991, of approximately 30,000 positive ELISAs, only 66 were confirmed.(64) Nowhere in the four Science papers was HTVL-III cytotoxicity mentioned. The only reference to any cellular abnormalities or pathology in general is in the first paper where one reads: The virus positive cultures consistently showed a high proportion of round giant cells containing numerous nuclei (Fig. 1a). These cells resemble those induced by HTLV-I and -II except that the nuclei exhibit a characteristic ring formation. (Fig. 1a is a light microscopic examination of clone H4/HTLV-III). The H4 clone was obtained from the HT cell line using irradiated mononuclear cells from peripheral blood of a healthy blood donor as a feeder. At present, it is known that the HT cell line and thus H4 are HUT78, derived in 1980 from a patient with mature T4-cell leukaemia,(65,66) However, other cell lines derived from patients with the same clinical syndrome are known to exhibit similar morphologies including multinucleated giant cells.(67) Thus the cellular morphological characteristics observed in the first paper may have been an intrinsic property of the HT cell line, or the result of the culture conditions, or both, and not due to HTLV-III. Finally, Gallo and his colleagues did not provide any data on the immunological status of those individuals from whom viral isolation was attempted, and no data was presented proving that: 1. HTLV-III (HIV) is both a necessary and sufficient cause of T4- cell depletion; 2. T4-cell depletion is both necessary and sufficient for the appearance of the AIDS indicator diseases. Conclusions The data and arguments that have been presented by Gallo and his colleagues do not constitute proof of HIV isolation or an unambiguous role for HIV in the pathogenesis of AIDS. Although some researchers currently use methods of viral isolation essentially the same as that described by Gallos group, most use less rigorous methods including singleton detection of p24 (by antibody techniques), or RT. Notwithstanding, with all of these techniques, including that described by Gallo and his colleagues, which itself seen to be greatly problematic, HIV cannot be isolated from 20%-70% of HIV positive and AIDS patients(68,69) Thus we are faced with a problem of considerable importance. The HIV antibody tests, both ELISA and WB, the only routinely used tests proving the existence in vivo of HIV, have yet to be verified against the only suitable gold standard, viral isolation. The available evidence suggests that this long overdue but most basic requirement of test evaluation is likely to prove an immense problem, and while the HIV antibody tests are useful prognostic markers in the high risk groups, their use as diagnostic and epidemiological tools for HIV infection is questionable.References 1. Essex M, McLane MF, Lee TH, et al. Antibodies to Cell Membrane Antigens Associated with Human T-Cell Leukemia Virus in Patients with AIDS. Science 1985;220:859-862. 2. Gallo RC, Sarin PS, Gelmann EP, et al. Isolation of Human T- Cell Leukemia Virus in Acquired Immune Deficiency Syndrome (AIDS). Science 1983;220:865-867. 3. Gallo RC. The First Human Retrovirus. Sci Am 1986; 255:78-88. 4. Marx JL. Human T-Cell Leukemia Linked to AIDS. Science 1983;220:806-809. 5. Barre-Sinoussi F, Chermann JC, Rey F, et al. Isolation of a T-Lymphotrophic Retrovirus from a patient at Risk for Acquired Immune Deficiency Syndrome (AIDS). Science 1983;220:868-871. 6. Popovic M, Sarngadharan MG, Read E, et al. Detection, Isolation,and Continuous Production of Cytopathic Retroviruses (HTLV-III) from Patients with AIDS and Pre-AIDS. Science 1984;224:497-500. 7. Gallo RC, Salahuddin SZ, Popovic M, et al. Frequent Detection and Isolation of Cytopathic Retroviruses (HTLV-III) from Patients with AIDS and at Risk for AIDS. Science 1984;224:500-502. 8. Schupbach J, Popovic M, Gilden RV, et al. Serological analysis of a Subgroup of Human T-Lymphotrophic Retroviruses (HTLV-III) Associated with AIDS. Science 1984;224:503-505. 9. Sarngadharan MG, Popovic M,Bruch L, et al. Antibodies Reactive to Human T-Lymphotrophic Retroviruses (HTLV-III) in the Serum of Patients with AIDS. Science 1984:224:506-508. 10. Culliton BJ. Gallo Inquiry Takes Puzzling New Turn. Science 1990:250:202-203. 11. Culliton BJ. Inside the Gallo Probe. Science 1990;248:1494-1498. 12. Hamilton DP. What Next in the Gallo Case? Science 1991;254:944-945. 13. Palca J. Draft of Gallo Report Sees the Light of Day. Science 1991;253:1347-1348. 14. Cohen J. HHS: Gallo Guilty of Misconduct. Science 1993:259:168-170. 15. Gallo RC, Sarin PS, Kramarsky B. et al. First isolation of HTLV-III. Nature 1986;321:119. BibliographyThe evidence that Robert Gallo and his colleagues presented on 4th May 1984 regarding HTLV-III (HIV) isolation and the role of HIV in the pathogenesis of AIDS is critically analysed. It is concluded that the evidence does not constitute proof of the isolation of a retrovirus, that the virus is exogenous or that the virus is causally related to AIDS. Medicine Essays