Human T-lymphotropic Virus Type III Research Articles

New cholesterol-specific antibodies remodel HIV-1 target cells’ surface and inhibit their in vitro virus production

The importance of membrane rafts in HIV-1 infection is still in the focus of interest. Here, we report that new monoclonal anticholesterol IgG antibodies (ACHAs), recognizing clustered membrane cholesterol (e.g., in lipid rafts), rearrange the lateral molecular organization of HIV-1 receptors and coreceptors in the plasma membrane of HIV-1 permissive human T-cells and macrophages. This remodeling is accompanied with a substantial inhibition of their infection and HIV-1 production in vitro. ACHAs promote the association of CXCR4 with both CD4 and lipid rafts, consistent with the decreased lateral mobility of CXCR4, while Fab fragments of ACHAs do not show these effects. ACHAs do not directly mask the extracellular domains of either CD4 or CXCR4 nor do they affect CXCR4 internalization. No significant inhibition of HIV production is seen when the virus is preincubated with the antibodies prior to infection. Thus, we propose that the observed inhibition is mainly due to the membrane remodeling induced by cholesterol-specific antibodies on the target cells. This, in turn, may prevent the proper spatio-temporal juxtaposition of HIV-1 glycoproteins with CD4 and chemokine receptors, thus negatively interfering with virus attachment/entry.

AIDS in Africa: an epidemiologic paradigm

THE ACQUIRED IMMUNE DEFICIENCY SYNDROME (AIDS) has become recognized as a global health problem. Cases have now been reported in 74 countries with more than 25,000 cases in the United States, nearly 3,000 cases in other countries of the Americas, more than 3,000 cases in Europe, and several thousand cases suspected and many more unrecognized in Africa (1,2). It is estimated that at least several million people worldwide have been infected with the causative agent, referred to as human T-lymphotropic virus type III (HTLV-III)/lymphadenopathy virus (LAV), or more recently as human immunodeficiency virus (HIV) (3). As many as 10 to 30% of these HIV-infected individuals may develop AIDS within the next 5 to 10 years (4-6). With the present lack of a curative therapy or vaccine, this disease now ranks as the most serious epidemic of the past 50 years. Although the immunopathogenesis of HIV infection is similar in most AIDS patients (7), the epidemiology and clinical features of the infection in different countries may vary, depending on cultural differences, endemic diseases, and other unidentified risk factors. In Africa, the different clinical features of AIDS and the difficulty in identifying the risk factors frequently associated with AIDS in the United States, such as homosexuality and intravenous drug use, have raised questions regarding the nature of the disease and the factors responsible for HIV dissemination in that continent (1,2,4). Here we review the epidemiologic and clinical features of AIDS in Africa and discuss the potential problems faced by public health officials in developing prevention and control strategies. Historical Perspective Shortly after the recognition of AIDS in the United States, cases of the disease were identified among Africans residing in Europe (8). Immunologically, these cases were identical to AIDS cases in the United States, with marked depression of CD[4.sup.+] lymphocytes (T-helper cells) and cell-mediated immunosuppression. Clinically, the African cases resembled Haitian AIDS cases with prominent gastrointestinal symptoms and opportunistic infections, such as oroesophageal candidiasis, cryptococcosis, toxoplasmosis, and mycobacterial infections (8-10). As of 31 March 1986, 177 cases of AIDS were reported among Africans residing in ten European countries (Table 1) (2). These cases originated from 24 African countries, mostly in Central Africa. In contrast to the European cases, African cases had a male to female ratio of 1.7:1, and 90% had no identifiable risk factors. Even among Europeans with AIDS and a recent history of travel to Africa, nearly 90% denied homosexuality or intravenous drug use. These unusual epidemiologic features prompted a series of investigations in 1983 to determine the pattern of AIDS in Central Africa. During a 4-week period, 38 patients with AIDS and 20 patients with AIDS-related diseases were identified in a large general hospital in Kinshasa, Zaire (11). Cases were equally distributed among men and women; females with the disease were younger and more often unmarried than male AIDS patients; and clusters of AIDS cases among men and women were linked by heterosexual contact. In a simultaneous investigation of 26 cases in Kigali, Rwanda, 43% of the female patients were identified as prostitutes (12). The fact that there was no evidence of homosexual transmission or intravenous drug use indicated that the pattern of AIDS transmission was different, and that heterosexual contact might be an important factor in transmission. Although the recognition of AIDS in Africa is consistent with the temporal occurrence of the disease in the United States and Haiti, several case reports and retrospective serologic surveys of banked sera have suggested that HIV infection may have occurred earlier in Africa (13-15). The earliest serologic response to HIV was found in serum collected from Kinshasa, Zaire, in 1959 (14). Sera from West and East Africa in the 1960's and early 1970's have also shown a high prevalence of weakly Positive specimens (for example, seropositivity in 1. …

Evaluation of AIDS-prevention measures among drug users. The Amsterdam experience (doctoral thesis)

The antibodies to human T-lym-photropic virus type I/II (HTLV-I/II) were determined in non-intravenous drug-using female prostitutes from Merida Yucatan, Mexico. Serum specimens from 282 female prostitutes collected during 1990 were tested initially by enzyme immunoassay and further confirmed by western blot assays. Of these, 5 (1.8%, 95% confidence interval 0.2 to 3.3) were shown to be HTLV-I/II positive (reactivity to p24gag and gp68/r21eenv). All five specimens were shown to be infected with HTLV-II by immunoassays using type-specific synthetic peptides and recombinant proteins. Long-term cell lines developed from two individuals demonstrated active viral replication and were of CD8 phenotype. Polymerase chain reaction analysis from four of these five prostitutes demonstrated HTLV-II-specific amplification of all four specimens, of which one was subtype a (HTLV-IIa) and three were subtype b (HTLV-IIb). These data show that HTLV-II is the predominant HTLV type among female prostitutes from the Yucatan.

An HTLV-I/II Vaccine: From Animal Models to Clinical Trials?

A human T-lymphotropic virus type I/II (HTLV-I/II) vaccine is necessary in view of two etiologically related, life-threatening diseases, namely, adult T-cell leukemia/lymphoma and tropical spastic paraparesis/HTLV-I-associated myelopathy. When the risk of developing autoimmune diseases such as uveitis, polymyositis, and arthritis is included, one can estimate the life-long risk of infected individuals to develop an HTLV associated pathology as approximately 10%. The populations at risk are, in a large majority, from developing countries but the epidemic of HTLV-II infection in intravenous drug users (IVDU) represents a possible reservoir for dissemination in the general population. The number of HTLV-I-infected individuals (15 to 25 million), together with the severity of associated disease, justifies the development of a vaccine. Different vaccine preparations have been developed, using mostly recombinant pox and adenoviruses, but DNA plasmid technology will soon become a feasible approach. Various animal models exist for experimental viral infections, involving rats, rabbits, or monkeys, but up to now, neither hematological nor neurological disorders have been induced by HTLV infection in such animal models. For long-term protection from HTLV-I-associated diseases, vaccination should induce both neutralizing antibodies and specific cell-mediated immunity. This will require the incorporation of both env and gag coding sequences in the vaccine preparations. Preventive clinical trials may involve different cohorts of seronegative young girls from endemic areas prior to sexual activity and IVDU in the industrialized world. In parallel, one should consider therapeutic vaccine trials in HTLV-I-positive mothers and IVDU to protect them against disease development. The observed rate of seroconversion in these different cohorts makes such trials feasible.

Human T Lymphotropic Virus Type II (HTLV-II) Infection Among Female Prostitutes in Yucatan, Mexico

The antibodies to human T-lymphotropic virus type I/II (HTLV-I/II) were determined in non-intravenous drug-using female prostitutes from Merida Yucatan, Mexico. Serum specimens from 282 female prostitutes collected during 1990 were tested initially by enzyme immunoassay and further confirmed by western blot assays. Of these, 5 (1.8%, 95% confidence interval 0.2 to 3.3) were shown to be HTLV-I/II positive (reactivity to p24gag and gp68/r21eenv). All five specimens were shown to be infected with HTLV-II by immunoassays using type-specific synthetic peptides and recombinant proteins. Long-term cell lines developed from two individuals demonstrated active viral replication and were of CD8 phenotype. Polymerase chain reaction analysis from four of these five prostitutes demonstrated HTLV-II-specific amplification of all four specimens, of which one was subtype a (HTLV-IIa) and three were subtype b (HTLV-IIb). These data show that HTLV-II is the predominant HTLV type among female prostitutes from the Yucatan.

Antibody to Human T-Lymphotropic Virus Type I/II (HTLV-I/II) Among Male Inmates Entering Maryland Prisons

Serum specimens that had been obtained for routine operational procedures from consecutive entering male inmates during Spring 1987 and the same calendar period in 1988 were tested to identify prevalence and risk groups for antibody to HTLV-I/II. Specimens were assayed for antibody to HTLV-I/II using ELISA, RIPA, and Western blot techniques. Demographics were compared by serostatus using chi 2 and Fisher's exact tests. Of the 1,932 inmates entering prison, 49.3% were 25 years of age or older, 70.1% were black, 62.4% were committed from the Baltimore metropolitan area, 34.1% were intravenous drug users, and 7.0% demonstrated antibody to HIV-1. Among 1,932 inmates, 18 (0.9%) were HTLV-I/II seropositive. All seropositives were black; age greater than 25 years old was significantly (p less than 0.01) associated with seropositivity. Reactivity to HTLV-I/II did not vary significantly by year of entry, HIV-1 serostatus, jurisdiction, offense category, or sentence. Prevalence of HTLV-I/II among incoming male inmates was elevated compared to available local population comparisons. Additional blinded epidemiological serosurveys of antibody to HTLV-I/II are indicated for prison populations in order to monitor the extent and scope of infection in this population.

Antibody to Human T-Lymphotropic Virus Type I/II (HTLV-I/II) Among Male Inmates Entering Maryland Prisons

Serum specimens that had been obtained for routine operational procedures from consecutive entering male inmates during Spring 1987 and the same calendar period in 1988 were tested to identify prevalence and risk groups for antibody to HTLV-I/II. Specimens were assayed for antibody to HTLV-I/II using ELISA, RIPA, and Western blot techniques. Demographics were compared by serostatus using X2 and Fisher's exact tests. Of the 1,932 inmates entering prison, 49.3% were 25 years of age or older, 70.1% were black, 62.4% were committed from the Baltimore metropolitan area, 34.1% were intravenous drug users, and 7.0% demonstrated antibody to HIV-1. Among 1,932 inmates, 18 (0.9%) were HTLV-I/II seropositive. All seropositives were black; age >25 years old was significantly (p < 0.01) associated with seropositivity. Reactivity to HTLV-I/II did not vary significantly by year of entry, HIV-1 serostatus, jurisdiction, offense category, or sentence. Prevalence of HTLV-I/II among incoming male inmates was elevated compared to available local population comparisons. Additional blinded epidemiological serosurveys of antibody to HTLV-I/II are indicated for prison populations in order to monitor the extent and scope of infection in this population.

Surgical Approach to Generalized Lymphadenopathy in Homosexual Men

Sixty patients considered at risk for acquired immune deficiency syndrome (AIDS) were referred for evaluation of generalized lymphadenopathy. All patients were seropositive for antibody to human T-lymphotropic virus type III (HTLV-III). Multiple lymph node biopsies from different nodal areas were performed. The results were evaluated in order to see if the diagnostic yield is increased by the performance of multiple lymph node biopsies. In no case was additional diagnostic information provided by performing multiple biopsies. In patients with diffuse lymphadenopathy who are at risk for AIDS, single node excisional biopsy is indicated to rule out opportunistic infection or/and tumor.

Surgical approach to generalized lymphadenopathy in homosexual men.

Sixty patients considered at risk for acquired immune deficiency syndrome (AIDS) were referred for evaluation of generalized lymphadenopathy. All patients were seropositive for antibody to human T-lymphotropic virus type III (HTLV-III). Multiple lymph node biopsies from different nodal areas were performed. The results were evaluated in order to see if the diagnostic yield is increased by the performance of multiple lymph node biopsies. In no case was additional diagnostic information provided by performing multiple biopsies. In patients with diffuse lymphadenopathy who are at risk for AIDS, single node excisional biopsy is indicated to rule out opportunistic infection or/and tumor.

Control of hepatitis B and human T lymphotropic virus type III (HTLV-III) in homosexuals in Sheffield

Control of hepatitis B and human T lymphotropic virus type III (HTLV-III) in homosexuals in Sheffield

Polyclonal polymorphic B-cell lymphoproliferative disorder with prominent pulmonary involvement in children with acquired immune deficiency syndrome.

Four cases of pediatric Acquired Immune Deficiency Syndrome (AIDS) with lymphoproliferative disorder are described and other lymphoid lesions in previously reported cases of pediatric AIDS are reviewed. The lymphoproliferative disorder was characterized by polyclonal, polymorphic B-cell content without evidence of cellular atypia, necrosis or prominent mitotic activity but with predominantly extranodal systemic and prominent pulmonary involvement. Since the lesion has overlapping features it is considered to be intermediate between benign and malignant lymphoproliferations and designated as polyclonal, polymorphic B-cell lymphoproliferative disorder (PBLD) of pediatric AIDS. The PBLD is part of a spectrum of lymphoid lesions in pediatric AIDS consisting of follicular lymphoid hyperplasia of nodal and extranodal sites, pulmonary lymphoid hyperplasia/lymphoid interstitial pneumonitis complex (PLH/LIP complex) in cases previously reported by the authors, and also malignant lymphoma reported by others. It is possible that Epstein-Barr virus (EBV) by itself or in synergism with human T-lymphotropic virus-type III (HTLV-III) is related to pathogenesis of PBLD in children with AIDS.

Anticardiolipin antibodies associated with HTLV-III infection.

Anticardiolipin antibody levels were determined in 73 homosexual men. Thirty of these patients had acquired immunodeficiency syndrome (AIDS), 16 patients had the AIDS-related complex (ARC) and 27 were healthy. Antibodies to human T-lymphotropic virus type III (HTLV-III) were detected in all patients with AIDS and ARC and in 11 of the healthy homosexuals. Eight patients with positive fluorescent treponemal antibody absorption test were excluded from the study. High levels of IgG-anticardiolipin antibodies were present in 23 of the 28 patients with AIDS; 12 of the 14 with ARC; five of the 10 HTLV-III positive healthy homosexuals; and none of the 13 HTLV-III negative healthy homosexuals. High levels of IgM-ACA were detected only in four patients with AIDS. The IgG-anticardiolipin levels were higher in the HTLV-III positive patients than in the HTLV negative group (P = 0.013). None of the patients with anticardiolipin antibodies exhibited venous thrombosis.

Subacute encephalomyelitis of AIDS and its relation to HTLV-III infection.

Subacute encephalitis, characterized by demyelination, gliosis of the gray and white matter, focal necrosis, microglial nodules, atypical oligodendrocyte nuclei, and multinucleation of cells, was present in 27 of 30 (90%) autopsied patients with acquired immune deficiency syndrome (AIDS) or AIDS-related complex. Subacute encephalitis was mainly distributed in the frontal (58%) and temporal (69%) lobes, basal ganglia (77%), amygdala (80%), and hippocampus (64%). Ten (37%) with moderate or severe subacute encephalitis were demented; 82% with mild subacute encephalitis had no recognized neurologic disorder. Human T-lymphotropic virus type III (HTLV-III) was isolated from neural tissue or CSF in 11 of 13 patients, 10 with subacute encephalitis, and 1 without CNS lesions. We conclude that subacute encephalitis is common in AIDS patients and is most likely caused by CNS infection with HTLV-III.

Dermatologic findings and manifestations of acquired immunodeficiency syndrome (AIDS)

We present a review of the spectrum of human T-lymphotropic virus type III (HTLV-III) infection with particular emphasis on cutaneous manifestations in 217 patients. Correlations are made with immunodeficiency as measured by absolute T-helper cell number. A classification is presented of these dermatologic findings.

Neoplastic complications of HTLV-III infection. Lymphomas and solid tumors

Neoplastic disease arose in 29 of 200 patients infected with human T lymphotropic virus type III (HTLV-III) seen at a suburban hospital. Seventeen patients had Kaposi's sarcoma, one of whom also had colon carcinoma. Nine patients had lymphoproliferative disorders (seven lymphomas, one T suppressor cell chronic lymphocytic leukemia, and one multiple myeloma), including three with concomitant Kaposi's sarcoma and one with colon cancer. One other patient had colon cancer, one had a seminoma, and one had pancreatic cancer. Kaposi's sarcoma as a complication of AIDS occurred mainly in homosexuals (17 of 42 homosexuals, one of 17 drug abusers, one of five heterosexually promiscuous patients, and one of six patients who had previously received transfusions). The high-grade lymphomas did not show a predilection for any particular AIDS risk group. Three of four solid tumors arose in elderly AIDS patients. Twenty-five of 75 patients with CDC-defined AIDS had a neoplastic disorder (26 are still alive and may yet demonstrate malignancy). Few other diseases of man have been associated with as high an incidence of neoplastic transformation as occurs with HTLV-III infection.

Acquired immunodeficiency syndrome: a perspective.

AbstractInfection by the Human T‐Lymphotropic Virus Type III (HTLV‐III) may lead to the devastating and ultimately fatal disease, acquired immunodeficiency syndrome (AIDS). As the virus is transmitted in similar ways to the hepatitis B virus, concern has developed within the dental profession regarding the possibility of clinicians acquiring AIDS through treatment of infected patients. This paper aims to place the significance of HTLV‐III infection to dental practice in perspective.

A second discriminator for biological false positive results in enzyme-linked immunosorbent assays for antibodies to human immunodeficiency virus (HTLV-III/LAV).

Two commercially available enzyme-linked immunosorbent assays (ELISA) were compared in screening a large population of volunteer blood donors. One ELISA utilized the human T-lymphotropic virus, Type III (HTLV-III) grown on National Institutes of Health T-lymphocyte cell line, H-9, as antigen source; the second used lymphadenopathy associated virus (LAV) grown on Pasteur Institutes' T-lymphocyte cell line, CEM-F. Biological false positives (BFP) occurred at a rate of approximately 0.5 percent using each antigen source. However, distinct populations of BFP donors were detected when the two antigen sources were compared. Results indicate that at least two separate sets of antigens are recognized in ELISA by our normal population and result in BFP. Sequential utilization of tests using these distinct sources adds a second discriminator to identification of BFP, with the potential for decreasing the requirement for Western blot analysis.

Isolation of HTLV-III from CSF and neural tissues of patients with AIDS-related neurological syndromes

Summary Virus isolation studies were conducted on 56 central nervous system (CNS) specimens from 45 patients in order to determine if the human T-lymphotropic virus type III (HTLV-III) is directly involved in the pathogenesis of the neurological disorders frequently encountered in the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex (ARC). We now report the recovery of HTLV-III from at least one CNS specimen from 24 of 33 patients with AIDS-related neurological syndromes. In one patient, HTLV-III was isolated from the cerebrospinal fluid (CSF) during acute aseptic meningitis associated with HTLV-III seroconversion. HTLV-III has also been isolated from CSF of 6 of 7 patients with AIDS or ARC and unexplained chronic meningitis. In addition, of 16 patients with AIDS-related dementia, 10 were culture-positive for HTLV-III from CSF, brain tissue or both. Furthermore, we have cultured HTLV-III from spinal cord of a patient with myelopathy and from sural nerve of a patient with peripheral neuropathy. These findings suggest that HTLV-III (1) is also neurotropic, (2) is capable of causing acute meningitis, (3) is responsible for the AIDS-related chronic meningitis and dementia, and (4) may be the cause of the spinal cord degeneration and peripheral neuropathy seen in AIDS and ARC.

Molecular characterization of human immunodeficiency virus from Zaire: nucleotide sequence analysis identifies conserved and variable domains in the envelope gene

To examine the genetic relatedness of human immunodeficiency viruses (HIV) from different geographic locations, we molecularly cloned the genome of HIV isolated from a Zairian AIDS patient. Restriction mapping of the recombinant clone, designated HIV-Zr6, revealed both common (as observed in other HIV isolates) and unique restriction sites. The DNA clone of HIV-Zr6, shown to give rise to infectious cytopathic virus after transfection of cultured lymphoid cells, was sequenced in several regions. The long terminal repeat (LTR), open reading frame 1 (ORF1), C-terminal envelope ( env) gene domain, and ORF2 showed less than 6% difference in nucleotide sequence when compared to other HIV isolates including human T-lymphotropic virus-type III (HTLV-III) clone BIO, lymphadenopathy-associated virus-1 (LAV-1), and AIDS-associated retrovirus-2 (ARV-2). About 15% difference in nucleotide sequences was noted in the N-terminal env gene domain. Alignments of en v gene sequences revealed conserved, moderately variable, and hypervariable stretches in the predicted amino acid sequences. This model provides a basis for assessing the significance of sequence variation on properties controlled by the viral Env glycoproteins such as cell tropism and immunogenicity.

Risk of AIDS to Health Care Workers

This article reviews evidence on the risk of acquired immunodeficiency syndrome (AIDS) to health workers and suggests guidelines for the clinical care of AIDS patients. No health worker in the world has yet contracted AIDS from a patient. However seroconversion to human T-lymphotropic virus type III (HTLV-III) has occurred in a small number. A serologic study of 1758 US health workers who had direct contact with AIDS patients found HTLV-III antibodies in the blood of 26 (1.5%) but 23 of these workers were in another high-risk group for AIDS (homosexual men). Similar studies in San Francisco and London that included large numbers of health workers who sustained needlestick injuries while working with AIDS patients have failed to detect seroconversion. A further study of the siblings children and parents of 39 adult AIDS victims also found no evidence of infection suggesting that AIDS does not occur by casual contact. HTLV-III appears to be less communicable than the hepatitis B virus which health service staff have contracted from infected blood. It is recommended that when a patient known to be positive for HTLV-III is admitted to the hospital all specimens from that patient should be labelled with a biohazard sticker. Specimens should be handled and processed in the same way as those from hepatitis B patients. Staff should wear gloves and a plastic apron when attending to these patients. Although isolation is not necessary it is unwise to place patients with HTLV-III in the same ward with patients who are immunocompromised for other reasons given the risk of 2-way transmission of infection. Finally every effort should be made to maintain confidentiality and lists of HTLV-III-positive patients should not be displayed.