Syed Zaki Salahuddin

Restricted expression of human T-Cell leukemia-lymphoma virus (HTLV) in Transformed human umbilical cord blood lymphocytes

The productive infection and transformation of fresh human lymphocytes by several HTLV isolates have recently been reported. We extend these observations here with the description of multiple immortalized, non-producer, human umbilical cord blood lymphocyte cultures developed by cocultivation or fusion of fresh cells with T cells cultured from leukemia-lymphoma patients. These transformed neonatal leukocytes exhibit morphological, cytochemical, and other phenotypic characteristics similar to those of other HTLV-infected cells but, in contrast to the usual productive infection seen, these cells contain only low amounts of viral proteins and do not release virus particles. These cells contain at least one copy of HTLV proviral DNA/cell and transcribe viral RNA similar in size to virus-producing cells. Virus expression in these cultures was not enhanced by IUdR treatment. These cell cultures should be useful in studies of the regulation of viral expression in human cells and of the viral proteins and nucleic acids involved in T-cell immortalization and growth.

Apparent Transmission of Human T-Cell Leukemia Virus Type III to a Heterosexual Woman with the Acquired Immunodeficiency Syndrome

A 24-year-old woman developed the acquired immunodeficiency syndrome with lymphadenopathy, oral candidiasis, and Kaposis sarcoma. Her only known risk factor for the syndrome was sexual contact with an asymptomatic Haitian man. The woman had serologic evidence for infection with human T-cell lymphotropic virus type III, and this virus was recovered from the saliva of her sexual partner. Epidemiologic and virologic studies of the cases of such patients provide further evidence of a primary pathogenetic role for this retrovirus in the acquired immunodeficiency syndrome.

Interaction of HBLV (HHV-6) With EBV and HIV

A novel human herpesvirus, HBLV, also known as human herpesvirus-6, was originally isolated by us from AIDS and from patients with a variety of hematological disorders (1,2). Since then, HHV-6 has been isolated from AIDS patients from Africa, healthy blood donors and from infants with roseola infantum (Exanthem subitum) (3,4,5,6) by others and from patients with chronic fatigue syndrome by us (7). HHV-6 is a new member of the human herpesvirus family, and is different from other herpesviruses by immunologic and molecular analysis (1,2,8). However, the virus showed restricted sequence similarity to human cyto-megalovirus (9) and Marek’s disease herpesvirus of chickens by DNA hybridization (10). HHV-6 possesses wide cell tropism and replicates and lyses fresh and established human CD4 positive cells (7,11,12).

Chronic HTLV-III Infection in EBV-Genome Containing B-Cell Lines

We have shown that B-cell lines lacking the EBV genome could not be infected with HTLV-III regardless of the isolate used. However, upon conversion to EBV positivity these lines could be infected (1). We were interested in obtaining B-cell lines which could continuously support HTLV-III infection similar to T-cell lines and (2) would also produce an infectious virus. Moreover, we wanted to examine the HTLV-III antigen/protein profiles of such cell lines. It is possible that continuous infection of HTLV-III in B-cells may contribute to aberrant humoral responses and/or increased frequency of B-cell malignancies in AIDS patients (3). Two B-cell lines containing the EBV genome were used. LDV-7 an EBV-nonproducer B-cell line (4) after infection with HTLV-III, was designated as DA-1. Another EBV-transformed nonproducer B-cell line (Craig) after HTLV-III infection, was designated as DA-2. For comparison purposes, H-9, a T-cell line, was used (2).

Human Herpesvirus-6 (Human B-Lymphotrophic Virus)

In 1986, a novel human B-lymphotropic virus (HBLV) was isolated by us from AIDS patients and from patients with other lymphoproliterative disorders (Figs. 1 and 2) (1,2,3). Since the discovery of HBLV, now known as Human Herpesvirus-6 (HHV-6), other isolates of HHV-6 have been reported from AIDS patients in Africa (4,5,6), from healthy donors (7), infants with Roseola (Exanthem subitum) (8), and from patients with Chronic Fatigue Syndrome (9). Because of the advances in technology, considerable progress has been made in characterization of HHV-6. In this review, we briefly describe the biological, molecular, and immunological aspects of HHV-6.

The Family of Human T-Cell Leukemia Viruses and Their Role in the Cause of T-Cell Leukemia and AIDS

HTLV is the generic name we gave the first human retroviruses. The majority of isolates are very closely related; we call them human T-cell leukemia virus type I (HTLV-I). HTLV-I is endemic (at low rates) in the Caribbean, South and Central America, southeast U.S., southern Japan, and especially Africa. Viruses closely related to HTLV-I, but distinct from it, have been isolated from Old World monkeys. This and other facts led us to propose that the ancestral origin of HTLV is in Africa. Evidence indicates that HTLV-I is the direct cause of an aggressive form of adult T-cell leukemia and lymphoma. The mechanisms involved in the in vitro immortalization and in vivo malignancy are not yet clear but apparently do not involve any visible consistent chromosomal change, consistent virus expression, or known onc genes. Whichever the mechanism for growth induction by HTLV-I, its efficiency in causing malignancy may be because it has dual major effects on infected cells: (1) immortalization of some T cells, and (2) interference with function and cytopathic changes in many others. In collaboration with D. Golde and colleagues, we also discovered a second class of human T-lymphotropic retroviruses (HTLV-II). It shares many features with HTLV-I but has major genomic differences.

Human T-Cell Leukemia Viruses, T-Cell Leukemia and Aids

HTLV is the name we gave the first retrovirus isolates. Most of these are very closely related, and are called human T-cell leukemia virus type I (HTLV-I). HTLV-I is endemic, but at low rates, in southern Japan, the Caribbean, South and Central America, the southeastern U.S., and especially Africa. Viruses closely related to, but distinct from, HTLV-I have been demonstrated in Old World monkeys. This finding, as well as seroepidemiology, led us to propose that HTLV originated in Africa. HTLV-I has been shown to be the direct cause of an aggressive form of adult T-cell leukemia/lymphoma. The mechanisms which result in in vitro immortalization and in vivo malignancy are not yet known but apparently do not seem to involve visible consistent chromosomal changes, continuous expression of virus, or any of the known onc genes. Whatever the mechanism for growth induction in vitro by HTLV-I, its efficiency in causing malignancy may be because of its dual major effects on infected cells. These are: (1) immortalization of some T cells, especially those which are 0KT4+, and (2) abrogation of function and/or cytopathic changes in others. We have discovered a second class of human T-lymphotropic retroviruses (HTLV-II), in collaboration with D. Golde and colleagues. It shares many of the properties of HTLV-I but has major difference in the genome. It has been isolated only twice, once from a patient with hairy cell leukemia, and recently from a patient with AIDS. HTLV-III is the third member of the HTLV family.