A historical reflection on the discovery of human retroviruses

The discovery of HIV-1 as the cause of AIDS was one of the major scientific achievements during the last century. Here the events leading to this discovery are reviewed with particular attention to priority and actual contributions by those involved. Since I would argue that discovering HIV was dependent on the previous discovery of the first human retrovirus HTLV-I, the history of this discovery is also re-examined. The first human retroviruses (HTLV-I) was first reported by Robert C. Gallo and coworkers in 1980 and reconfirmed by Yorio Hinuma and coworkers in 1981. These discoveries were in turn dependent on the previous discovery by Gallo and coworkers in 1976 of interleukin 2 or T-cell growth factor as it was called then. HTLV-II was described by Gallo's group in 1982. A human retrovirus distinct from HTLV-I and HTLV-II in that it was shown to have the morphology of a lentivirus was in my mind described for the first time by Luc Montagnier in an oral presentation at Cold Spring Harbor in September of 1983. This virus was isolated from a patient with lymphadenopathy using the protocol previously described for HTLV by Gallo. The first peer reviewed paper by Montagnier's group of such a retrovirus, isolated from two siblings of whom one with AIDS, appeared in Lancet in April of 1984. However, the proof that a new human retrovirus (HIV-1) was the cause of AIDS was first established in four publications by Gallo's group in the May 4th issue of Science in 1984

A reflection on HIV/AIDS research after 25 years

Dr. Robert C. Gallo provides a personal reflection on the 25 year history of AIDS

Living Invisible: HTLV-1-Infected Persons and the Lack of Care in Public Health

Human T-cell lymphotropic virus type 1 (HTLV-1) infection is commonly confounded with Human Immunodeficiency Virus (HIV) infection and it is unknown to many health professionals. It is endemic in many countries and there is no effective treatment available. Although a few individuals have severe symptoms, most patients remain asymptomatic throughout their lives. Further, HTLV-1 is considered a neglected public health problem and limited studies cover specific patients' needs and emotional experiences. To better understand how women and men living with HTLV-1 experience the disease and what issues exist in their healthcare processes, we conducted a qualitative study of both symptomatic and asymptomatic patients at an outpatient clinic at the Emílio Ribas Infectious Diseases Institute in São Paulo, Brazil. We found that the main focus of health staff was on illness risk, but not identifying infected relatives and preventing new infections. This point of view, ultimately neglected patients' complex demands, and overshadows the prevention of new infections and contributes to the lack of care in public health for HTLV-1 infected subjects. Furthermore, this perpetuates the infection among these populations and the patients experience an “invisibility” of their specific needs, such as reproductive rights and feel that their rights as citizens are ignored

Increased production of viral proteins by a 3'-LTR-deleted infectious clone of human T-cell leukemia virus type 1

We previously reported that a full-length provirus of HTLV-1 was directly constructed from the HTLV-1-transformed cell line MT-2 using overlapping polymerase chain reaction (PCR) and cloned into a plasmid vector (pFL-MT2). 293T cells transfected with pFL-MT2 alone did not produce virus particles because there was no expression of the viral transactivator protein Tax, whereas cells transfected with pFL-MT2 plus a Tax expression vector produced virus-like particles. In the process of constructing the HTLV-1 provirus by overlapping PCR, we also constructed an incomplete molecular clone, in which the 3' long terminal repeat (LTR) was replaced with the endogenous human gene, which resulted in the expression of a tax gene shorter by 43 bp. This incomplete molecular clone alone expressed Tax and produced the viral protein in transfected cells. Various clones were then constructed with different lengths of the 3' LTR and lacking the reverse-direction TATA box. The clones contained over 113 bp of the 3' LTR, with no reverse-direction TATA box, which might express the full-length tax gene, and did not produce the viral antigen. These results suggest that Tax in which the C-terminal portion is deleted is more strongly expressed than the wild-type protein and has transcriptional activity

Mechanisms of HTLV-1 persistence and transformation

Adult T-cell leukaemia (ATL) is caused by the human T-cell lymphotropic virus type 1 (HTLV-1). HTLV-1 has elaborated strategies to persist and replicate in the presence of a strong immune response. In this review, we summarise these mechanisms and their contribution to T-cell transformation and ATL development

Identification of Replication Competent Murine Gammaretroviruses in Commonly Used Prostate Cancer Cell Lines

A newly discovered gammaretrovirus, termed XMRV, was recently reported to be present in the prostate cancer cell line CWR22Rv1. Using a combination of both immunohistochemistry with broadly-reactive murine leukemia virus (MLV) anti-sera and PCR, we determined if additional prostate cancer or other cell lines contain XMRV or MLV-related viruses. Our study included a total of 72 cell lines, which included 58 of the 60 human cancer cell lines used in anticancer drug screens and maintained at the NCI-Frederick (NCI-60). We have identified gammaretroviruses in two additional prostate cancer cell lines: LAPC4 and VCaP, and show that these viruses are replication competent. Viral genome sequencing identified the virus in LAPC4 and VCaP as nearly identical to another known xenotropic MLV, Bxv-1. We also identified a gammaretrovirus in the non-small-cell lung carcinoma cell line EKVX. Prostate cancer cell lines appear to have a propensity for infection with murine gammaretroviruses, and we propose that this may be in part due to cell line establishment by xenograft passage in immunocompromised mice. It is unclear if infection with these viruses is necessary for cell line establishment, or what confounding role they may play in experiments performed with these commonly used lines. Importantly, our results suggest a need for regular screening of cancer cell lines for retroviral “contamination”, much like routine mycoplasma testing

The HBZ gene, a key player in HTLV-1 pathogenesis

Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia/lymphoma (ATL) and is also associated with a variety of lymphocyte-mediated diseases. The HTLV-1 basic leucine zipper (HBZ) gene, found to be consistently expressed in ATL, has recently been the subject of intensive research efforts. In this review, we summarize recent findings about HBZ and discuss its roles and functions not only in the virus life cycle, but also in HTLV-1 disease pathogenesis

Exacerbated inflammatory cellular immune response characteristics of HAM/TSP is observed in a large proportion of HTLV-I asymptomatic carriers

BACKGROUND: A small fraction of Human T cell Leukemia Virus type-1 (HTLV-I) infected subjects develop a severe form of myelopathy. It has been established that patients with HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) show an exaggerated immune response when compared with the immunological response observed in HTLV-I asymptomatic carriers. In this study the immunological responses in HAM/TSP patients and in HTLV-I asymptomatic carriers were compared using several immunological assays to identify immunological markers associated with progression from infection to disease. METHODS: Immunoproliferation assays, cytokine levels of unstimulated cultures, and flow cytometry analysis were used to evaluate the studied groups. Nonparametric tests (Mann-Whitney U test and Wilcoxon matched-pairs signed ranks) were used to compare the difference between the groups. RESULTS: Although both groups showed great variability, HAM/TSP patients had higher spontaneous lymphoproliferation as well as higher IFN-γ levels in unstimulated supernatants when compared with asymptomatic carriers. Flow cytometry studies demonstrated a high frequency of inflammatory cytokine (IFN-γ and TNF-α) producing lymphocytes in HAM/TSP as compared to the asymptomatic group. This difference was accounted for mainly by an increase in CD8 cell production of these cytokines. Moreover, the HAM/TSP patients also expressed an increased frequency of CD28-/CD8+ T cells. Since forty percent of the asymptomatic carriers had spontaneous lymphoproliferation and IFN-γ production similar to HAM/TSP patients, IFN-γ levels were measured eight months after the first evaluation in some of these patients to observe if this was a transient or a persistent situation. No significant difference was observed between the means of IFN-γ levels in the first and second evaluation. CONCLUSIONS: The finding that a large proportion of HTLV-I carriers present similar immunological responses to those observed in HAM/TSP, strongly argues for further studies to evaluate these parameters as markers of HAM/TSP progression