On June 5 1981, MMWR published a report of Pneumocystis carinii pneumonia in five previously healthy young men in Los Angeles, California; two had died. This report later was acknowledged as the first published scientific account of what would become known as human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS). Thirty years after that first report, the most recent estimate is that 33.3 million persons were living with HIV infection worldwide at the end of 2009.
In 1981 I was working on my PhD (on poliovirus) when I first heard about AIDS. Someone from the department came back from a trip to San Francisco with lurid and scary tales. Over the next couple of years, my interest in retroviruses grew and when I finished my PhD in 1984, I went off to California to work on HTLV and HIV.
In the United States, CDC estimates that 1,178,350 persons were living with HIV at the end of 2008, with 594,496 having died from AIDS since 1981. At this 30-year mark, efforts are being accelerated under the National HIV/AIDS Strategy of the United States, with goals of reducing the number of persons who become infected with HIV, increasing access to care and optimizing health outcomes for persons living with HIV, and reducing HIV-related health disparities.
I worked on HIV for 10 years before moving on to other things. I still maintain a close interest in the topic. 30 years – it seems like yesterday.
In October 2009 it was reported that 68 of 101 patients with chronic fatigue syndrome (CFS) in the USA were infected with a novel gamma retrovirus, xenotropic murine leukaemia virus-related virus (XMRV), a virus previously linked to prostate cancer. This finding, if confirmed, would have a profound effect on the understanding and treatment of an incapacitating disease affecting millions worldwide.
No Evidence of XMRV or Related Retroviruses in a London HIV-1-Positive Patient Cohort. 2011 PLoS ONE 6(3): e18096. doi:10.1371/journal.pone.0018096
Background
Several studies have implicated a recently discovered gammaretrovirus, XMRV (Xenotropic murine leukaemia virus-related virus), in chronic fatigue syndrome and prostate cancer, though whether as causative agent or opportunistic infection is unclear. It has also been suggested that the virus can be found circulating amongst the general population. The discovery has been controversial, with conflicting results from attempts to reproduce the original studies.
Methodology/Principal Findings
We extracted peripheral blood DNA from a cohort of 540 HIV-1-positive patients (approximately 20% of whom have never been on anti-retroviral treatment) and determined the presence of XMRV and related viruses using TaqMan PCR. While we were able to amplify as few as 5 copies of positive control DNA, we did not find any positive samples in the patient cohort.
Conclusions/Significance
In view of these negative findings in this highly susceptible group, we conclude that it is unlikely that XMRV or related viruses are circulating at a significant level, if at all, in HIV-1-positive patients in London or in the general population.
Lentiviruses owe their name (lenti means slow in latin) to the long period of time elapsing between the initial infection and the onset of the disease, that can protract over a period of months or even years. Viruses belonging to the Lentivirus genus are present in primates, ungulates (horse, cattle, sheep and goat) and felids (cat). Primates are the natural host for several lineages of closely related simian and human immunodeficiency viruses (SIV and HIV) that are the causative agents of acquired immunodeficiency syndrome (AIDS).
Lentivirus vectors bears an obvious advantage over other retrovirus vectors in that they offer the possibility to efficiently target non-dividing and differentiated cells, such as neurons. Paradoxically, the use of retrovirus vectors is hindered by the same process that makes them interesting for gene therapy, i.e., integration. This process is largely nonspecific and, as it has been shown in vivo, may either be of no consequence to the cell or lead to serious drawbacks. Although this problem may in theory be minimized in gene therapy applications targeting terminally differentiated cells, the problem of integration is serious. To this end, a number of alternative strategies have been developed, ranging from the redirection of retrovirus integration to particular chromosomal locations, to the ablation of the integration process altogether. Although in its infancy, the efforts to redirect retrovirus integration must be pursued and researchers may possibly transpose to lentiviruses a mechanism of specific integration used by other viruses.
The Inside Out of Lentiviral Vectors. (2011) Viruses 3(2): 132-159; doi:10.3390/v3020132
Lentiviruses induce a wide variety of pathologies in different animal species. A common feature of the replicative cycle of these viruses is their ability to target non-dividing cells, a property that constitutes an extremely attractive asset in gene therapy. In this review, we shall describe the main basic aspects of the virology of lentiviruses that were exploited to obtain efficient gene transfer vectors. In addition, we shall discuss some of the hurdles that oppose the efficient genetic modification mediated by lentiviral vectors and the strategies that are being developed to circumvent them.
“It’s hard to visualise what something as small and complex as the HIV virus actually looks like. But now Ivan Konstantinov and his team from Visual Science have created the most-detailed 3D model of the virus to date (see video above). An image of this visualisation just won first place in the 2010 International Science and Engineering Visualization Challenge, sponsored jointly by the journal Science and the National Science Foundation (NSF). The model contains 17 different viral and cellular proteins and the membrane incorporates 160 thousand lipid molecules, of 8 different types, in the same proportions as in an actual HIV particle. It denotes the parts encoded by the virus’s own genome in orange, while grey shades indicate structures taken into the virus when it interacts with a human cell. To create the visualisation, the team consulted over 100 articles on HIV from leading science journals and talked to experts in the field. Then they reconstructed viral proteins from X-rays before assembling the structure of an entire HIV particle. The final appearance was achieved by experienced designers and 3D graphics specialists.”
Endogenous retroviruses (ERVs) have spread through mammalian genomes throughout evolution, resulting in thousands of copies or fragments of ERVs, encompassing an estimated 7% of the human genome. However, despite their abundance, specific functions could only rarely be assigned to ERVs. The LTRs of such viruses can serve as strong promoters/enhancers, boosting the transcription of viral or adjacent cellular genes. In a recent discovery of a pathologic example in humans, the derepression of an LTR was found to induce the driver proto-oncogene CSF1R in Hodgkin’s lymphoma. The promoter activity of LTRs can display various tissue specificities and is sometimes limited to germ cells. For example, an LTR from the human endogenous retrovirus 9 (ERV9) predominantly transcribes in testis.
Maintaining genomic integrity in the germ line is a fundamental prerequisite for the evolutionary stability of a species. To achieve this, germ cells with damaged DNA need to be efficiently eliminated. This elimination is particularly important when an individual’s fertility is maintained over several decades, as is the case in humans and great apes (Hominidae). In these species, the already long time frame of fertility in females is even more extended in males. However, only very limited knowledge exists on how the genomic integrity of the male germ line is controlled and preserved in humans.
p63 is a homolog of the tumor suppressor p53. In somatic cells, p53 is the quintessential mediator of apoptosis in response to DNA damage, thus acting as the guardian of the genome. Tumor suppressor p53 binds and transcriptionally activates multiple proapoptotic genes. Moreover, p53 directly associates with mitochondria, and by interacting with anti- and proapoptotic members of the Bcl2 family of outer membrane permeability regulators, triggers the release of cytochrome c, jumpstarting apoptosis. This paper shows that unique isoforms of p63 are highly and specifically expressed in human testis as a result of an upstream insertion of an ERV9 LTR with strong promoter activity that occurred 10 to 15 million years ago during primate evolution at the branching point to long-lived Hominidae. Upon DNA damage, the resulting germ cell-associated, transcriptionally active p63 suppresses proliferation and induces apoptosis. Conversely, GTAp63 expression is frequently lost in human testicular cancers.
Scientists are studying a retrovirus that has been dormant in chimpanzees and their ancestors for at least one million years. The virus, known as CERV2, is present in the genomes of chimpanzees, but not those of humans, suggesting that chimpanzees’ ancestors became infected after they diverged from human ancestors 5–6 million years ago. The virus was clearly replicating around the time that the first humans were trotting around Africa and beginning to think about colonizing the rest of the world. As a receptor, the ancient virus exploited a transport protein that normally transports copper into and out of cells.
Identification of a receptor for an extinct virus. PNAS USA October 25, 2010 doi: 10.1073/pnas.101234410
The resurrection of endogenous retroviruses from inactive molecular fossils has allowed the investigation of interactions between extinct pathogens and their hosts that occurred millions of years ago. Two such paleoviruses, chimpanzee endogenous retrovirus-1 and -2 (CERV1 and CERV2), are relatives of modern MLVs and are found in the genomes of a variety of Old World primates, but are absent from the human genome. No extant CERV1 and -2 proviruses are known to encode functional proteins. To investigate the host range restriction of these viruses, we attempted to reconstruct functional envelopes by generating consensus genes and proteins. CERV1 and -2 enveloped MLV particles infected cell lines from a range of mammalian species. Using CERV2 Env-pseudotyped MLV reporters, we identified copper transport protein 1 (CTR1) as a receptor that was presumably used by CERV2 during its ancient exogenous replication in primates. Expression of human CTR1 was sufficient to confer CERV2 permissiveness on otherwise resistant hamster cells, and CTR1 knockdown or CuCl2 treatment specifically inhibited CERV2 infection of human cells. Mutations in highly conserved CTR1 residues that have rendered hamster cells resistant to CERV2 include a unique deletion in a copper-binding motif. These CERV2 receptor-inactivating mutations in hamster CTR1 are accompanied by apparently compensating changes, including an increased number of extracellular copper-coordinating residues, and this may represent an evolutionary barrier to the acquisition of CERV2 resistance in primates.
Human T Lymphotropic Virus Type 1 (HTLV-1): Molecular Biology and Oncogenesis. (2010) Viruses 2(9): 2037-2077. doi:10.3390/v2092037
Human T lymphotropic viruses (HTLVs) are complex deltaretroviruses that do not contain a proto-oncogene in their genome, yet are capable of transforming primary T lymphocytes both in vitro and in vivo. There are four known strains of HTLV including HTLV type 1 (HTLV-1), HTLV-2, HTLV-3 and HTLV-4. HTLV-1 is primarily associated with adult T cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-2 is rarely pathogenic and is sporadically associated with neurological disorders. There have been no diseases associated with HTLV-3 or HTLV-4 to date. Due to the difference in the disease manifestation between HTLV-1 and HTLV-2, a clear understanding of their individual pathobiologies and the role of various viral proteins in transformation should provide insights into better prognosis and prevention strategies. In this review, we aim to summarize the data accumulated so far in the transformation and pathogenesis of HTLV-1, focusing on the viral Tax and HBZ and citing appropriate comparisons to HTLV-2.
Mouse mammary tumor virus (MMTV), which was discovered as a milk‑transmitted, infectious cancer-inducing agent in the 1930s, has been used since that time as an animal model for the study of human breast cancer. Like other complex retroviruses, MMTV encodes a number of accessory proteins that both facilitate infection and affect host immune response. In vivo, the virus predominantly infects lymphocytes and mammary epithelial cells. High level infection of mammary epithelial cells ensures efficient passage of virus to the next generation. It also results in mammary tumor induction, since the MMTV provirus integrates into the mammary epithelial cell genome during viral replication and activates cellular oncogene expression. Thus, mammary tumor induction is a by-product of the infection cycle. A number of important oncogenes have been discovered by carrying out MMTV integration site analysis, some of which may play a role in human breast cancer.
Because MMTV has existed as an infectious virus in mice for millions of years, it has evolved to take advantage of its host’s biology, using host genes from transcription factors to immune regulatory molecules, to establish infection. Although it causes mammary tumors, this does not occur until relatively late in life and thus the virus has persisted, since infected mothers are able to transmit virus to offspring. The lack of acute MMTV-induced pathogenesis is most likely due to different host means of limiting virus infection, including factors that operate at the cellular level like intrinsic restriction factors and immune response genes. As additional host-antiviral genes are discovered, MMTV will continue to serve as an important model for testing the ability of these factors to function in vivo. In addition to serving as an important means for studying virus infection, MMTV has provided a number of critical models for understanding human breast cancer. Finally, the use of the MMTV LTR to direct oncogene expression to murine epithelial cells has resulted in the creation of numerous transgenic mouse strains that serve as critical models for understanding human breast cancer. It is likely that such transgenic mice will continue to be a critical tool as additional human breast cancer genes are identified through large-scale human genetic studies.
The recent identification of retrovirus XMRV and a second retrovirus of a different subtype in chronic fatigue syndrome has aroused much interest, not least among sufferers. However, it remains highly controversial whether the detection of these viruses represents true infection or laboratory artifacts. In this paper, Professor Robin Weiss, the UK’s leading authority on retroviruses, gives his critical appraisal of this confusing data and concludes:
Many people suffering from CFS greeted the first report with enthusiasm and relief because of the persistent skepticism of physicians about whether CFS is a defined disease with a single cause. If the association of at least two kinds of murine-related retrovirus with the syndrome stands the test of time, it will represent a very important discovery. CSF patients would then be assured of having a recognized infection with the possibility of effective treatment – indeed, some of them are already so convinced they have started treatment with anti-retroviral drugs (first developed against HIV) in the hope of clearing infection and their symptoms. Blood banks would have to consider whether to screen donations for the implicated retroviruses. But before such steps could be justified, it will be essential to perform truly blinded tests on cases and proper controls in several laboratories. Profoundly disappointing as this would be for patients, without such additional studies, laboratory artifacts cannot be ruled out; also, with the signal exceptions of HIV and human T-lymphotrophic virus, the history of retroviral associations with human disease is not encouraging.
On June 5 1981, MMWR published a report of Pneumocystis carinii pneumonia in five previously healthy young men in Los Angeles, California; two had died. This report later was acknowledged as the first published scientific account of what would become known as human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS). Thirty years after that first report, the most recent estimate is that 33.3 million persons were living with HIV infection worldwide at the end of 2009.
Endogenous retroviruses (ERVs) have spread through mammalian genomes throughout evolution, resulting in thousands of copies or fragments of ERVs, encompassing an estimated 7% of the human genome. However, despite their abundance, specific functions could only rarely be assigned to ERVs. The LTRs of such viruses can serve as strong promoters/enhancers, boosting the transcription of viral or adjacent cellular genes. In a recent discovery of a pathologic example in humans, the derepression of an LTR was found to induce the driver proto-oncogene CSF1R in Hodgkin’s lymphoma. The promoter activity of LTRs can display various tissue specificities and is sometimes limited to germ cells. For example, an LTR from the human endogenous retrovirus 9 (ERV9) predominantly transcribes in testis.
