With two catalytic activities and many substrates, how does HIV’s reverse transcriptase enzyme know what to do to which substrate? Zooming in on the enzyme’s molecular interactions provides tantalizing clues.
Dynamic binding orientations direct activity of HIV reverse transcriptase. Nature 453, 184-189
The reverse transcriptase of human immunodeficiency virus (HIV) catalyses a series of reactions to convert the single-stranded RNA genome of HIV into double-stranded DNA for host-cell integration. This task requires the reverse transcriptase to discriminate a variety of nucleic-acid substrates such that active sites of the enzyme are correctly positioned to support one of three catalytic functions: RNA-directed DNA synthesis, DNA-directed DNA synthesis and DNA-directed RNA hydrolysis. However, the mechanism by which substrates regulate reverse transcriptase activities remains unclear. Here we report distinct orientational dynamics of reverse transcriptase observed on different substrates with a single-molecule assay. The enzyme adopted opposite binding orientations on duplexes containing DNA or RNA primers, directing its DNA synthesis or RNA hydrolysis activity, respectively. On duplexes containing the unique polypurine RNA primers for plus-strand DNA synthesis, the enzyme can rapidly switch between the two orientations. The switching kinetics were regulated by cognate nucleotides and non-nucleoside reverse transcriptase inhibitors, a major class of anti-HIV drugs. These results indicate that the activities of reverse transcriptase are determined by its binding orientation on substrates.
Viruses are small infectious agents responsible for many human diseases, including acquired immunodeficiency syndrome (AIDS). Like other viruses, the human immunodeficiency virus 1 (HIV-1; the cause of AIDS) enters human cells and uses the cellular machinery to replicate before bursting out of its temporary home. During the initial stage of HIV infection, a particular group of cells in the human immune system, CD8+ T cells, are thought to be important in controlling the level of the virus. These immune system cells recognize pieces of viral protein called antigens displayed on the surface of infected cells; different subsets of CD8+ T cells recognize different antigens. When a CD8+ T cell recognizes its specific antigen (or more accurately, a small part of the antigen called an epitope ), it releases cytotoxins (which kill the infected cells) and cytokines, proteins that stimulate CD8+ T cell proliferation and activate other parts of the immune system. With many viruses, when a person first becomes infected (an acute viral infection), antigen-specific CD8+ T cells completely clear the infection. But with HIV-1 and some other viruses, these cells do not manage to remove all the viruses from the body and a chronic (long-term) infection develops, during which the immune system is constantly exposed to viral antigen.
In HIV-1 infections (and other chronic viral infections), virus-specific CD8+ T cells lose their ability to proliferate, to make cytokines, and to kill infected cells as patients progress to the longterm stages of infection. That is, the virus-specific CD8+ T cells gradually lose their effector functions and become functionally impaired or exhausted. Polyfunctional CD8+ T cells (those that release multiple cytokines in response to antigen) are believed to be essential for an effective CD8+ T cell response, so scientists trying to develop HIV-1 vaccines would like to stimulate the production of this type of cell. To do this they need to understand why these polyfunctional cells are lost during chronic infections. Is their loss the cause or the result of viral persistence? In other words, does the constant presence of viral antigen lead to the exhaustion of CD8+ T cells during chronic HIV infection? In this study, the researchers investigate this question by looking at the polyfunctionality of CD8+ cells responding to several different viral epitopes at various times during HIV-1 infection, starting very early after infection with HIV-1 had occurred.
The researchers enrolled 18 patients recently infected with HIV-1 and analyzed their CD8+ T cell responses to specific epitopes at various times after enrollment using a technique called flow cytometry. They found that the epitope-specific CD8+ cells produced several effector proteins after antigen stimulation during the initial stage of HIV-1 infection, but lost their polyfunctionality in the face of persistent viral infection. The CD8+ T cells also increased their production of programmed death 1 (PD-1), a protein that has been shown to be associated with the functional impairment of CD8+ T cells. Some of the patients began antiretroviral therapy during the study, and the researchers found that this treatment, which reduced the viral load, reversed CD8+ T cell exhaustion. Finally, the appearance in the patients blood of viruses that had made changes in the specific epitopes recognized by the CD8+ T cells to avoid being killed by these cells, also reversed the exhaustion of the T cells recognizing these particular epitopes.
These findings suggest that the constant presence of HIV-1 antigen causes the functional impairment of virus-specific CD8+ T cell responses during chronic HIV-1 infections. Treatment with antiretroviral drugs reversed this functional impairment by reducing the amount of antigen in the patients. Similarly, the appearance of viruses with altered epitopes, which effectively reduced the amount of antigen recognized by those epitope-specific CD8+ T cells without reducing the viral load, also reversed T cell exhaustion. These results would not have been seen if the functional impairment of CD8+ cells were the cause rather than the result of antigen persistence. By providing new insights into how the T cell response to viruses evolves during persistent viral infections, these findings should help in the design of vaccines against HIV and other viruses that cause chronic viral infections.
The function of the RNA genome of the human immunodeficiency virus (HIV) is determined both by its sequence and by its ability to fold back on itself to form specific higher-order structures. In order to describe physical structures in a region of the HIV RNA genome known to play multiple, critical roles in viral replication and pathogenesis. In this week’s PLoS Biology scientists from the University of North Carolina show how they have devised a high-throughput, quantitative, and comprehensive structure-mapping approach that locates flexible (unpaired) nucleotides within a folded RNA, assaying hundreds of nucleotides at a time. They find that the first 10% of the HIV-1 genome has a single predominant structure and that regulatory motifs have significantly greater structure than do protein-coding segments. The HIV genome interacts with numerous proteins, including multiple copies of nucleocapsids. They also directly map RNA-protein interactions inside virions and discover that the nucleocapsid interacts with viral RNA in at least three distinct ways, depending on the context within the overall genome structure. The group hopes that further application of the high-throughput RNA-structure analysis tools described will make it possible to address diverse structure-function relationships in intact cellular and viral RNAs.
Replication and pathogenesis of the human immunodeficiency virus (HIV) is tightly linked to the structure of its RNA genome, but genome structure in infectious virions is poorly understood. High-throughput SHAPE (selective 29-hydroxyl acylation analyzed by primer extension) technology uses many of the same tools as DNA sequencing, was used to quantify RNA backbone flexibility at single-nucleotide resolution and from which robust structural information can be immediately derived. We analyze the structure of HIV-1 genomic RNA in four biologically instructive states, including the authentic viral genome inside native particles. Remarkably, given the large number of plausible local structures, the first 10% of the HIV-1 genome exists in a single, predominant conformation in all four states. We also discover that noncoding regions functioning in a regulatory role have significantly lower SHAPE reactivities, and hence more structure, than do viral coding regions that function as the template for protein synthesis. By directly monitoring protein binding inside virions, we identify the RNA recognition motif for the viral nucleocapsid protein. Seven structurally homologous binding sites occur in a well-defined domain in the genome, consistent with a role in directing specific packaging of genomic RNA into nascent virions. In addition, we identify two distinct motifs that are targets for the duplex destabilizing activity of this same protein. The nucleocapsid protein destabilizes local HIV-1 RNA structure in ways likely to facilitate initial movement both of the retroviral reverse transcriptase from its tRNA primer and of the ribosome in coding regions. Each of the three nucleocapsid interaction motifs falls in a specific genome domain, indicating that local protein interactions can be organized by the long-range architecture of an RNA. High-throughput SHAPE reveals a comprehensive view of HIV-1 RNA genome structure, and further application of this technology will make possible newly informative analysis of any RNA in a cellular transcriptome. High-throughput SHAPE analysis reveals structures in HIV-1 genomic RNA strongly conserved across distinct biological states. 2008 PLoS Biol 6: e96
The structure of all retroviruses is similar, although there are some minor differences. Virus particles are far too small to see, the closest we can come to are electron micrographs. To make transmission electron micrographs, the specimen (containing virus particles) are fixed and stained with a metal-containing dye. The more dye different areas of the specimen take up, the darker they appear in the electron micrograph.
In the centre of an HIV particle, there are two molecules of RNA which together make up the genome of the virus. Associated with the RNA are two enzymes, reverse transcriptase and integrase. The genome is enclosed in a conical core consisting of the nucleocapsid proteins. Outside this is an icosahedral protein capsid, which in turn is enclosed by the matrix protein layer. The whole particle is surrounded by a lipid bilayer known as the virus envelope. The transmembrane protein penetrates through the envelope and anchors the surface glycoprotein on the outside of the particle.
To see more detail in virus particles, special imaging techniques are needed. Cryo-electron tomography makes a three dimensional reconstruction from a series of two dimensional transmission electron micrographs taken at extremely low temperatures in order to preserve the structure of the particle. The individual micrographs represent slices though the virus particle which are put together on a computer to construct a three dimensional representation with false colours added for additional clarity.
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In the absence of interventions, 30-45% of exposed infants acquire human immunodeficiency virus type 1 (HIV-1) through mother-to-child transmission. It remains unclear why some infants become infected while others do not, despite significant exposure to HIV-1 in utero, during delivery and while breastfeeding. Ths paper discusses the correlates of vertical transmission with an emphasis on factors that increase maternal HIV-1 levels, either systemically or locally in genital secretions and breast milk. Immune responses may influence maternal viral load, and data suggest that maternal neutralising antibodies reduce infection rates. In addition, infants may be capable of mounting HIV-specific cellular immune responses. The authors propose that both humoral and cellular responses are necessary to reduce infection because cell-free as well as cell-associated virus appears to play a role in vertical transmission. These distinct forms of the virus may be targeted most effectively by different components of the immune system. They also discuss the use of antiretrovirals to reduce transmission, focusing on the mechanisms of action of regimens currently used in developing country settings. Their conclusion is that that prevention relies not only on reducing maternal HIV-1 levels within blood, genital tract and breast milk, but also on pre- and/or post-exposure prophylaxis to the infant. However, HIV-1 has the capacity to mutate under drug pressure and rapidly acquires mutations conferring antiretroviral resistance. This review concludes with data on persistence of low-level resistance after delivery as well as recent guidelines for maternal and infant regimens designed to limit resistance.
Dendritic cells (DCs) initiate immune responses to pathogens or vaccine antigens. The HIV-1 gp120 envelope glycoprotein is an antigen that is a focus of vaccine design strategies. gp120 can signal via several cell surface receptors. A recent paper studied how gp120 proteins interact with DCs in cell culture. Certain gp120s stimulate DCs from some, but not all, human donors to produce IL-10, a cytokine that is generally immunosuppressive. In addition, whether or not the DCs produce IL-10, their ability to mature properly when activated is impaired by gp120 - the gp120-treated DCs have a reduced ability to stimulate T cell growth when the two cell types are cultured together. These various effects of gp120 are caused by its binding to cell surface receptors of the mannose C-type lectin receptor family, including (but probably not exclusively) one called DC-SIGN. gp120 binds to these receptors via mannose residues that are present on some of the glycan structures that overlay much of its protein surface. Removing the mannoses by digesting gp120 with a suitable enzyme prevents IL-10 induction and impairment of DC maturation, as does the use of inhibitors of the binding of gp120 to DC-SIGN and similar receptors. Such immunosuppressive mechanisms might suppress immune responses to Env-containing vaccines, demannosylation may be a way to improve the immunogenicity of gp120 or gp140 proteins.
An estimated 15 percent of all human cancers worldwide may be caused by viruses (Viruses and Human Cancer. Yale J Biol Med. 2006 79: 115 122). Both DNA and RNA viruses are capable of causing cancer in humans. Although it is convenient to consider human tumor viruses as a discrete group of viruses, the six viruses which cause human cancers have very different genomes, replication cycles, and come from five different virus families. The path from virus infection to tumour formation is slow and inefficient. Only a minority of infected individuals progress to cancer, usually years or even decades after primary infection. Virus infection alone is generally not sufficient for cancer, and additional events and host factors, such as immunosuppression, somatic mutations, genetic predisposition, and exposure to carcinogens must also play a role.
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Hepatitis B and C viruses Hepatitis C virus (HCV) is an enveloped RNA virus of the Flavivirus family. It is capable of causing both acute and chronic hepatitis in humans by infecting liver cells. It is estimated that approximately 3 percent of the world s population are hepatitis C carriers. Chronic infection with hepatitis C virus results in cirrhosis, which in turn can lead to primary hepatocellular carcinoma. Between 1 and 2 percent of infected patients with cirrhosis of the liver will develop primary hepatocellular carcinoma per year of infection. Transmission of HCV occurs through the blood, by shared needles in intravenous drug abuse, sexual activity, and birth being the primary routes. The hepatitis B virus (HBV) of the family Hepadnaviridae is a DNA virus, but uses reverse transcription as part of its replication cycle. Hepatitis B virus also is a blood-borne pathogen that can result in acute and chronic hepatitis. Chronic hepatitis (infections lasting more than three months) can lead to cirrhosis and liver failure, and to the development of hepatocellular carcinoma. Hepatitis B infections is a significant global health problem with an estimated 2 billion people infected and 1.2 million deaths per year attributed to subsequent hepatitis, cirrhosis and hepatocellular carcinoma.
Epstein-Barr virus (EBV) and human herpesvirus 8 (HHV- EBV and HHV-8 (also known as Kaposi sarcoma herpesvirus) are both herpesviruses that possess large double-stranded DNA genomes. As with all herpesviruses, they encode enzymes involved in DNA replication and repair and nucleotide biosynthesis. They also both possess the ability to establish latency in B lymphocytes and reactivate into the lytic cycle. Both also are associated with naturally occurring tumors in humans.
EBV is a ubiquitous virus that is most commonly known for being the primary agent for infectious mononucleosis (glandular fever). Up to 95 percent of all adults are estimated to be seropositive for EBV, and most infections are subclinical. EBV is associated with a number of malignancies: B and T cell lymphomas, Hodgkin s disease, post-transplant lymphoproliferative disease and nasopharyngeal carcinoma. Burkitt’s lymphoma, post-transplant lymphoproliferative disease show an increased frequency in patients with immunodeficiency, suggesting a role for immunosurveillance in the suppression of malignant transformation.
In 1994, HHV-8 DNA was identified in biopsies from tumors of a patient with Kaposi sarcoma, a relatively rare malignancy prior to the AIDS epidemic. In addition to it likely being an essential cofactor for the development of Kaposi sarcoma, HHV-8 also is believed to have a role in Castleman’s disease and primary effusion lymphoma. The HHV-8 genome is expressed in these tumors and encodes transforming proteins and anti-apoptotic factors. As with EBV, the predominant cell type infected is the B lymphocyte, although in these cells the lytic cycle occurs rather than being repressed. This may play a crucial role in the pathogenesis of Kaposi sarcoma by elaboration of virus and host cytokines promoting cell proliferation, angiogenesis, and enhancement of virus spread.
Human Papillomavirus (HPV) Human papillomaviruses are small non-enveloped DNA tumour viruses that commonly cause benign papillomas or warts in humans. Persistent infection with high-risk subtypes of HPV is associated with the development of cervical cancer. HPV infects epithelial cells, and, after integration in host DNA, the production of oncoproteins, mainly E6 and E7, disrupts natural tumor suppressor pathways and is required for proliferation of cervical carcinoma cells. HPV is also believed to play a role in other human cancers, such as head and neck tumors, skin cancers in immunosuppressed patients, and other anogenital cancers.
Cervical cancer is the second leading cause of cancer mortality in women worldwide, causing 240,000 deaths annually. Of approximately 490,000 cases reported each year, more than 80 percent occur in the developing world, where effective but costly Pap smear screening programs are not in place. Early precancerous changes and early cancers detected by Pap smears are effectively treated and cured with surgical therapy or ablation. In the absence of effective screening, the disease is detected late.
The immune system plays an important role in the prevention of persistent HPV infection and progression of precancerous lesions. Human papillomavirus is a poor natural immunogen. As a double stranded DNA virus, there is no RNA intermediate, nor does infection cause cytolysis, allowing initiation of innate immune responses. HPV mainly encodes non-secreted nucleoproteins, which are poorly cross-presented and compared to other viruses its non-structural proteins are expressed at low levels. However, genital infection with HPV is usually transient. Additionally, inadequate T cell responses may lead to failure to clear HPV-infected cells. AIDS patients, renal transplant patients receiving immunosuppressive therapy, and individuals with T cell deficiencies have increased rates of HPV persistence, anogenital lesions, and cervical cancer.
Human T lymphotropic virus type I (HTLV-1) HTLV-1 is a retrovirus and is associated with adult T-cell leukemia. This virus has a worldwide distribution, with an estimated 12 to 25 million people infected. However, disease is only observed in less than 5 percent of infected individuals. It is transmitted through blood transfusions, sexual contact, and during birth. HTLV-1 displays a special tropism for CD4 cells, which clonally proliferate in adult T cell leukemia, though how this is caused is not known.
HTLV-1 infection has a very long latency period of 20 to 30 years, but once tumor formation begins, progression is rapid. Standard chemotherapy often can bring about an initial response with a partial or complete remission; however, relapse is common, and median survival is eight months. The HTLV-1 Tax gene has been postulated to play an important role in tumour formation through the activation of virus transcription and the hijacking of cellular growth and cell division machinery, but the mechanisms leading to adult T cell leukemia are not well understood.
These six viruses illustrate the diverse biological pathways to malignancy and the challenges of treating the resulting diseases. The study of viruses and human cancer has led to optimism about the development of new strategies for the prevention of the infections that can lead to carcinogenesis. Antiviral drugs such as lamuvidine used against heptatitis B and ganciclovir for Kaposi sarcoma specifically target the virus replication machinery. The presence of virus gene products in tumour cells can provide important targets for directed therapies that specifically can distinguish tumour cells from normal cells. The inability of traditional cancer therapy, such as chemotherapy and radiation, to distinguish cancer cells from normal cells is a significant drawback and leads to toxicities for patients undergoing treatment. Targeted therapies directed against virus proteins or generate immune responses in order to either prevent infection or kill infected cells or cancer cells hold much promise for more effective and tolerable treatment strategies for virus-related tumours.
HIV’s status as an ‘incurable’ infection, although in many cases doctors are able to stave off the onset of full-blown AIDS by giving patients sustained courses of drugs.
This item was based on an article published in May 2007:
Decay of the HIV reservoir in patients receiving antiretroviral therapy for extended periods: implications for eradication of virus.
J Infect Dis. 2007 195:1762-1764
The persistence of latently infected resting CD4+ T cells has been clearly demonstrated in human immunodeficiency virus (HIV)-infected individuals receiving effective antiviral therapy. However, estimates of the half-life of this viral reservoir have been quite divergent. We demonstrate clear evidence for decay of this HIV reservoir in patients who initiated antiviral therapy early in infection. The half-life of this latent viral reservoir was estimated to be 4.6 months. It is projected that it will take up to 7.7 years of continuous therapy to completely eliminate latently infected resting CD4+ T cells in infected individuals who initiate antiviral therapy early in HIV infection.
which was recently backed up by a second publication from the same research group:
Persistence of HIV in Gut-Associated Lymphoid Tissue despite Long-Term Antiretroviral Therapy.
J Infect Dis. 2008 Feb 8
Human immunodeficiency virus (HIV) persists in peripheral blood mononuclear cells despite sustained, undetectable plasma viremia resulting from long-term antiretroviral therapy. However, the source of persistent HIV in such infected individuals remains unclear. Given recent data suggesting high levels of viral replication and profound depletion of CD4(+) T cells in gut-associated lymphoid tissue (GALT) of animals infected with simian immunodeficiency virus and HIV-infected humans, we sought to determine the level of CD4(+) T cell depletion as well as the degree and extent of HIV persistence in the GALT of infected individuals who had been receiving effective antiviral therapy for prolonged periods of time. We demonstrate incomplete recoveries of CD4(+) T cells in the GALT of aviremic, HIV-infected individuals who had received up to 9.9 years of effective antiretroviral therapy. In addition, we demonstrate higher frequencies of HIV infection in GALT, compared with PBMCs, in these aviremic individuals and provide evidence for cross-infection between these 2 cellular compartments. Together, these data provide a possible mechanism for the maintenance of viral reservoirs revolving around the GALT of HIV-infected individuals despite long-term viral suppression and suggest that the GALT may play a major role in the persistence of HIV in such individuals.
Many HIV patients can manage their infection with a cocktails of antiretroviral drugs which can reduce their “viral load” - the amount of virus circulating in the blood plasma - to undetectable levels. But this work shows that even in such “non-infectious” patients HIV is still lurking in gut tissues, and still infecting other immune cells in the blood. It might not ever be possible to completely eradicate the virus from the body, even though people are doing well, says Anthony Fauci, director of the US National Institute of Allergy and Infectious Diseases.
If you’ve studied virology, you’ll be familiar with the concept of a virus attachment protein, the protein(s) a virus uses to bind to the receptors on a host cell during infection. That’s all very well, but what happens after the virus has replicated and the new particles want to leave to find new host cells? How do they avoid getting stuck on the cell surface like flies on fly-paper? Mammals have evolved various mechanisms to foil the spread of viruses. One such restriction factor prevents HIV-1 from leaving infected cells and is counteracted by an HIV protein called Vpu. Without its Vpu protein, the HIV-1 gets stuck to the surface of the human cell in which it has replicated. The mysterious factor that tethers HIV-1 to the host cell is probably a cell-membrane protein.
Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu. Nature 451, 425-430
Human cells possess an antiviral activity that inhibits the release of retrovirus particles, and other enveloped virus particles, and is antagonized by the HIV-1 accessory protein, Vpu. This antiviral activity can be constitutively expressed or induced by interferon-alpha, and it consists of protein-based tethers, which we term ‘tetherins’, that cause retention of fully formed virions on infected cell surfaces. Using deductive constraints and gene expression analyses, we identify CD317, a membrane protein of previously unknown function, as a tetherin. Specifically, CD317 expression correlated with, and induced, a requirement for Vpu during HIV-1 and murine leukaemia virus particle release. Furthermore, in cells where HIV-1 virion release requires Vpu expression, depletion of CD317 abolished this requirement. CD317 caused retention of virions on cell surfaces and, after endocytosis, in CD317-positive compartments. Vpu co-localized with CD317 and inhibited these effects. Inhibition of Vpu function and consequent mobilization of tetherin’s antiviral activity is a potential therapeutic strategy in HIV/AIDS.
The human genome contains a number of remnants or fossils of ancient viral infections referred to as human endogenous retroviruses (HERV). Like fossils, these HERV are usually considered to be dead or inert as under normal circumstances, HERVs are functionally defective or controlled by host factors. However, recent work has demonstrated that T cells in the human immune system respond to HERV when a person is infected with the human immunodeficiency virus (HIV). In HIV-1-infected individuals, intracellular defense mechanisms are compromised. The T cells responding to HERV share characteristics with T cells that effectively control cytomegalovirus, a common chronic viral infection. T cells responding to HERV can also kill target cells carrying HERV protein. For some HIV-positive people, the strength of their response against HERV is related to having a lower HIV viral load. This study has important implications for new directions in HIV vaccine research. One of the key obstacles to creating an effective HIV vaccine is overcoming the ability of some of the virus variants produced when HIV evades the immune responses that the body mounts to control infections.
The authors hypothesized that HIV-1 infection would remove or alter controls on HERV activity. Expression of HERV could potentially stimulate a T cell response to HERV antigens, and in regions of HIV-1/HERV similarity, these T cells could be cross-reactive. They show that the levels of HERV production in HIV-1-positive individuals exceed those of HIV-1-negative controls. To investigate the impact of HERV activity on specific immunity, they examined T cell responses to HERV peptides in 29 HIV-1-positive and 13 HIV-1-negative study participants. There was an inverse correlation between anti-HERV T cell responses and HIV-1 plasma viral load. In HIV-1-positive individuals, HERV-specific T cells are capable of killing cells presenting their cognate peptide. These data indicate that HIV-1 infection leads to HERV expression and stimulation of a HERV-specific CD8+ T cell response. HERV-specific CD8+ T cells have characteristics consistent with an important role in the response to HIV-1 infection: a phenotype similar to that of T cells responding to an effectively controlled virus (cytomegalovirus), an inverse correlation with HIV-1 plasma viral load, and the ability to lyse cells presenting their target peptide. These characteristics suggest that elicitation of anti-HERV-specific immune responses is a novel approach to immunotherapeutic vaccination. As endogenous retroviral sequences are fixed in the human genome, they provide a stable target, and HERV-specific T cells could recognize a cell infected by any HIV-1 viral variant. HERV-specific immunity is an important new avenue for investigation in HIV-1 pathogenesis and vaccine design. If T cells that recognize HERV can stably target HIV-infected cells, they could be an important factor in controlling HIV infection.
With two catalytic activities and many substrates, how does HIV’s reverse transcriptase enzyme know what to do to which substrate? Zooming in on the enzyme’s molecular interactions provides tantalizing clues.
The human genome contains a number of remnants or fossils of ancient viral infections referred to as human endogenous retroviruses (HERV). Like fossils, these HERV are usually considered to be dead or inert as under normal circumstances, HERVs are functionally defective or controlled by host factors. However, recent work has demonstrated that T cells in the human immune system respond to HERV when a person is infected with the human immunodeficiency virus (HIV). In HIV-1-infected individuals, intracellular defense mechanisms are compromised. The T cells responding to HERV share characteristics with T cells that effectively control cytomegalovirus, a common chronic viral infection. T cells responding to HERV can also kill target cells carrying HERV protein. For some HIV-positive people, the strength of their response against HERV is related to having a lower HIV viral load. This study has important implications for new directions in HIV vaccine research. One of the key obstacles to creating an effective HIV vaccine is overcoming the ability of some of the virus variants produced when HIV evades the immune responses that the body mounts to control infections.