Acquired Immunodeficiency Syndrome Vaccine Research Articles

HLA-DQB1*06 and breadth of Nef core region-specific T-cell response are associated with slow disease progression in antiretroviral therapy-naive Chinese HIV-1 subtype B patients

ABSTRACT Vaccines still are an important way to prevent and treat acquired immunodeficiency syndrome (AIDS). 1 For developing an effective T cell-based AIDS vaccine, it is critical to define the human leukocyte antigen (HLA) type and epitope that elicit the most potent responses. This study involved 29 antiretroviral therapy-naive and chronic human immunodeficiency virus (HIV)-1 subtype B-infected individuals. A polymerase chain reaction-sequence-specific primer was used to detect the HLA typing, and the enzyme-linked immunospot assay to quantify the T-cell immune function. The results showed that the HLA-DQB1*06-positive group had higher CD4 counts and lower viral load (VL) compared with the HLA-DQB1*06-negative group; A higher magnitude of HIV-1-specific T-cell response and breadth were observed in the HLA-DQB1*06-positive group; the T-cell response was proportional to VL (R 2 = 0.488, P = 0.0368) in the HLA-DQB1*06-positive group. The total T-cell responses to HIV-1 Nef core region were quantified at the single-peptide level. Nine (90%) peptides were recognized in 18 (62.1%) individuals. The breath of Nef core region-specific T-cell response was correlated positively with CD4+ T cell count and inversely with VL, which improved disease outcomes. These data revealed that HLA-DQB1*06 had a protective effect on the course of HIV-1 and T-cell targeting of certain specific Nef epitopes, contributing to HIV-1 suppression. The results suggested the potential use of HLA-DQB1*06 and Nef core region in HIV-1 T-cell vaccine design.

Receptor binding domain based HIV vaccines.

This paper analyzes the main trend of the development of acquired immunodeficiency syndrome (AIDS) vaccines in recent years. Designing an HIV-1 vaccine that provides robust protection from HIV-1 infection remains a challenge despite many years of effort. Therefore, we describe the receptor binding domain of gp120 as a target for developing AIDS vaccines. And we recommend some measures that could induce efficiently and produce cross-reactive neutralizing antibodies with high binding affinity. Those measures may offer a new way of the research and development of the potent and broad AIDS vaccines.

Development of human dendritic cells and their role in HIV infection: antiviral immunity versus HIV transmission

Although dendritic cells (DCs) represent a small cell population in the body, they have been recognized as professional antigen presenting cells and key players of both innate and acquired immunity. The recent expansion of basic knowledge concerning differentiation and function of various DC subsets will greatly help to understand the nature of protective immunity required in designing acquired immunodeficiency syndrome (AIDS) vaccines. However, human immunodeficiency virus (HIV) not only targets CD4+ T cells but also myeloid cells, including macrophages and DC. When HIV infects DC, its replication is highly restricted in DC. Nevertheless, even a low level of HIV production is sufficient to enhance HIV replication in activated CD4+ T cells, through antigen presentation activity by HIV-infected DC. Considering how antiviral immunity is initiated and memory response is maintained, such efficient DC–T cell transmission of HIV should play an important role in the disturbed immune responses associated with HIV infection. Recently, accessory proteins encoded by HIV have been shown to interact with various proteins in DC, and thereby affect DC–T cell transmission. In this review, we summarize the current understanding about DC biology, antiviral immune responses and DC restriction factors, all of which will be important issues for the development of an effective AIDS vaccine in the future.

C-terminal tail of human immunodeficiency virus gp41: functionally rich and structurally enigmatic

The human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) pandemic is amongst the most important current worldwide public health threats. While much research has been focused on AIDS vaccines that target the surface viral envelope (Env) protein, including gp120 and the gp41 ectodomain, the C-terminal tail (CTT) of gp41 has received relatively little attention. Despite early studies highlighting the immunogenicity of a particular CTT sequence, the CTT has been classically portrayed as a type I membrane protein limited to functioning in Env trafficking and virion incorporation. Recent studies demonstrate, however, that the Env CTT has other important functions. The CTT has been shown to additionally modulate Env ectodomain structure on the cell and virion surface, affect Env reactivity and viral sensitivity to conformation-dependent neutralizing antibodies, and alter cell–cell and virus–cell fusogenicity of Env. This review provides an overview of the Env structure and function with a particular emphasis on the CTT and recent studies that highlight its functionally rich nature.

Vaccine Design for CD8 T Lymphocyte Responses

Vaccines are arguably the most powerful medical intervention in the fight against infectious diseases. The enormity of the global human immunodeficiency virus type 1 (HIV)/acquired immunodeficiency syndrome (AIDS) pandemic makes the development of an AIDS vaccine a scientific and humanitarian priority. Research on vaccines that induce T-cell immunity has dominated much of the recent development effort, mostly because of disappointing efforts to induce neutralizing antibodies through vaccination. Whereas T cells are known to limit HIV and other virus infections after infection, their role in protection against initial infection is much less clear. In this article, we will review the rationale behind a T-cell-based vaccine approach, provide an overview of the methods and platforms that are being applied, and discuss the impact of recent vaccine trial results on the future direction of T-cell vaccine research.

Immunology and the elusive AIDS vaccine

Developing a human immunodeficiency virus (HIV) vaccine is critical to end the global acquired immunodeficiency syndrome (AIDS) epidemic, but many question whether this goal is achievable. Natural immunity is not protective, and despite immunogenicity of HIV vaccine candidates, human trials have exclusively yielded disappointing results. Nevertheless, there is an indication that success may be possible, but this will be dependent on understanding the antiviral immune response in unprecedented depth to identify and engineer the types of immunity required. Here we outline fundamental immunological questions that need to be answered to develop a protective HIV vaccine, and the immediate need to harness a much broader scientific community to achieve this goal.

High‐level expression of human immunodeficiency virus antigens from the tobacco and tomato plastid genomes

Transgene expression from the plant's plastid genome represents a promising strategy in molecular farming because of the plastid's potential to accumulate foreign proteins to high levels and the increased biosafety provided by the maternal mode of organelle inheritance. In this article, we explore the potential of transplastomic plants to produce human immunodeficiency virus (HIV) antigens as potential components of an acquired immunodeficiency syndrome (AIDS) vaccine. It is shown that the HIV antigens p24 (the major target of T-cell-mediated immune responses in HIV-positive individuals) and Nef can be expressed to high levels in plastids of tobacco, a non-food crop, and tomato, a food crop with an edible fruit. Optimized p24-Nef fusion gene cassettes trigger antigen protein accumulation to up to approximately 40% of the plant's total protein, demonstrating the great potential of transgenic plastids to produce AIDS vaccine components at low cost and high yield.

AIDS vaccine: Efficacy, safety and ethics

Human immunodeficiency virus (HIV) has infected 50 million people worldwide and killed 16 million so far, and the epidemic is still spreading with 16,000 new cases of HIV infection daily and a projection of 100 million infected individuals by the end of the next decade. There is no question that a safe and effective acquired immunodeficiency syndrome (AIDS) vaccine is urgently needed to bring the current AIDS pandemic under control. But, is preventive AIDS vaccine an attainable goal? Unfortunately, the results of many laboratory and clinical studies over the past two decades are not encouraging. We comment on the efficacy, safety and ethics of AIDS vaccine, and the urgent need for a new strategy for AIDS vaccine development.

AIDS: How Do We Overcome This Social or Biodisaster?

Some 40 million people in the world now live with the human immunodeficiency virus (HIV), which causes the acquired immunodeficiency syndrome (AIDS). The introduction of highly active antiretroviral therapy (HAART) has dramatically reduced AIDS mortality in developed countries, but problems with HAART itself, such as side effects and the emergence of the drug-resistant viruses. Despite tremendous effort to develop either a preventive or therapeutic AIDS vaccine, no effective ones have emerged despite promising candidate anti-HIV drugs as a back up for HAART. Given that, although not a curable, AIDS is preventable and controllable, it is urgent to disseminate effective HIV prevention and treatment to the virus-infected people all over the world in order to stop the global AIDS epidemic as soon as possible.

Caring for Healthcare Workers A Global Perspective

From the International Healthcare Worker Safety Center, University of Virginia Health System, University of Virginia, Charlottesville. Received December 6, 2006; accepted December 6, 2006; electronically published January 3, 2006. Infect Control Hosp Epidemiol 2007; 28:1-4 2006 by The Society for Healthcare Epidemiology of America. All rights reserved. 0899-823X/2007/2801-0001$15.00. This issue of the journal reflects broadly upon the risks of bloodborne pathogen exposure—risks faced by healthcare workers (HCWs) everywhere. The articles cover an array of issues, including the impact of work schedules, healthcare settings, culture-specific practices, and the implementation of safety-engineered sharp devices on the occupational risk of injuries from sharp devices and blood contact. It is a fitting occasion to reflect on the state of the art in providing a safe working environment for HCWs and to consider a future path towards equitable access to its basic elements. It has been more than 2 decades since the first case of needlestick-transmitted infection with human immunodeficiency virus (HIV; then referred to as “human T-lymphotropic virus III”) was reported in The Lancet, triggering a high alert for the exposure risk faced by HCWs. Although lifethreatening bloodborne pathogens had been a recognized risk to HCWs for at least a century, it was the epidemic of acquired immunodeficiency syndrome (AIDS) that delivered the wakeup call leading to remedial action. Today, infection from bloodborne pathogens, primarily HIV, hepatitis B virus (HBV), and hepatitis C virus (HCV), remains the most lifethreatening occupational risk for HCWs. Despite this fact, we can take heart from the dramatic reduction that has occurred in the magnitude of this risk as a direct result of effective prevention initiatives during the past 20 years. It constitutes one of the remarkable success stories in the annals of public health practice. As a public health target, HCWs are usually considered to be (and treated as) a narrow subset of the general population. But globally, their numbers are large and their impact is felt everywhere. The total number of HCWs worldwide is estimated to be 35.7 million, which is greater than the population of Morocco, the 35th most populous nation in the world. HCWs provide care in every country and to every social and cultural group, in sophisticated and humble settings alike. Their global reach is matched only by the significance of their work. In all corners of the globe we depend on them for lifesustaining services. The effective assault on bloodborne pathogens that plague HCWs began with the availability of the hepatitis B vaccine in 1982. In the United States in 1983, the incidence of HBV among HCWs was 3 times higher than the incidence in the general population; by 1995, it was 5 times lower. The annual incidence fell from 386 to 9 infected HCWs per 100,000. In the early 1980s, it was estimated that more than 12,000 HCWs were occupationally infected with HBV annually, resulting in an estimated 250 deaths per year. Between 1990 and 1998, during which time high rates of HCW vaccination were achieved in the United States, only 13 cases of acute HBV infection in HCWs were reported. The advent of the hepatitis B vaccine was a major advance in preserving the health and lives of HCWs. The risk of occupational infection with HIV, although alarming, has never reached the scale of hepatitis B. As of 1997, a total of 94 documented and 170 possible cases of occupational HIV infection had been identified worldwide; nearly two-thirds of cases were reported from the United States. Since then, 15 more documented cases have been identified. However, most countries, especially those with a high population prevalence of HIV infection, have never instituted surveillance systems that would capture data on such cases. Although the development of an AIDS vaccine still eludes us, new treatments for HIV infection appear to have had an appreciable impact on the risk of occupational exposure and infection. In 1997, it was shown that postexposure prophylaxis with zidovudine alone after occupational blood exposure to HIV reduced the risk of seroconversion by more than 80%. Combination antiretroviral drug regimens, introduced in 1997, are believed to be even more effective at preventing seroconversion in HIV-exposed individuals. Combination treatment has altered the risk equation for HCWs in other ways, as well. Shortly after these drugs became widely available in 1997, there was a precipitous drop in the number of HIV-positive in-patients in US hospitals. The risk of HCWs being exposed to HIV dropped in direct proportion to the decline in the number of HIV-infected patients in hospitals. Furthermore, a low viral load, which is common in patients receiving combination drug therapies, is associated with reduced transmission risk when an occupational exposure to

Phase 1 Safety and Immunogenicity Evaluation of a Multiclade HIV‐1 DNA Candidate Vaccine

Gene-based vaccine delivery is an important strategy in the development of a preventive vaccine for acquired immunodeficiency syndrome (AIDS). Vaccine Research Center (VRC) 004 is the first phase 1 dose-escalation study of a multiclade HIV-1 DNA vaccine. VRC-HIVDNA009-00-VP is a 4-plasmid mixture encoding subtype B Gag-Pol-Nef fusion protein and modified envelope (Env) constructs from subtypes A, B, and C. Fifty healthy, uninfected adults were randomized to receive either placebo (n=10) or study vaccine at 2 mg (n=5), 4 mg (n=20), or 8 mg (n=15) by needle-free intramuscular injection. Humoral responses (measured by enzyme-linked immunosorbant assay, Western blotting, and neutralization assay) and T cell responses (measured by enzyme-linked immunospot assay and intracellular cytokine staining after stimulation with antigen-specific peptide pools) were measured. The vaccine was well tolerated and induced cellular and humoral responses. The maximal CD4(+) and CD8(+) T cell responses occurred after 3 injections and were in response to Env peptide pools. The pattern of cytokine expression by vaccine-induced HIV-specific T cells evolved over time, with a diminished frequency of interferon- gamma -producing T cells and an increased frequency of interleukin-2-producing T cells at 1 year. DNA vaccination induced antibody to and T cell responses against 3 major HIV-1 subtypes and will be further evaluated as a potential component of a preventive AIDS vaccine regimen.

Construction and characterization of recombinant fowlpox virus coexpressing HIV-1 CN gp120 and IL-2

The acquired immunodeficiency syndrome (AIDS) has now become one of the most serious infectious disease in the world, the safe and effective AIDS vaccines would be the best tools to control the disease. Fowlpox virus has been studied recently as a potential vector for the delivery of heterologous vaccine antigen. In this study, a recombinant fowlpox virus coexpressing gp120 of Chinese prevalent HIV-1 strain and IL-2 was constructed and the cellular immune responses against HIV-1 gp120 in BALB/c mice were evaluated. Chinese vaccine strain 282E4 of fowlpox virus was used as the vector to construct the recombinant fowlpox virus (rFPV) coexpressing HIV-1 gp120 and IL-2 via homologous recombination, and the recombinant virus was identified by PCR and Western blotting. The specific DNA fragment was amplified by PCR from the genomes of rFPV. Western blotting analysis showed that HIV-1 gp120 and IL-2 was expressed not only in chicken embryo fibroblast (CEF) cells infected by rFPV, but also in mammalian cells infected by rFPV. After the recombinant fowlpox virus was inoculated into BALB/c mice, specific CTL activities in the immunized mice were detected in the spleen. The results demonstrated that rFPV had good immunogenicity and could induce BALB/c mice to produce specific cellular immunity. IL-2 played a role of immunoadjuvant and enhanced the cellular immune response. The study provides the basis for the preparation of a Chinese vaccine candidate against HIV-1.

Synthesis of an oligosaccharide–polylysine dendrimer with reducing sugar terminals leading to acquired immunodeficiency syndrome vaccine preparation

AbstractA novel cellobiose–polylysine dendrimer with reducing sugar terminals was synthesized in which the reactive reducing end of a disaccharide cellobiose was directing outward. Hexa‐O‐benzyl‐4′‐(1‐carboxyethyl)‐cellobioside (HBCEC) was synthesized through the reaction of a 4′‐hydroxyl group of benzyl hexa‐O‐benzyl‐cellobioside with methyl 2‐chloropropionate, followed by the removal of the methyl ester group. HBCEC was reacted with polylysine dendrimer generation 3 (G3) to produce benzylated cellobiose–polylysine dendrimer G3. After debenzylation, a cellobiose–polylysine dendrimer G3 was obtained in which the reducing end of the cellobiose was the terminal group of the dendrimer. For the preparation of a dendrimer‐type acquired immunodeficiency syndrome vaccine, the cellobiose–polylysine dendrimer was reacted with a tripeptide (glycyl–prolyl–leucine) and a cyclic oligopeptide from the human immunodeficiency virus by reductive amination; this produced a tripeptide‐bound cellobiose–polylysine dendrimer and an insoluble compound, respectively. The structure analysis was carried out with NMR and matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry. © 2005 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 43: 2195–2206, 2005

Potent cross-group neutralization of primary human immunodeficiency virus isolates with monoclonal antibodies--implications for acquired immunodeficiency syndrome vaccine.

Human immunodeficiency virus type 1 (HIV-1) is phylogenetically classified into groups and clades (or subtypes). Human neutralizing monoclonal antibodies (nMAbs), originally isolated from individuals infected with HIV-1 group M-clade B, neutralized not only primary HIV-1 clade B isolates in vitro but also primary isolates of other group M clades (A, C, D, E, and F). This corrected the previously held notion that primary HIV-1 isolates are resistant to neutralizing antibodies. Here we show that anti-HIV-1 group M-clade B nMAbs potently neutralized primary isolates of the phylogenetically distant HIV-1 group O. We and others have previously shown that passive immunization with human nMAbs protected adult or neonatal primates against infection with simian-human immunodeficiency virus strains encoding HIV-1 group M-clade B envelope genes. The in vitro cross-group neutralization shown here underscores the broad potential of these nMAbs against divergent virus variants and the relevance of their epitopes in the design of acquired immunodeficiency syndrome vaccines.

Baboons as an animal model for human immunodeficiency virus pathogenesis and vaccine development.

Baboons (Papio cynocephalus) provide a valuable animal model for the study of human immunodeficiency virus (HIV) pathogenesis because HIV-2 infection of baboons causes a chronic viral disease that progresses over several years before clinical signs of acquired immunodeficiency syndrome (AIDS) appear. Since HIV-2-infected baboons develop a chronic viral infection, insights into the immuno-biology of viral latency, clinical stages of disease, virus infection of lymphatic tissue and HIV transmission can be gained using this animal model. The development of an AIDS-like disease in baboons is viral isolate and baboon subspecies dependent. Thus, viral virulence factors and host resistance can be studied as well as the mechanisms of innate and acquired immunity. The control of virus infection is dependent upon cytotoxic and non-cytotoxic antiviral activity of CD8+ T cells. In this regard, some of the HIV-2-infected baboons develop potent antiviral cellular immune responses that have a similar magnitude to that found in HIV-1-infected long-term survivors (or non-progressors). In our laboratory, baboons have been used to study DNA vaccine strategies using new cationic liposome formulations and granulocyte macrophage-colony stimulating factor and B7-2 as genetic adjuvants. The results demonstrate the value of using baboons as an animal model of AIDS pathogenesis and vaccine development.

Preparation and induction of immune responses by a DNA AIDS vaccine.

In an effort to evaluate the feasibility of developing a safe DNA vaccine for acquired immunodeficiency syndrome (AIDS), we have prepared a plasmid-based immunogen modeled after a naturally occurring noninfectious mutant of the simian immunodeficiency virus (SIV). The mutant SIV genome produces defective virus particles that are noninfectious in vitro and nonpathogenic in vivo in rhesus macaques. Analysis of the mutant genome revealed a 1.6 kb deletion that is in frame and spans integrase, vif, vpx, and most of vpr and results in a pol/vpr gene fusion. This deletion was introduced into the parental pathogenic molecular clone and the U3 region of the 5' LTR was replaced with a cytomegalovirus promoter to produce a candidate DNA vaccine, pIV. After transfection with this plasmid, SIV gag and envelope proteins are expressed and properly processed in vitro. When injected into rabbits, pIV elicited an antibody response to SIV gp130 envelope glycoprotein with titers reaching 1:2048, and a strong lymphoproliferative response to SIV gp130 and whole SIV. The potential to produce defective virus particles in vivo without integrating into the host genome should result in both a strong humoral and cellular immune response in rhesus macaques. In addition, this approach offers a safe alternative to live attenuated vaccines and DNA vaccines that are capable of integration.

Cytotoxic T lymphocytes specific for the simian immunodeficiency virus.

A non-human primate model for acquired immunodeficiency syndrome (AIDS), the simian immunodeficiency virus (SIV)-infected rhesus monkey, was used to explore the role of the AIDS virus-specific cytotoxic T-lymphocyte (CTL) response in disease pathogenesis. This CTL response was measured using the major histocompatibility complex (MHC) class I/peptide tetramer technology. Large numbers of tetramer-binding CD8+ T lymphocytes were demonstrable not only in the peripheral blood, but in lymph nodes and even in semen of chronically SIV-infected monkeys. The central role of these effector T lymphocytes in containing SIV spread during primary infection was demonstrated by showing that early SIV clearance during primary infection correlated with the emergence of the tetramer binding CD8+ T lymphocytes and that in vivo depletion of CD8+ lymphocytes eliminated the ability of the infected monkeys to contain SIV replication. These observations suggest that an effective AIDS vaccine should elicit a potent virus-specific CTL response. In fact, a live, recombinant SIV vaccine constructed using the attenuated pox virus vector modified vaccinia Ankara (MVA) elicited a high-frequency CTL response, comparable in magnitude to that elicited by SIV infection itself. This suggests that vaccine modalities such as MVA may prove useful in creating an effective human immunodeficiency virus (HIV) vaccine. These studies also indicate the power of both the SIV/macaque model and MHC class I/peptide tetramers for assessing AIDS vaccine strategies.

Potent and Stable Attenuation of Live-HIV-1 by Gain of a Proteolysis-resistant Inhibitor of NF-κB (IκB-αS32/36A) and the Implications for Vaccine Development

Live-attenuated human immunodeficiency viruses (HIVs) are candidates for Acquired Immunodeficiency Syndrome (AIDS) vaccine. Based on the simian immunodeficiency virus (SIV) model for AIDS, loss-of-function (e.g. deletion of accessory genes such as nef) has been forwarded as a primary approach for creating enfeebled, but replication-competent, HIV-1/SIV. Regrettably, recent evidence suggests that loss-of-function alone is not always sufficient to prevent the emergence of virulent mutants. New strategies that attenuate via mechanisms distinct from loss-of-function are needed for enhancing the safety phenotype of viral genome. Here, we propose gain-of-function to be used simultaneously with loss-of-function as a novel approach for attenuating HIV-1. We have constructed an HIV-1 genome carrying the cDNA of a proteolysis-resistant nuclear factor-kappaB inhibitor (IkappaB-alphaS32/36A) in the nef region. HIV-1 expressing IkappaB-alphaS32/36A down-regulates viral expression and is highly attenuated in both Jurkat and peripheral blood mononuclear cells. We provide formal proof that the phenotypic and attenuating characteristics of IkappaB-alphaS32/36A permit its stable maintenance in a live, replicating HIV-1 despite 180 days of forced ex vivo passaging in tissue culture. As compared with other open-reading frames embedded into HIV/SIV genome, this degree of stability is unprecedented. Thus, IkappaB-alphaS32/36A offers proof-of-principle that artifactually gained functions, when used to attenuate the replication of live HIV-1, can be stable. These findings illustrate gain-of-function as a feasible strategy for developing safer live-attenuated HIVs to be tested as candidates for AIDS vaccine.

International grant making by U.S. foundations.

International grant making by U.S. foundations.

The maginot line and AIDS vaccines

Despite extensive and costly efforts, attempts to develop a vaccine against human immunodeficiency virus (HIV), the causative agent of the acquired immunodeficiency syndrome (AIDS), have been unsuccessful. Using the Maginot Line as a metaphor, we discuss the reasons why an antibody-based vaccine strategy against HIV has failed. The concept of a vaccine that exclusively promotes cell-mediated immunity against the virus is outlined, and important factors in the formulation of this novel vaccine are delineated. In particular, vaccine adjuvants and HIV peptides that elicit a cell-mediated immune response are crucial components of this immunization strategy. Examination of primate immune systems that resist retroviral pathogenicity will also play an important role in the development of a successful AIDS vaccine.