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.     

Role of natural killer cells in HIV pathogenesis

Although the majority of research on immune cell recognition of HIV-infected cells has focused on CD8⁺ T cells with an eye towards vaccine development, innate immune recognition by natural killer (NK) cells has become a focus in recent years. Genetic and mechanistic data indicate that NK cells play a role during pathogenesis, and research on NK biology in the context of the broader immune response shows that NK cells are required to mount an effective antiviral response. HIV is able to escape cytotoxic T lymphocyte recognition by downmodulation of major histocompatibility complex class I receptors, which should enhance NK cytotoxicity against infected targets. However, the virus has evolved elaborate mechanisms to evade NK cell responses. Moreover, NK cell function as a whole is compromised through poorly understood mechanisms as a result of viremia. Further work on the role of NK cells during all stages of disease will further our understanding of the immune response against HIV.     

The viral envelope in the evolution of HIV: a hypothetical approach to inducing an effective immune response to the virus

The human immunodeficiency virus (HIV) is ‘perceived’ by the host immune system as partly-self because of the presence of host cell wall membrane on the viral envelope. This perception leads to an ineffective immune response to the virus. It is proposed that only viral core antigens without the envelope will be perceived as non-self by the host immune system and can provoke an effective immune response. In normal uninfected persons, core antigens could therefore serve as a vaccine. In HIV infected persons, uncommitted immunocytes from the peripheral leucocytes freed from antibodies will in vitro process autologous viral core antigens as non-self antigens and lead to an effective immune response against the HIV when reinjected into the patient. The use of autologous viral core antigens provides, at the same time, a means for testing viral core antigens as possible vaccines without any risk to a third person. This immunotherapy of the HIV, when confirmed, will support core antigens as possible vaccines and could also be applied to the large group of retroviral and other enveloped viruses that cause chronic infections and malignant tumours in man and animals, with considerable benefits to human and animal health.     

Dendritic cells and natural killer cells in the pathogenesis of HIV infection

Dendritic cells (DC) and natural killer (NK) cells, the main cellular components of the innate immune system, participate in the most ancient first line of defense against infections. Both types of cells patrol peripheral tissues, whereas their rapid recruitment and activation at mucosal surfaces [the major entry point for the human immunodeficiency virus (HIV)] is a hallmark of acute inflammatory response. The ability of HIV to survive and replicate in the human host relies upon several molecular mechanisms eluding the immune surveillance of both adaptive immunity and of DC and NK cells beginning with the acute phase of primary HIV infection. DC and NK cells, unlike CD4⁺ T cells, are impaired more functionally rather than being depleted by HIV infection. In this article we will review some of the aspects of DC/NK cells interaction with HIV infection both in vitro and in vivo, and we will also speculate on the potential consequence for HIV pathogenesis and for the capacity of the virus to escape the surveillance of the innate immune system.     

Energy transformations in the biosynthesis of the immune system: their relevance to the progression and treatment of AIDS.

Dysfunction of the immune system is observed in diseases where metabolic respiration is inhibited. Anabolites that enhance oxidative phosphorylation will provide the ATP essential for the biosynthesis of the cellular components and antibodies of the immune system. The induction of Coenzyme Q10 has been observed to protect against tumor growth and to enhance viral immunity in experimental animals. In a pilot study in AIDS patients the energy mediating catalyst elicited remarkable improvement. Additional cellular respiratory stimulants are considered as palliative synergists designed to enhance immunity in HIV infection. Competing antagonists to metabolic respiration acting to negate the effect of F delta in mediating optimal immune response to HIV are evaluated.     

Robust HIV-specific immune responses were induced by DNA vaccine prime followed by attenuated recombinant vaccinia virus (LC16m8 strain) boost

Recombinant vaccinia virus-based vaccine combined with DNA vaccine has produced a protective immune response against HIV infection in non-human primates. In this study, we explored the immunogenicity of a recombinant vaccinia virus (LC16m8 strain), which has been used in children without severe side effects. The vaccinia virus expressing an HIV(89.6)env gene (vLC-Env) alone or combined with a DNA vaccine expressing the HIV(89.6)env gene (pCAG-Env) was characterized in BALB/c mice. Vaccination of vLC-Env induced much higher HIV-specific humoral and cell-mediated immune responses than that of pCAG-Env. Priming with pCAG-Env further enhanced vLC-Env induced immune responses, especially cell-mediated immune response. Moreover, efficient expression of Env protein was achieved following infection of bone marrow dendritic cells by vLC-Env in vitro. Administration of vLC-Env-infected dendritic cells to mice generated a high cell-mediated immune response. These results demonstrate that priming with pCAG-Env and boosting with vLC-Env represents a logical candidate for vaccination against HIV infection.     

Idiotypic cascades associated with the CD4-HIV gp120 interaction: principles for idiotype-based vaccines.

Idiotypes (Id) are antigenic determinants expressed on the variable (V) region of the immunoglobulin molecule. Id-bearing antibodies, or Ab-1, are produced upon stimulation with a given antigen. Ab-1 may elicit the production of anti-idiotypic antibodies (anti-Id) or Ab-2. The anti-Id also expresses Id determinants and may in turn elicit the production of anti-anti-Id or Ab-3. The production of Ab-1, Ab-2, and Ab-3 responses resulting from stimulation with the antigen is representative of components within an Id cascade. The existence of this Id cascade is the basis for the development of Id based strategies for controlling the immune response to infectious agents and tumors. In this review we will focus on several aspects regarding the Id cascades that may be operational during the immune response to the human immunodeficiency virus (HIV). In light of several studies which suggest the existence of Id-anti-Id interactions operating during the course of HIV infection, we will discuss the potential applications of Id based strategies in manipulating the immune response to HIV.     

Idiotypic Cascades Associated with the CD4-HIV gpl20 Interaction: Principles for Idiotype-Based Vaccines

Idiotypes (Id) are antigenic determinants expressed on the variable (V) region of the immunoglobulin molecule. Id-bearing antibodies, or Ab-1, are produced upon stimulation with a given antigen. Ab-1 may elicit the production of anti-idiotypic antibodies (anti-Id) or Ab-2. The anti-Id also expresses Id determinants and may in turn elicit the production of anii-anti-Id or Ab-3. The production of Ab-1, Ab-2, and Ab-3 responses resulting from stimulation with the antigen is representative of components within an Id cascade. The existence of this Id cascade is the basis for the development of Id based strategies for controlling the immune response to infectious agents and tumors. In this review we will focus on several aspects regarding the Id cascades that may be operational during the immune response to the human immunodeficiency virus (HIV). In light of several studies which suggest the existence of Id-anti-Id interactions operating during the course of HIV infection, we will discuss the potential applications of Id based strategies in manipulating the immune response to HIV.     

The immunology of HIV-infected long-term non-progressors--a current view

Long-term non-progressors (LTNP) are human immunodeficiency virus (HIV)-infected individuals characterized by the absence of disease, low viral loads and stable or even increasing CD4(+) T cell counts for prolonged periods of time. In these subjects, an HIV-specific immune response which is either stronger or directed against a wider array of viral epitopes than that seen in progressors, can be often detected. Here, we summarize the characteristics of HIV-specific CD4(+) and CD8(+) T cell responses in LTNP, and discuss how a highly effective T cell-mediated immune response against HIV might contribute to the establishment of this particular condition.     

Human immunodeficiency virus and human papilloma virus - why HPV-induced lesions do not spontaneously resolve and why therapeutic vaccination can be successful

HIV and HPV can both cause chronic infections and are acquired during sexual contact. HIV infection results in a progressive loss of CD4+ T cells that is associated with an increased prevalence of HPV infections, type-specific persistence and an increase in HPV-associated malignancies. On the one hand this illustrates the important role of HPV-specific CD4+ helper T-cell immunity, on the other it shows the Achilles heel of the HPV-specific immune response. The use of highly active antiretroviral therapy (HAART) results in a rapid reduction of HIV and a reconstitution of systemic CD4+ T-cell levels. The use of HAART thus has the potential to raise immunity to HPV but to the surprise of many, the incidence of HPV-induced diseases has increased rather than declined since the introduction of HAART. Here, the knowledge on how HPV-induced diseases develop in the face of a non-compromised immune system will be used to explain why the effect of HAART on HPV-induced diseases is modest at best. Furthermore, exciting new data in the field of therapeutic vaccines against HPV will be discussed as this may form a more durable and clinically successful therapeutic approach for the treatment of HPV-induced high-grade lesions in HIV-positive subjects on HAART.     

Role of cytokines and chemokines in the regulation of innate immunity and HIV infection

The earliest defense against microbial infection is represented by the responses of the innate (or natural) immune system, that also profoundly regulates the adaptive (or acquired) T- and B-cell immune responses. Activation of the innate immune system is primed by microbial invasion in response to conserved structures present in large groups of microorganisms (LPS, peptidoglycan, double-stranded RNA), and is finely tuned by different cell types (including dendritic cells, macrophages, natural killer cells, natural killer T cells, and gammadelta T cells). In addition, several soluble factors (complement components, defensins, mannose-binding lectins, interferons, cytokines and chemokines) can play a major role in the regulation of both the innate and adaptive immunity. In this review, we will briefly overview the regulation of some cellular subsets of the innate immune system particularly involved in human immunodeficiency virus (HIV) infection and then focus our attention on those cytokines and chemokines whose levels of expression are more profoundly affected by HIV infection and that, conversely, can modulate virus infection and replication.     

Host factors in the pathogenesis of HIV disease

Host factors play an important role in determining rates of disease progression in human immunodeficiency virus (HIV)-infected individuals. HIV is able lo subvert the host immune system by infecting CD4+ T cells that normally orchestrate immune responses and by inducing the secretion of proinflammatory cytokines that the virus can utilize to its own replicative advantage. The recognition that certain chemokine receptors serve as necessary co-factors for HIV entry into its target cells as well as the fact that ligands for these receptors can modulate the efficiency of HIV infection has expanded the number and scope of host factors that may impact the pathogenesis of HIV disease. This area of investigation will no doubt yield novel therapeutic strategies for intervention in HIV disease; however, caution is warranted in light of the enormous complexity of the pleiotropic cytokine and chemokine networks and the uncertainty inherent in manipulating these systems. HIV-infected long-term non-progressors represent an excellent model to study potential host factors involved in HIV disease pathogenesis. Genetic factors certainly have a major impact on the immune responses mounted by the host. In this regard, a polymorphism in the gene for the HIV co-receptor CC chemokine receptor 5 (CCR5), which serves as a coreceptor for macrophage (M)-tropic strains of HIV, affords a high degree of protection against HIV infection in individuals homozygous for the genetic defect and some degree of protection against disease progression in HIV-infected heterozygotes. HIV-specific immune responses, including cytotoxic T-lymphocyte (dX) responses and neutralizing antibody responses, also appear to play salutary roles in protecting against disease progression.     

Prevention of SHIV transmission by topical IFN-β treatment

Understanding vaginal and rectal HIV transmission and protective cellular and molecular mechanisms is critical for designing new prevention strategies, including those required for an effective vaccine. The determinants of protection against HIV infection are, however, poorly understood. Increasing evidence suggest that innate immune defenses may help protect mucosal surfaces from HIV transmission in highly exposed, uninfected subjects. More recent studies suggest that systemically administered type 1 interferon protects against simian immunodeficiency virus infection of macaques. Here we hypothesized that topically applied type 1 interferons might stimulate vaginal innate responses that could protect against HIV transmission. We therefore applied a recombinant human type 1 interferon (IFN-β) to the vagina of rhesus macaques and vaginally challenged them with pathogenic simian/human immunodeficiency virus (SHIV). Vaginal administration of IFN-β resulted in marked local changes in immune cell phenotype, increasing immune activation and HIV co-receptor expression, yet provided significant protection from SHIV acquisition as interferon response genes were also upregulated. These data suggest that protection from vaginal HIV acquisition may be achieved by activating innate mucosal defenses.     

A response to P.H. Duesberg with reference to an idiotypic network model of AIDS immunopathogenesis

Professors in British Columbia, Canada have devised an autoimmunity model of AIDS (MIAMI model) based on an atypical network theory of regulation of the immune system. It presents different stimuli as cofactors for AIDS: allogenic stimuli in some risk groups and MHC mimicking antigenic stimuli in other risk groups. V regions are on helper T cells that are somewhat anti-self class II MCH. Helper T cell idiotypes interact with both class II MHC and particular suppressor T cell idiotypes, therefore both may be similar. In fact, foreign lymphocytes also can induce an immune response similar to that of MHC image (MI). Hence the MI response is against the anti-self MHC, i.e., foreign idiotypes identify self, particularly self MHC. Further, the HIV envelope protein (gp120) binds to CD4 at a site that overlaps the site where CD4 interacts with class II MHC. Thus recombinant gp120 well as antibodies that recognize the gp120 undying site of CD4 can prevent the interaction of CD4 with class II MHC. Some mutations of CD4 effect the gp120 binding site but not the class II binding site and vice versa and others effect both. This similarity and others HIV can be considered an image of class II MHC, and the anti HIV immune response may be anti MHC image (AMI). MI and AMI responses are against each other and against idiotypic determinants expressed on helper and suppressor T cells respectively. A dual attack on the idiotypes of helper and suppressor T cells accompany these responses thereby causing an imminent collapse of the entire immune system. The model's significant predictive power thereby suggests that we may be able to prevent HIV from causing AIDS by inducing immunological tolerance to HIV components that resemble MHC molecules. This model rejects the 11 paradoxes identified by Duesberg who surmises that HIV is not a cofactor or cause of AIDS.     

Vaccination against HIV.

The spread of AIDS progresses unrelentingly despite all efforts of public education and the only real hope of epidemiological control lies in the development of an effective vaccine. The very nature of the AIDS virus (HIV) and the manner with which it interacts with the host makes development of a practical vaccine very difficult. Recent successes using whole inactivated virus as immunogen in the SIVmac animal model system now show that it is possible to protect against infection. However, due to supposed limited efficacy in the field of such a vaccine and the fact that large scale production and administration of a multi-shot whole HIV-based product would be technically impossible, it is now important to identify which of the proteins are responsible and which immune response is protective. With this knowledge a recombinant or synthetic vaccine could be produced on a large scale. However, despite recent protection of a few chimpanzees against HIV infection itself there is currently no proven effective and practical vaccine even in the laboratory and it will be many years before such a product is available to the general public.     

Gamma interferon production in response to Mycobacterium bovis BCG and Mycobacterium tuberculosis antigens in infants born to human immunodeficiency virus-infected mothers

In utero sensitization to infectious pathogens can establish immunological memory and may influence the immune response to unrelated antigens. Little is known about the influence of intrauterine human immunodeficiency virus (HIV) exposure on the cellular immune response to mycobacterial antigens. Whole-blood culture gamma interferon (IFN-gamma) production in response to mycobacterial antigens was measured at birth and 6 weeks of age to determine the characteristics of the IFN-gamma response in HIV-exposed infants to Mycobacterium bovis BCG and mycobacterial antigens. At birth, we observed an increased immune activation in response to phytohemagglutinin among HIV-exposed, uninfected infants. In a proportion of these infants, we also observed an increased immune activation in response to purified protein derivative, BCG, and early secreted antigen target 6. Increases in the IFN-gamma response to the four antigens between birth and 6 weeks of age, observed in all HIV-unexposed infants, was absent in a substantial proportion of HIV-exposed, uninfected infants. The immunological differences persisted at 6 weeks of age, suggesting a sustained impact of in utero immune priming by HIV. Intrauterine exposure to HIV affects the infants' cellular immune response to mycobacterial antigens, either specifically or as a consequence of nonspecific, broadly reactive immune activation. Further studies will be important to help determine optimal vaccination and disease prevention strategies for this vulnerable population group.     

Living in oblivion: HIV immune evasion

The human and simian immunodeficiency viruses (HIV and SIV, respectively) are members of the lentiviridae subgroup of retroviruses that cause a progressive failure of the host immunological functions culminating in the clinical collapse known as AIDS, or acquired immunodeficiency syndrome. In the absence of antiviral therapy, this course is inexorable in spite of an initially vigorous immune response. Two fundamental characteristics of the biology of primate lentiviruses explain this apparent paradox. First, HIV and SIV infect CD4(+)targets such as helper T lymphocytes and macrophages, that is, cells that normally play an essential role in the emergence and maintenance of an effective antiviral response. Second, these viruses have evolved a number of strategies to evade control by the immune system. These include mutational escape, latency, masking of antibody-binding sites on the viral envelope, downmodulation of the class I major histocompatibility complex (MHC-I), and upregulation of the Fas ligand on the surface of infected cells. Examining the mechanisms of these phenomena not only helps to understand how HIV wins its war against the immune system, but it also suggests as yet unexploited avenues to combat the virus through therapies and to develop a vaccine.