AVOIDING DECEPTIVE IMPRINTING OF THE IMMUNE RESPONSE TO HIV-1 INFECTION IN VACCINE DEVELOPMENT

Lymphocyte clonal restriction is caused by priming the immune system with an antigen and has been referred to infectious disease study as “original antigenic sin” (OAS), described first for influenza by Francis []. OAS is a dominant feature of a normal immune response. Benefits of OAS come from the initial contact with the pathogen, which induces immunological memory. Memory is achieved by priming B and T cells of an immunologically naïve host, and confers protection against infection with the antigen-related pathogen.

Thus, a restricted antibody response to viral or parasite antigens is not per se pathogenic. However, the interplay between a “locked-in” immune response and the high genetic variation of the pathogenic agent can result in a deception of the immune system. In the following, clonal restriction of the immune response to HIV is described by giving examples of restricted anti-HIV antibody formation in maternally infected children.

Clonal restriction results in host resistance of infected individuals to emerging HIV variants and quasispecies. The problems of classical approaches of vaccine design in AIDS and the lack of protection in vaccinated patients is reviewed.     

Proposition of treatment to improve the immune response: possible application to AIDS

The molecular similarity between certain human antigenic determinants with those of HIV has been already described. In this matter, we have previously demonstrated, by a chromatographic method, the cross reactivity of human serum albumin with HIV gp 120. The hypothesis that this similarity could be one of the reasons why the virus escapes to the immune system is presented in this paper and a treatment is proposed to enhance the efficiency of the immune response: it is based on the blocking of the determinants of the self, expressed in the thymus, which are in common with the virus. Repeated injections within the thymus of neutralizing antibodies against the pathogen, obtained from a sufficiently distant animal species and purified by affinity chromatography, would prevent the T cells of the host recognizing these epitopes, common to the host and to the virus, from clonal deletion and would improve the immune response.     

Humans and Ferrets with Prior H1N1 Influenza Virus Infections Do Not Exhibit Evidence of Original Antigenic Sin after Infection or Vaccination with the 2009 Pandemic H1N1 Influenza Virus

The hypothesis of original antigenic sin (OAS) states that the imprint established by an individual''s first influenza virus infection governs the antibody response thereafter. Subsequent influenza virus infection results in an antibody response against the original infecting virus and an impaired immune response against the newer influenza virus. The purpose of our study was to seek evidence of OAS after infection or vaccination with the 2009 pandemic H1N1 (2009 pH1N1) virus in ferrets and humans previously infected with H1N1 viruses with various antigenic distances from the 2009 pH1N1 virus, including viruses from 1935 through 1999. In ferrets, seasonal H1N1 priming did not diminish the antibody response to infection or vaccination with the 2009 pH1N1 virus, nor did it diminish the T-cell response, indicating the absence of OAS in seasonal H1N1 virus-primed ferrets. Analysis of paired samples of human serum taken before and after vaccination with a monovalent inactivated 2009 pH1N1 vaccine showed a significantly greater-fold rise in the titer of antibody against the 2009 pH1N1 virus than against H1N1 viruses that circulated during the childhood of each subject. Thus, prior experience with H1N1 viruses did not result in an impairment of the antibody response against the 2009 pH1N1 vaccine. Our data from ferrets and humans suggest that prior exposure to H1N1 viruses did not impair the immune response against the 2009 pH1N1 virus.     

Marginal zone B-cell depletion impairs murine host defense against Borrelia burgdorferi infection

Marginal zone B (MZB) cells are a B-cell subset that produces T-cell-independent antibodies to blood-borne antigens. In this study, we examined the effects of MZB cell depletion on the immune response to the Lyme disease spirochete Borrelia burgdorferi, an extracellular pathogen for which T-cell-independent antibody is an important host defense. MZB cell depletion of C3H/HeJ mice using monoclonal antibody to LFA-1 and alpha(4)beta(1) integrins reduced B. burgdorferi-specific immunoglobulin M (IgM) titers, enhanced pathogen burden, and led to more severe arthritis assessed within the first 2 weeks of infection. In addition, MZB cell-depleted mice had reduced levels of B. burgdorferi-specific IgG, which correlated with diminished splenic CD4+ T-cell-activation, proliferation, and cytokine production. Passive transfer of immune mouse serum from infected control mice into infected MZB cell-depleted mice reduced pathogen burden but did not alter the expression of T-cell activation markers on splenic CD4+ T cells. These findings demonstrate that MZB cells not only are a source of pathogen-specific IgM important for limiting spirochete burden and pathology but also play a prominent role in the priming of splenic T-cell responses to a blood-borne pathogen.     

Immunology of avian influenza virus: a review

Avian influenza virus can cause serious disease in a wide variety of birds and mammals, but its natural host range is in wild ducks, gulls, and shorebirds. Infections in poultry can be inapparent or cause respiratory disease, decreases in production, or a rapidly fatal systemic disease known as highly pathogenic avian influenza (HPAI). For the protection of poultry, neutralizing antibody to the hemagglutinin and neuraminidase proteins provide the primary protection against disease. A variety of vaccines elicit neutralizing antibody, including killed whole virus vaccines and fowl-pox recombinant vaccines. Antigenic drift of influenza viruses appears to be less important in causing vaccine failures in poultry as compared to humans. The cytotoxic T lymphocyte response can reduce viral shedding in mildly pathogenic avian influenza viruses, but provides questionable protection against HPAI. Influenza viruses can directly affect the immune response of infected birds, and the role of the Mx gene, interferons, and other cytokines in protection from disease remains unknown.     

Domestic cats infected with lion or puma lentivirus develop anti-feline immunodeficiency virus immune responses

Attenuated live viral strains have afforded significant protection against virus challenge in HIV vaccine models. Although both cellular and humoral immunity are assumed to be vital for protection, specific parameters consistently associated with control of infection have been elusive. Our previous studies have shown that lentiviruses from 2 nondomestic feline species--lion (Pathera leo) and puma (Felis concolor)--persistently but nonpathogenetically infect domestic cats (Felis domestica). Moreover, infection with either the puma lentivirus (PLV) or lion lentivirus (LLV) conferred partial protection against superinfection with virulent feline immunodeficiency virus (FIV), the feline equivalent of HIV. To determine whether domestic cats infected by the lentiviruses of pumas or lions generate cross-reactive immune responses, we infected groups of 5 domestic cats with PLV, LLV, or a sham control and then monitored virus load, hematologic parameters, antibody protection, proliferative responses, and the ability of blood mononuclear cells to inhibit LLV, PLV, and FIV replication in vitro. All cats inoculated with LLV or PLV developed persistent infection, and low-level cell-associated viremia has been previously described. Infected cats also generated robust antibody titers and lymphocytes that proliferated in response to viral antigens and downregulated PLV, LLV, and FIV replication in vitro. This latter activity was CD8 cell associated for PLV and LLV inhibition but not for FIV inhibition. Thus, cats infected with the phylogenetically more ancient and less pathogenic feline lentiviruses generated humoral and cell-mediated immune responses reactive against both the homologous viruses and the heterologous FIV of domestic cats, which correlated with decreased viral load. These results are analogous to protection studies with attenuated primate immunodeficiency viruses and provide a system by which to examine adaptation, interference, and cross protection among lentiviruses.     

Replicating adenovirus HIV/SIV recombinant priming alone or in combination with a gp140 protein boost results in significant control of viremia following a SHIV89.6P challenge in Mamu-A*01 negative rhesus macaques

Previously, replicating adenovirus type 5 host range (Ad5hr)-HIV/SIV recombinant priming in combination with SIV envelope boosting, resulted in significant, durable protection in 39% of rhesus macaques after SIVmac251 challenge. Both Env-specific antibody mediating ADCC, and cellular immunity correlated with protection. Here we evaluate the relative immunogenicities of novel HIV proteins and their contribution to protection in a SHIV89.6P model. All groups were primed with Ad-HIVenv89.6P, SIVgag239, and SIVnef239 recombinants. One group was not boosted, one received HIV89.6Pgp140DeltaCFI protein, and one a novel HIV-1 poly-peptide "peptomer". The HIV89.6Pgp140DeltaCFI protein in adjuvant strongly boosted Env-specific antibody and memory T cell responses in blood and tissue, resulting in significant reductions in acute and set point viremia. Macaques not boosted, showed a significant reduction in set point viremia, a full 32 weeks after the last Ad priming immunization. The HIV peptomer-boosted group showed a trend toward chronic viremia reduction, but was not protected.     

Human immunodeficiency virus infection elicits early antibody not detected by standard tests: implications for diagnostics and viral immunology

The FDA-approved tests for diagnosis of HIV exposure depend on detection of specific antibody in serum. HIV infection is missed in some individuals because they score seronegative by the standard clinical EIA and Western blot assays. This apparent immunological "silent" period following infection may last for months and has been reported to be as long as 3 years in rare cases. Is there truly a lack of an immune response or is there a more subtle, narrowly focused antibody response in these HIV-infected individuals which is not detected by the current tests? Using a nondenaturing serological assay (immunofluorescence of live infected T-cells), we found that each of four infected individuals "seronegative" by the standard tests did possess antibody against native HIV proteins expressed on infected cells. These antibodies reacting with native HIV antigenic epitopes were of the IgG isotype, they cross-reacted with many, but not all, of seven random HIV-1 isolates, and one of the sera immunoprecipitated HIV gp160 from NP-40-solubilized infected cells. These results show that seronegative, high-risk, infected individuals can actually be seropositive and that different types of assays using native antigenic epitopes may be required for screening. Implementation of these findings thus may decrease HIV transmission. These results also highlight the importance of protein conformation for many natural viral antigenic epitopes.     

Host-parasite interaction in fungal infections

The outcome of host-parasite interactions in fungal infections is determined by the balance between pathogenicity of the organism and the adequacy of the host defenses. A wide variety of host defense mechanisms are involved in protection against fungal infections. These include nonspecific mechanisms such as intact skin and mucus membranes, indigenous microbial flora, and the fungicidal activity of neutrophils and monocytes. Such mechanisms constitute the major host defense against opportunistic fungal infections caused by ubiquitous organisms of low virulence. The effective role of immunoglobulins and complement as opsonins varies with the fungal pathogen involved. Specific immune responses of both the humoral and cell-mediated type develop in response to infections by pathogenic fungi. Antibodies, in general, are not of major importance in protection against these infections. Specifically sensitized T lymphocytes produce lymphokines that activate macrophages. Activated macrophages are the major line of defense against systemic fungal pathogens. The type and degree of impairment in immune responses determines the susceptibility and severity of diseases. The type of immune response also determines the tissue reactions in these diseases and sometimes may be involved in the pathogenesis of the disease process. The role of natural killer cell activity, antibody-dependent cellular cytotoxicity, and biological response modifiers in various fungal infections has been described recently. The microbial factors of importance in fungal infections are adherence, invasion, presence of an antiphagocytic capsule, and ability to grow under altered physiological states of the host. The differences in the virulence of fungal strains is of minor importance in determining the outcome in general. The seriousness of the alteration of the host state rather than the pathogenic properties of the fungus determine the severity of the disease.     

Why infection-induced anorexia? The case for enhanced apoptosis of infected cells

A medically important paradox is why the body's own cytokines lead to reduced appetite and apparently inefficient metabolism as part of the acute-phase response. This self-induced nutrient restriction occurs just when the body must maintain a fever and other defensive functions. This paradox is often ignored or considered a metabolic derangement. Others, recognizing it to be a programmed response which must have net beneficial effects, consider the nutrient restriction to be an attempt to deny resources to infectious organisms. However, this explanation fails to address how the pathogen can be harmed more than the host. The hypothesis presented here offers an explanation. Apoptosis, or cell suicide, is becoming recognized as a useful defense against intracellular parasites, and nutrient restriction promotes apoptosis. Thus, nutrient restriction may encourage apoptosis of infected cells. Nutrient restriction can thereby offer protection by simultaneously limiting nutrients to both the host cells and the infectious organisms.     

Studies on the generation and expression of H-2-controlled T helper function in chimeric mice: evidence for two levels of H-2 resitriction.

F1 leads to parental, semisyngeneic/semiallogeneic and fully allogeneic bone marrow radiation chimeras were used as a source of helper T cells in the in vitro anamnestic response to dinitrophenylated keyhole limpet hemocyanin. In F1 leads to parental and in semisyngeneic/semiallogeneic chimeras, a small population of helper T cells restricted to the H-2 haplotype present in the donor only was shown to co-exist with T cells restricted to the shared haplotype. Only the population restricted to the donor H-2 could be demonstrated in allochimeras, presumably due to a lack of antigen-presenting cells of host origin during priming. Under assay conditions where, in addition to T cell/macrophage interactions, a direct T-B cell contact was necessary ("linked" cooperation), the H-2 restrictions observed were absolute. When direct T-B cell contact was made unnecessary by a special experimental protocol ("unlinked" cooperation), H-2 restriction between T and B cells was overcome. Thus, the cellular interactions during the anamnestic immune response to T-dependent antigens seem to be H-2-restricted at two levels: T cell/macrophage and T-B cell interactions.     

Immunomodulation by viruses: the myxoma virus story

Summary: Myxoma virus is a poxvirus pathogen of rabbits that has evolved to replicate successfully in the presence of an active immune response by an infected host. To accomplish this, the virus has developed a variety of strategies to avoid detection by or obstruct specific aspects of the antiviral response whose consolidated action is antagonistic to virus survival. We describe two distinct viral strategies carried out by viral proteins with which myxoma virus subverts the host immune response. The first strategy is the production of virus-encoded proteins known as viroceptors or virokines that mimic host receptors or cytokines. These seek to actively block extracellular immune signals required for effective virus clearance and produce a local environment in the infected tissue that is "virus friendly". The second strategy, carried out by intracellular viral proteins, seeks to retard the innate antiviral responses such as apoptosis, and hinder attempts by the infected cell to communicate with the cellular arm of the immune system. By studying these viral strategies of immune evasion, the myxoma system can provide insights into virus-host interactions and also provide new insights into the complex immune system.     

Intercellular communication for innate immunity

An effective innate immune response relies on the detection of pathogen associated molecular patterns (PAMPs) by various host pattern recognition receptors (PRRs) that result in the production of pro-inflammatory cytokines and chemokines. Viruses and bacteria have co-evolved with the immune system and developed multiple strategies to usurp or circumvent host machinery and blunt the innate immune response in infected cells. Recently, it has become apparent that infected or dying cells can transmit PAMPs and host PRR signalling proteins to uninfected bystander cells to thereby bypass pathogen evasion strategies, and potentiate innate immune signalling. This bystander activation of innate immunity represents an alternative method by which the host can control infections via cell-to-cell communication. In this review, we discuss what is currently known about the intercellular transfer of pathogen- or host-derived RNA, DNA and proteins from infected cells to neighbouring cells and how this impacts on host innate immunity.     

Lactate dehydrogenase-elevating virus: an ideal persistent virus?

Conclusions LDV contradicts all commonly held views about mechanisms of virus persistence, namely that persistence is primarily associated with noncytopathic viruses, or the selection of immune escape variants or other mutants, or a decrease in expression of certain viral proteins by infected cells, or replication in immune-privileged sites, or a general suppression of the host immune system, etc. [1, 2, 5, 54, 77, 78]. LDV is a highly cytocidal virus that invariably establishes a life-long, viremic, persistence in mice, in spite of normal anti-viral immune responses.One secret of LDV's success in persistence is its specificity for a renewable, nonessential population of cells that is continuously regenerated, namely a subpopulation of macrophages. Since the continuous destruction of these cells is not associated with any obvious health effects, this macrophage population seems nonessential to the well-being of its host. The only function identified for this subpopulation of macrophages is clearance of the muscle type of LDH and some other enzymes [59, 67, 68]. Furthermore, the effects of LDV infection on the host immune system, namely the polyclonal activation of B cells and its associated production of autoantibodies, and the slight impairment of primary and secondary antibody responses also do not seem to be severe enough to cause any clinical consequences.But how does LDV replication in macrophages escape all host defenses? Persistence is not dependent on the seletion of immune escape variants or other mutants ([58] and Palmer, Even and Plagemann, unpublished results). Also, LDV replication is not restricted to immune-privileged sites [5]. LDV replication persists in the liver, lymphoidal tissues and testis [66]. Only the latter could be considered a site not readily accessible to immune surveillance.Most likely, resistance of LDV replication to antiviral immune responses is related to the unique structure of its envelope proteins and the production of large quantities of viral antigens. High titers of anti-LDV antibodies are generated in infected mice but they neutralize LDV infectivity only very inefficiently and, even though the antiviral antibodies are mainly of the IgG2a and IgG2b isotypes, they do not mediate complement lyses of virions [31]. Interaction of the antibodies and complement with the VP-3/VP-2 heterodimers in the viral envelope may be impeded by the exposure of only very short peptide segments of these proteins at the envelope surface and the presence of large oligosaccharide side chains. Furthermore, since LDV maturation is restricted to intracytoplasmic cisternae [59, 71], the question arises of whether any of the viral proteins are available on the surface of infected cells for ADCC.CTLs also fail to control LDV replication. Altough CTLs specific for N/VP-1 are rapidly generated, these have disappeared by 30 days p.i. [26]. The reasons for this loss are unknown, but high-dose clonal exhaustion [41, 51, 77, 78] is a reasonable possibility since, regardless of the infectious dose, large amounts of LDV proteins are present in all the lymphoidal tissues at the time of the induction of the CTL response. Furthermore, after exhaustion of CTLs in the periphery, continuous replication of LDV in the thymus [65] assures that the mice become permanently immunologically tolerant with respect to LDV antigen-specific CTLs as a result of negative selection in the thymus. LDV might be a primary example for the effectiveness of a permanent clonal CTL deletion in adult animals under natural conditions of infection.The presumed modes of transmission of LDV in nature and the events associated with its infection of mice are strikingly similar to those observed during the acute and asymptomatic phases of infection with human immunodeficiency virus (HIV) [24, 29, 74, 78]. These include: (1) primary inefficient transmission via sexual and transplacental routes but effective transmission via blood; (2) primary replication in renewable populations of lymphoidal cells with production of large amounts of virus after the initial infection of the host followed by persistent low level of viremia in spite of antiviral immune responses; (3) persistence, reflecting continuous rounds of productive, cytocidal infection of permissive cells [59, 74] and the rate of generation of permissive cells which may be the main factor in determining the level of virus production (in the case of HIV, the rate of activation of CD4⁺ T cells to support a productive HIV replication might be the factor determining the rate of virus production and the progression of the disease); (4) rapid antibody formation but delayed production of neutralizing antibodies with limited neutralizing capacity; (5) rapid but transient generation of virus-specific CTLs; and (6) accumulation of large amounts of virus in newly formed germinal centers in the spleen and lymph nodes concomitant with an initiation of a permanent polyclonal activation of B cells resulting in an elevation of plasma IgG2a.The events described under points 2–6 might be generally associated with natural viremic persistent virus infections. Such persistent viruses, by necessity, have evolved properties that allow them to escape all host defenses and control of their infection by immunological processes is, therefore, difficult, if not impossible. Prevention of infection and chemotherapy may be the only approaches available to combat such virus infections.     

HIV-1 vaccines and adaptive trial designs

Developing a vaccine against the human immunodeficiency virus (HIV) poses an exceptional challenge. There are no documented cases of immune-mediated clearance of HIV from an infected individual, and no known correlates of immune protection. Although nonhuman primate models of lentivirus infection have provided valuable data about HIV pathogenesis, such models do not predict HIV vaccine efficacy in humans. The combined lack of a predictive animal model and undefined biomarkers of immune protection against HIV necessitate that vaccines to this pathogen be tested directly in clinical trials. Adaptive clinical trial designs can accelerate vaccine development by rapidly screening out poor vaccines while extending the evaluation of efficacious ones, improving the characterization of promising vaccine candidates and the identification of correlates of immune protection.     

Immunopathogenic mechanisms of HIV infection: cytokine induction of HIV expression

In this paper Zeda Rosenberg and Anthony Fauci review the prevailing hypotheses on the mechanisms by which human immunodeficiency virus (HIV) progressively and relentlessly destroys immune function in infected individuals. Although HIV can directly kill CD4+ T cells in vitro, the protracted course of HIV infection in vivo suggests that other pathogenic mechanisms are also involved. As a member of the lentivirus family, HIV can remain latent within the genome of the infected cell. Activation of HIV expression from a latent or low-level state of replication is dependent, in part, on the state of activation of the host cell. As a result, activation of HIV-infected CD4+ T cells or monocyte/macrophages during normal immune responses may ultimately result in the activation of HIV expression and spread of the infection. Thus, HIV may have developed the ability to use normal immune processes to its own reproductive advantage.     

Independent evolution of Fc‐ and Fab‐mediated HIV‐1‐specific antiviral antibody activity following acute infection

Fc‐related antibody activities, such as antibody‐dependent cellular cytotoxicity (ADCC), or more broadly, antibody‐mediated cellular viral inhibition (ADCVI), play a role in curbing early SIV viral replication, are enriched in human long‐term infected nonprogressors, and could potentially contribute to protection from infection. However, little is known about the mechanism by which such humoral immune responses are naturally induced following infection. Here, we focused on the early evolution of the functional antibody response, largely driven by the Fc portion of the antibody, in the context of the evolving binding and neutralizing antibody response, which is driven mainly by the antibody‐binding fragment (Fab). We show that ADCVI/ADCC‐inducing responses in humans are rapidly generated following acute HIV‐1 infection, peak at approximately 6 months postinfection, but decay rapidly in the setting of persistent immune activation, as Fab‐related activities persistently increase. Moreover, the loss of Fc activity occurred in synchrony with a loss of HIV‐specific IgG3 responses. Our data strongly suggest that Fc‐ and Fab‐related antibody functions are modulated in a distinct manner following acute HIV infection. Vaccination strategies intended to optimally induce both sets of antiviral antibody activities may, therefore, require a fine tuning of the inflammatory response.     

Neutrophil priming in host defense: role of oxidants as priming agents

Neutrophils play an essential role in the body's innate immune response to infection. To protect the host, these phagocytic cells possess an impressive array of microbicidal weapons that can be brought to bear on an invading pathogen, including a variety of toxic oxygen radical species and proteolytic enzymes. Although the neutrophil response is designed to restrict the damage to the smallest possible region where the pathogen is located, some of the damaging agents inevitably leak into the surrounding areas where they have the capacity to inflict tissue damage at sites of inflammation. Thus, it is essential that the host defense response of these cells is finely tuned to result in the appropriate level of response to any given situation. One of the regulatory mechanisms implicated in controlling neutrophil responses is priming. Through the action of priming agents, the level of activation and subsequent responses of the cell can be regulated so that a continuum of activation states is achieved. In this review, we describe key features of the priming response in host defense and disease pathogenesis and focus on the unique role of reactive oxygen species as priming agents.     

HIV immunotherapy comes of age: implications for prevention,treatment and cure

Antiretroviral therapy (ART) has reshaped the lives of millions of individuals infected with human immunodeficiency virus (HIV). Patients initiating ART early in the course of infection benefit from a considerable reduction in the risks of acquired immune deficiency syndrome (AIDS) and HIV-related inflammatory events. However, the absence of cure and lifelong requirements of treatment highlight the need of a vaccine and an immunotherapeutic strategy. Like for cancer, a paradigm shift has occurred with the contribution of immune activation and microbial translocation priming aberrant systemic immunity in restricting the ability of the host to mount an effective immune response. The approaches of implementing an effective vaccine to prevent infection and inhibition of immune activation with breakage of viral latency followed by vaccination should lead to an HIV-free generation.