This is a challenge, given the vast diversity of pathogens that can infect us. Which of the following compounds is produced and secreted by mast cells during an allergic reaction? Study Guides. Log in Sign Up. Forgot password? Register Now. Already have an account? Login here. The body's innate defenses against infection include. View Full Document. The body's innate defenses against infection include Description. Natural killer cells.
Some complement proteins. Which of the following helps activate our nonspecific innate defense system? When you cut yourself, the damaged cells immediately release chemical alarm signals, such as. Which of the following is an immediate effect of histamine release?
The major result of the inflammatory response is to. The two main functions of the lymphatic system are. A molecule that can elicit an adaptive immune response is called. One kind of vaccine consists of. Passive immunity depends upon.
Which of the following cell types is responsible for the humoral immune response? T cells, which mature in the thymus, differentiate into cells that either participate in lymphocyte maturation, or kill virus-infected cells. Both humoral and cell mediated responses are essential for antiviral defense. The contribution of each varies, depending on the virus and the host.
Antibodies generally bind to virus particles in the blood and at mucosal surfaces, thereby blocking the spread of infection. In contrast, T cells recognize and kill infected cells.
A key feature of the adaptive immune system is memory. Repeat infections by the same virus are met immediately with a strong and specific response that usually effectively stops the infection with less reliance on the innate system. When we say we are immune to infection with a virus, we are talking about immune memory. Vaccines protect us against infection because of immune memory.
The first adaptive response against a virus — called the primary response — often takes days to mature. In contrast, a memory response develops within hours of infection. Memory is maintained by a subset of B and T lymphocytes called memory cells which survive for years in the body.
Memory cells remain ready to respond rapidly and efficiently to a subsequent encounter with a pathogen. This so-called secondary response is often stronger than the primary response to infection. Consequently, childhood infections protect adults, and immunity conferred by vaccination can last for years.
The nature of the adaptive immune response can clearly determine whether a virus infection is cleared or causes damage to the host. However, an uncontrolled or inappropriate adaptive response can also be damaging. How does acute HIV infection lead to depletion of cells in gut associated lymphoid tissue GALT and irreversible damage to the host immune system?
Which molecular mechanisms may underlie the chronic immune activation eventually causing progressive immune exhaustion and profound immunodeficiency? These are central questions in the understanding of the pathogenesis of HIV infection, which remain unanswered despite intense research in this area since the discovery of HIV more than 25 years ago [ 7 , 8 ].
HIV targets central players of the immune system, including cells of the mononuclear lineage, such as T cells, monocytes, and macrophages, but whereas the role of the adaptive immune response has been extensively studied [ 4 ], much less knowledge exists regarding the role of innate immune recognition and inflammation during HIV infection.
Following sexual transmission of HIV, the virus first replicates locally in the vaginal or rectal mucosa, and this early stage before detectable viral RNA in plasma is termed the eclipse phase. Molecular analyses of subjects with acute HIV infection have indicated that productive infection arises from a single infectious virus [ 9 , 10 ], and other studies suggest that the first cells to be infected in the mucosa are resident memory T cells expressing CD4 and CCR5 [ 11 , 12 ].
Already at this early point of infection, innate immune activation may contribute by recruiting granulocytes, macrophages, and lymphocytes, the latter two of which are cellular targets of the virus.
This loss is largely irreversible and has profound immunological consequences, eventually manifesting as failure of the host immune defences and progression to AIDS later during infection [ 23 ]. At the time of peak viraemia, patients may develop symptoms of the acute retroviral syndrome, including influenza-like illness with fever, sore throat, lymphadenopathy, and exanthema [ 24 ]. However, viral reservoirs have already been established in cells with slower rate of decay than T cells, implying that the virus cannot be eliminated by highly active antiretroviral treatment HAART within the life time of the patient [ 25 ].
Eventually, the viral load decreases over weeks to reach a stable viral set point [ 26 ], and this initiates a more chronic phase of the infection. The central immunological parameters in the natural history of HIV infection is depicted in Figure 1 , which also illustrates how the innate immune system plays a part in early restriction of the virus and shaping of the adaptive immune response, but at the same time participates in the establishment and spread of infection.
This is discussed in details later in this review. Potential roles of the innate immune system during HIV infection.
This is mediated by the adaptive immune response, which is activated through processes driven by the innate immune response. Moreover, direct innate antiviral mechanisms contribute to control of virus replication during the chronic phase. This apparent state of basal immune hyper-activation in the infected host is evidenced by increased expression of activation markers, such as CD38, HLA-DR and Ki67, of which CD38 is considered the most reliable surrogate marker for immune activation, disease progression to AIDS, and death [ 36 ].
The profound immunological damage to the gastrointestinal tract leads to breaks in the mucosal barrier allowing translocation of microbial products, including bacterial lipopolysaccharide LPS , into the circulation.
A seminal study by Brenchley and colleagues demonstrated bacterial translocation during HIV infection and correlated plasma LPS levels with immune activation [ 38 ].
Bacterial translocation may therefore represent a crucial event in persistent immune activation, although it is probably not the only source of the microbial burden responsible for chronic immune activation Figure 1. These aspects are discussed in further detail below. Another important factor is the accelerated viral evolution at this stage, provided by an excessively high viral mutation rate and alteration in cellular tropism, resulting in progression from a pool of CCR5-trophic to dual trophic or dominantly CXCR4 trophic strains with increased virulence and broader target cell trophism [ 4 ].
HIV infection also profoundly affects blood and tissue B cells by inducing early class switching in polyclonal B cells, massive B cell apoptosis, and loss of germinal centers in lymphoid tissue [ 44 , 45 ]. Although the profound damage to the adaptive immune system dominates, it has been increasingly appreciated that most other parts of the immune system, particularly innate immune defences, are also significantly dysregulated [ 1 ].
Finally, important questions regarding the immunopathogenesis of HIV infection may be learned from the study of infection in natural hosts, or potentially from HIV-infected humanized mouse models [ 46 ]. Intriguingly, simian immunodeficiency virus SIV infection in sooty mangabeys that represent natural hosts of SIV leads to high viral load but only very modest immune activation [ 47 ].
In contrast, SIV infection in rhesus macaques, which are not natural hosts and therefore mount a strong immune response, resemble human HIV infection with production of inflammatory mediators at the expense of the development of immunodeficiency [ 47 , 48 ].
Such findings support the idea that immune activation is primarily disadvantageous to the host and a major driving force for immune exhaustion during human HIV infection. These observations therefore raise the question, whether HIV infection might be less detrimental for the immune system, had the immune response to the virus been less powerful. Since one of the fundamental characteristics of HIV pathogenesis is the failure of the immune system to recognize, control, and eliminate the virus, much focus has been on early events following viral infection.
The innate immune system constitutes the first line of defence against invading pathogens and is based on epithelial barriers, the complement system, and cells with phagocytotic and antigen presenting properties, such as granulocytes, macrophages, and DCs respectively [ 49 , 50 ].
Pattern recognition receptors PRR s have been assigned a central role in innate immune defences due to their ability to recognize evolutionarily conserved structures on pathogens, termed pathogen-associated molecular patterns PAMP s. A limited number of germ-line encoded receptors are responsible for triggering an innate immune response following the encounter with PAMPs, which are characterized by being invariant among entire classes of pathogens, essential for survival of the pathogen, and distinguishable from self [ 51 ].
TLR1, 2, 4, 5, 6, and 10 are expressed at the cell surface and mainly recognize hydrophobic molecules unique to microbes and not produced by the host. In contrast, TLR3, 7, 8, and 9 are located almost exclusively in endosomal compartments and are specialized in recognition of nucleic acids.
Hence, non-self discrimination is provided primarily by the exclusive localization of the ligands rather than solely based on a unique molecular structure different from that of the host [ 50 ]. Since microbial material is not exclusively present extracellularly or within endosomes, alternative cytosolic PRRs exist. Finally, cytosolic DNA receptors have been identified more recently and are the subject of much research interest in the field. Furthermore, a receptor for ssDNA may exist but has not presently been identified [ 72 ].
In the intracellular environment, various viral RNA and DNA structures are recognized by nucleotide sensors localized in endosomes or in the cytoplasm. This is depicted in Figure 3. Some degree of specificity and selectivity is conferred by complex differences in the response depending on cell type, timing and localization.
CLR-induced intracellular pathways, which involve activation of the kinase Raf-1, essentially modulate the responses of other PRRs but also exert functions independently from other PRRs [ 60 ]. These transcription factors bind to specific sequences present in gene promoter regions and activate transcription of antiviral and inflammatory genes. When considering how HIV may possibly be recognized by the innate immune system, it seems logical to contemplate the possible PAMPs that are part of the HIV particle or generated during different phases of the viral life cycle.
Being a member of the retroviridae family lentivirus subfamily , HIV is a spherical enveloped RNA virus with a diameter of roughly nm. The envelope contains viral glycoproteins and encloses a cone-shaped capsid containing two identical copies of the positive ssRNA genome of 10 kilobases together with several copies of reverse transcriptase RT , integrase, additional viral proteins and two cellular tRNAs [ 75 ]. The viral genome contains three major structural genes, including gag, pol, and env, as well as six regulatory genes, namely vif, vpr, tat, rev, vpu, and nef.
Similar to cellular mRNA, the viral genome has a 5' cap and is poly-adenylated at the 3' end. As illustrated in Figure 4 , the viral life cycle is initiated by binding of viral gp to the cellular CD4 surface molecule [ 76 ]. Such glycoproteins of the viral envelope may be recognized by surface TLRs and CLRs as described for other viruses, such as cytomegalovirus [ 52 — 54 ]. Furthermore, interaction between viral gp41 and the chemokine receptors CXCR4 or CCR5 is required for fusion of the viral envelope with the cellular plasma membrane and release of the viral capsid into the cytoplasm [ 77 — 79 ].
The process of reverse transcription takes place in the cytoplasm, possibly with most viral structures shielded from cellular recognition due to localization in the viral capsid [ 75 ]. The two strands of RNA are entwined within the core as a ribonuclear complex with viral proteins forming a dimeric RNA complex [ 81 ]. Theoretical possibilities for innate immune recognition during the life cycle of HIV. Some of these are recognized by PRRs and activate expression of antiviral and inflammatory gene products.
Subsequently, the viral ribonuclease H activity of RT degrades the viral genomic RNA template, except for two resistant purine rich sequences, which then serve as primers for the formation of a complementary DNA plus-strand [ 75 ].
Following formation of linear dsDNA, a pre-integration complex consisting of viral DNA and several viral proteins is formed and translocated into the nucleus [ 82 ].
This essential step in the HIV replication cycle is mediated by the virion-carried integrase, and once a linear copy of the viral genome has been inserted in the host cellular genome, the integration is for the lifetime of the cell. However, unintegrated circular DNA may persist in the nucleus and be transcribed, particularly in quiescent cells [ 83 ].
Indeed, there is recent evidence of cellular mechanisms for recognition and degradation of ssDNA of retroviral origin [ 72 ]. In Trex-deficient cells ssDNA derived from endogenous retro-elements accumulates, and mutations in the human Trex gene cause autoimmune manifestations [ 72 ]. Synthesis of new progeny virus is accomplished in a highly regulated manner utilizing host cell enzymes and dependent on cellular or microbial inflammatory or mitotic signals, including the HIV transactivator Tat [ 75 ].
These mRNAs undergo translation, processing, and maturation in the endoplasmic reticulum and Golgi. Gag and gag-pol proteins bind to the plasma membrane containing envelope glycoprotein, and the association of two copies of genomic ssRNA and cellular tRNA molecules finally promote cellular budding and virion release [ 75 ]. Only after release from the cell, the viral protease mediates cleavage of gag and gag-pol poly-proteins to finally accomplish maturation of the viral core and release of RT, thus completing the life cycle of the virus.
Based on the observation that initiation of HAART leads to an almost immediate decline in immune activation, which can be correlated to significant reduction in HIV viraemia, a direct contribution of HIV itself to immune activation has been proposed [ 85 — 87 ].
In a study focusing on the requirements for pDC activation, Beignon et al. Although the experimental set-up did not allow for a precise identification of the receptor involved, the data strongly pointed to TLR7, with a possible role for TLR9 [ 89 ]. An important strength of this study, however, was the utilization of live virus rather than the less physiological approach involving transfection of synthetic HIV-derived uridine-rich ssRNA.
Recently, evidence was presented suggesting that productive infection of DCs requires two distinct HIV-dependent innate signal transduction pathways [ 90 ]. This may seem surprising in comparison with other pathogens, which are often recognized by various overlapping families of PRRs. Considering the wide range of pathogenic microbes that may be present during the course of HIV infection, several TLRs may be involved in microbial recognition and immune activation.
However, despite some authorities arguing for HIV infection to be considered a disease of the gastrointestinal tract [ ], several studies question the dominant role assigned to the gastrointestinal mucosa and microbial translocation.
For instance, the finding of severe depletion of the GALT in natural hosts of SIV sooty mangabeys in the absence of immune activation and immunopathology, may indicate that microbial translocation does not necessarily lead to immune activation [ , ], or at least does not represent an exclusive explanation.
One important aspect necessary to address when describing interactions between HIV and the innate immune system, is the extensive difference observed between various cell types. Such differences add further complexity to the overall picture, since HIV targets several different cell types, including T cell subsets, monocytes, macrophages, and DCs. Therefore, entirely different recognition mechanisms and immune strategies may exist depending on the cell and tissue involved. This is in agreement with clinical studies, in which TLR expression and responsiveness are increased in viraemic HIV infection [ ].
It may have major implications that macrophages, which play important roles in transmission and as reservoirs of actively replicating virus, are unable to directly mount an antiviral response towards HIV, but instead become primed to respond to different microbial challenges contributing to immune activation. In this manner macrophages play a key role in inducing and maintaining immune activation in HIV infection [ , ].
Interestingly, TLR5 stimulation was reported to trigger reactivation of latent HIV provirus from T cells and to activate viral gene expression in central memory T cells [ ]. These novel findings underscore the profound cell type differences in HIV-host interactions and also indicate that innate and adaptive immunity should not be regarded as two separate arms but rather as tightly connected and mutually dependent systems.
This is illustrated in Figure 5. As described above, several lines of evidence strongly suggest that HIV-derived molecules and viral replication are major forces in driving acute and chronic immune activation. This is clearly demonstrated in the reversion of immune activation shortly following initiation of HAART in HIV-infected patients, even before the CD4 count has returned to normal [ 85 ]. However, it should be noted, that certain clinical studies examining immunological parameters in elite controllers have revealed some degree of immune activation despite very low or undetectable viral load [ ], arguing for non-HIV-derived microbial stimuli as a source of immune activation.
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