Why innate immunity fails in aids patients

HIV-specific proliferative responses of CD4 T cells are detected only in a fraction of viremic chronically infected adults and are inversely correlated with VL if present , ; IL-2 producing HIV-specific CD4 responses are associated with slow disease progression in adults , The proliferative capacity of HIV-specific CD4 T cells is selectively impaired in vertically infected children with uncontrolled viral replication , , but, in contrast to adult infection, can be rescued with administration of ART The magnitude of the response increases with age and is strongest in children maintaining viral suppression on ART Interestingly, proliferative and IL-2 producing CD4 responses were also detected in HIV-exposed uninfected infants but were mostly absent in infected children Polyfunctional HIV-specific CD4 T cell responses, especially Interleukin-2 producing cells, were less frequently detected in younger children, but if present, they were associated with low viral loads and remarkably slow disease progression However, it remains unclear whether these responses actually mediate viral control or are simply a proxy for undisrupted immunoregulatory networks.

Chronic HIV infection and persistent antigenic stimulation lead to more terminally differentiated T cell populations with loss of effector functions and proliferative capacity upon antigenic stimulation [reviewed in Ref.

As immune functions can be partially restored upon antibody-mediated blockade of these receptors , , , , they present an attractive target for immunotherapeutic intervention in HIV infection, although immune-related adverse events remain a concern , In pediatric subjects, few studies have been conducted to elucidate the role of immune exhaustion in chronic HIV infection.

This is consistent with another report that described a correlation of PD-1 expression on CD8 T cells with immune activation markers and the magnitude of HIV-specific CD8 T cell responses, but not with viral load, suggesting that immune exhaustion is driven more by chronic immune activation than directly by viral replication Persistent systemic immune activation plays a key role in the pathogenesis of HIV infection and is regarded as the driving force in generalized immune dysregulation, chronic inflammation , , depletion of CD4 T cells , , and progression to AIDS [reviewed in 4 ].

Similarly, in vertically HIV-infected infants, the subsequent rate of disease progression can be predicted by T cell activation levels at 1—2 months of age Both CD4 and CD8 immune activation show a strong inverse correlation with CD4 percentage, but interestingly no correlation is observed between immune activation and viral load in children 72 , In vertically HIV-infected children who maintain high CD4 counts without ART often referred to as pediatric slow progressors , immune activation levels are strikingly low despite high viral loads Muenchhoff et al.

This resembles the phenotype of non-pathogenic infection in the natural hosts of SIV, such as African Green Monkeys and Sooty Mangabeys , in whom CD4 counts are maintained despite high levels of viremia, due to attenuated immune activation In acute infection, sooty mangabeys also show high levels of immune activation and a robust innate immune response that is associated with a generalized upregulation of Interferon Stimulated Genes ISGs, see innate immunity , but this initial response is rapidly resolved, suggesting the involvement of active immunoregulatory mechanisms that dampen detrimental excessive immune activation After initiation of ART, immune activation levels in children and adults decrease but usually remain elevated compared to HIV-negative controls and this residual immune activation despite ART is associated with incomplete immune reconstitution, increased non-AIDS comorbidities, and mortality — [reviewed in Ref.

Persistent immune activation is associated with increased levels of pro-inflammatory cytokines and elevated coagulation markers that have been linked to cardiovascular disease and cancer in adults [reviewed in Ref. The cause of systemic immune activation in HIV infection has not yet been fully elucidated but appears to arise from a complex interplay between HIV and the host involving several molecular and cellular mechanisms including innate and adaptive immune responses that create a pro-inflammatory milieu, fibrosis of lymphoid tissue, uncontrolled co-infections, and breach of the intestinal barrier resulting in translocation of microbial products into the systemic circulation [reviewed in Ref.

From early stages of HIV infection, the gastrointestinal tract is a target for HIV-induced pathology, with severe depletion of mucosal CD4 T cells in particular Th17 cells , dendritic cells, and innate lymphoid cells , , disrupting mucosal immunity and the intestinal epithelial architecture [reviewed in 2 , ]. This breach in the mucosal barrier results in translocation of microbial products from the gut into the systemic circulation leading to immune activation Markers that are used to measure microbial translocation include direct microbial products like lipopolysaccharide LPS , a component of the Gram-negative bacterial cell wall, and conserved bacterial ribosomal 16sRNA, or indirect markers such as sCD14 as a soluble marker of monocyte activation The immaturity of the gut in early life, characterized by increased epithelial permeability and the evolution of the gut microbiota following bacterial and viral colonization might influence the degree of microbial translocation in pediatric populations.

Plasma levels of LPS in uninfected children initially increase after birth to reach a plateau at about 6 months of age and then decrease again after the age of 2 years In vertically HIV-infected infants, levels of microbial translocation are elevated compared to uninfected controls and persist at a higher level after initiation of ART Persistent microbial translocation correlates with cellular and soluble markers of immune activation in children on ART suggesting an important role in immune reconstitution In a recent study in untreated HIV-infected children, microbial translocation was strongly correlated with monocyte and T cell activation and PD-1 expression levels on CD4 and CD8 T cells demonstrating the connection between microbial translocation, immune activation, and immune exhaustion HIV-specific antibodies have been in the focus of intense research for several decades in the quest for a prophylactic HIV vaccine.

Recently, hope has been fueled by the results of the RV vaccine trial, which showed modest vaccine efficacy and identified antibodies against the V1V2 HIV-envelope region as a correlate of protection in vaccinees Antibodies can mediate antiviral activities by binding either to free virus or to viral particles on infected cells.

The Fc-region of the bound antibody can mediate phagocytosis of the virus or infected cells, activation of innate immune cells resulting in ADCC against infected cells see innate immunity , or activation of the complement system leading to opsonization and lysis of the virus or infected cells [reviewed in Ref.

An important function of antibodies especially in regard to sterilizing immunity is the ability to neutralize the virus by binding to the viral surface and inhibit cellular infection. The surface of HIV consists of the gp41 trans-membrane protein and the heavily glycosylated gp surface protein, which are both highly variable between different viral variants. Therefore, antibodies elicited by an effective protective vaccine would need to be broadly neutralizing across different viral subtypes A recent study identified several young children with HIV-specific antibodies that had surprisingly high neutralizing breadth These findings were especially surprising as it had previously been shown that infants produce lower antibody titers with less diversified somatic mutation upon infection and vaccination shortly after birth [reviewed in Ref.

As higher set point, viral load levels are associated with increased emergence of bNABs in adults and in these young children , it has been hypothesized that the high antigenic load in pediatric HIV infection boosts development of NAB breadth. Also other factors like the shift toward Th2 responses in early life as discussed above could promote B-cell function and somatic hypermutation.

Differential proportions of IgG-subclasses in children with a preponderance of IgG1 and IgG3 that have higher neutralizing potency , could also contribute to this finding. Further investigation in this field could yield important findings for vaccine development. The main obstacle to HIV eradication is a pool of long-lasting, treatment-resistant viral reservoirs that only decay slowly on ART and are a source for viral rebound after treatment cessation [reviewed in Ref.

In this regard, children might be partially protected against the early establishment of viral reservoirs in these cell populations, because neonates have much lower frequencies of CD4 T cells of central memory phenotype than adults 22 , The frequency of latently infected CD4 T cells in children strongly depends on early initiation of ART and the time to achieve virologic suppression A cross-sectional study found low to undetectable levels of integrated pro-viral DNA in CD4 cells of children starting treatment before 6 months of age after more than 3 years of follow-up A recent longitudinal study compared perinatally infected youth initiating treatment before or after 3 months of age In contrast to the late treatment group, all children starting ART before 3 months had undetectable HIV-RNA plasma levels using highly sensitive assays but integrated pro-viral DNA could be detected by PCR in all subjects even after follow-up periods of up to 17 years.

In the early-treated group, transitional memory CD4 T cells had a larger contribution to the pool of infected cells than longer lasting central memory CD4 T cells.

These findings are consistent with a study of adult post-treatment controllers who initiated ART during acute HIV infection , indicating that early treatment can prevent seeding of long-lived cellular reservoirs.

It has to be noted that only a fraction of integrated viral DNA codes for replication-competent virus and so the standard assay to measure the size of the functional latent viral reservoir at present is a limiting dilution viral outgrowth assay , Using this assay, only one of the early-treated children in this study had inducible replication-competent virus, as opposed to all children receiving ART at a later stage, although limited sample availability in pediatric studies reduces the sensitivity of these assays.

Caution also has to be taken as rebound viremia is observed even in patients with extraordinarily low viral burden in the peripheral blood compartment and a large proportion of the viral reservoir is actually located within the gut and other tissues that are not accessed in most studies Reliable biomarkers to predict successful drug-free remission upon treatment cessation are therefore needed.

Apart form timing of ART initiation, the size and constitution of the viral reservoir is affected by host immunological factors including persistent immune activation that fuels replenishment of the reservoir during ART [reviewed in Ref. To achieve a cure of HIV in a broader group of patients will therefore most likely require a multifaceted approach that could include induction of potent HIV-specific immunity prior to reversion of HIV-latency in combination with immunomodulatory interventions.

In summary, immunity to HIV in early life differs from that in adulthood not only in quantity but also in quality. This results from the adaptations of the immune system to the abundance of antigenic stimulation and pathogen exposure in utero and after birth.

The initial ontogeny of the immune system is characterized by a more tolerogenic state of innate and adaptive immunity that prevents potentially harmful autoimmunity and inflammatory responses, and is geared toward preferential protection against extracellular pathogens.

As a consequence, vertically acquired HIV infection is poorly controlled and marked by rapid progression to AIDS and death without effective interventions. Chronic infection results in systemic immune activation that drives immunopathology with functional immune exhaustion, increased susceptibility to co-infections, and inflammatory comorbidities.

For those children who become infected despite PMTCT, novel therapeutic strategies need to be developed targeting persistent immune dysregulation and the viral reservoir to potentially achieve drug-free remission. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Immunology 92 2 —7. Antigenic mutation within the T-cell epitopes can affect the binding capacity of MHC molecules to the viral peptides, resulting in the inability of the TCRs to recognise the MHC-peptide complex. Register Log in. Figure 1. Interaction between HIV and coreceptors of a T cell and a monocyte. Figure 2.

Overview of HIV infection of a target cell e. T cell. Figure 3. Bitesize category Pathogens and Disease. Related Articles Immune responses to bacteria. Chlamydia Trachomatis. Candida albicans. Aspergillus fumigatus. Chronic Obstructive Pulmonary Disease. Viruses versus vaccines: the economics of herd immunity. Biofilms and their role in pathogenesis. Virus replication. Viruses: Introduction. Ulcerative colitis and Trichuris infection. Microbial infection in cystic fibrosis.

Whereas antiviral and antiproliferative effects may be beneficial during acute infection at the expense of a certain degree of immune activation, innate immune activation may be deleterious later during chronic infection. The central question here seems to be, whether the net effect of IFN production is beneficial or harmful to the host, i.

In this respect, IFN seems to be a double-edged sword for the organism. Many questions remain to be answered before the full picture of the role of IFN during HIV infection has been clarified.

DCs are of pivotal importance, not only because they are among the earliest targets of HIV, but also due to their ability to capture antigens and initiate T cell responses [ ]. Based on differences in function and expression of surface markers, DCs can be divided into several subtypes, among which myeloid DCs mDC s are professional antigen presenting cells present in blood, skin and mucosal tissues, whereas pDCs are located in blood and secondary lymphoid organs and play important roles in innate immune responses to viruses through the production of type I IFN [ 74 ].

Although mDCs have been reported to play a role in stimulation of HIV-activated adaptive immune responses, it is well documented that mDCs from HIV-infected individuals have reduced capacity to present antigens and stimulate T cells [ , ]. Since pDCs are the major producers of type I IFN, it has been suggested that abnormal migration and localization patterns of this important cell type may be a key in understanding the interplay between HIV and type IFN [ , ].

Besides representing the origin of antiviral type I IFN, pDCs are also one of the main sources of the enzyme indoleamine 2,3 -dioxygenase IDO , which is involved in tryptophan catabolism and recently described as an important mediator of negative regulation of T cell responses due to tryptophan depletion and accumulation of toxic metabolites. In HIV-infected patients, the rate of tryptophan catabolism is increased and IDO expression is elevated in lymphoid tissues, thereby potentially mediating immunopathology [ ].

Within the T cell compartment, much interest has been focused on an altered balance between proinflammatory Th17 cells and regulatory T cells Treg s in HIV infection. Initial studies in SIV-infected macaques revealed a reduction in Th17 cells within a few weeks from infection and a negative correlation between plasma virus levels and frequency of Th17 cells [ ].

This was followed by Brenchley et al. These findings were confirmed in another study involving natural hosts to SIV, in which pathogenic SIV infection was characterized by selective depletion of Th17 cells and loss of the balance between Th17 cells and Tregs [ ].

Studying PBMCs from HIV-infected and -uninfected individuals, it has subsequently been demonstrated that HIV-infected patients display a profound loss of Th17 cells as well as a gradual decline in Tregs during disease progression [ ]. These findings were extended by another study reporting on complex perturbations of Th17 subsets during the course of HIV disease [ ]. Interestingly, the dysregulated Th17 response during HIV infection may be explained by the reported ability of type I IFN to negatively regulate Th17 development [ ].

Tregs is a small subpopulation of T cells involved in preventing or inhibiting autoimmune and inflammatory disorders [ ], but much controversy exists regarding the role of Tregs in HIV pathogenesis. In direct contrast however, several previous studies have reported decreased levels of Tregs in HIV-infected individuals [ ], and in one study, depletion of Tregs in HIV infection was found to be associated with immune activation [ ]. Collectively, relatively little is known about the precise role of Th17 cells and Tregs in HIV pathogenesis and future studies should shed light on this important issue.

HIV recognition by PRRs seems to be rather limited, which may indicate that HIV is particularly successful in preventing intimate encounter with the innate immune system. Accumulating evidence suggest that this virus actively avoids recognition by PRRs in order to prevent activation of a proinflammatory and antiviral responses.

Below, some of the strategies, by which HIV evades innate immune activation, are described. Within infected cells, HIV is able to interfere with signal transduction pathways as demonstrated by Doehle et al. The idea that HIV actively suppresses innate immune responses is further supported by studies in primary macrophages, in which HIV infection resulted in a striking absence of IRF3 or IFN gene expression, although the mechanism remains to be determined, since the phenomenon was found to be independent on viral entry, HIV accessory proteins, and reverse transcription [ ].

Mammalian cells harbour intrinsic cell-autonomous activities, which can act to suppress viral replication and collectively are referred to as host restriction factors. These host restriction factors are naturally connected to the innate immune response by virtue of their IFN inducibility [ ].

Interestingly, HIV accessory proteins are intimately counteracting these antiviral activities to allow viral replication and release [ ]. The result of APOBEC function is hypermutation, replication defects, diminished reverse transcription, and ultimately inhibition of viral replication.

More recently, an IFN-induced restriction factor that prevents retrovirus release from the plasma membrane was identified and named tetherin [ , ]. Tetherin is a glycosylated membrane protein, which results in accumulation of virion particles at the membrane and failure of these particles to be released. The protein exerts antiviral activity by retaining nascent virions on the plasma membrane hence preventing budding of progeny virus particles [ , ].

Tetherin function is counteracted by the HIV membrane protein vpu, thereby securing release of viral progeny [ ]. It is not yet clear, exactly how tetherin prevents virus release, but it has been hypothesized that it may form connections between lipid rafts on plasma and viral membranes, thereby physically preventing virus egress [ ].

An alternative way to gain understanding of the role of innate immune components in the antiviral response and immune activation during HIV infection is through epidemiological studies of genetic polymorphisms in human populations. One of the first studies addressing this question was the description of almost complete protection from HIV infection conferred by homozygosity of a 32 base deletion in CCR5 [ ].

Moreover, certain HLA alleles are associated with control of virus replication and slower progression to AIDS, although the underlying mechanism has not been elucidated [ ].

In contrast, a different TLR9 polymorphism has been linked to slow disease progression and found less frequently among individuals with high viral set point [ ].

At the genetic level, this may be explained by the fact that TLR7 is X-linked and therefore women may have higher expression of this receptor due to unbalanced X-inactivation. Taken together, these studies support the idea of type I IFN having dual functions, including antiviral activities and immune activation. The interactions between HIV and the innate immune system have only recently caught the attention of HIV researchers, and as a consequence remain poorly described.

The present picture is that, unlike most other pathogens, innate immune recognition of this virus may not be very elaborate. However, it is still not very well understood, how HIV evades innate immune recognition. This interesting issue points back to the central questions in HIV pathogenesis, as to why the host is unable to recognize and respond adequately to acute HIV infection to prevent the virus from establishing latent viral reservoirs and thereby lifelong chronic infection.

Recent insight into this subject indicates that some of the answers should indeed be sought in the interactions between HIV and the innate immune system [ ]. The failing early recognition and control of infection by the innate immune system is likely to be of major importance in the pathogenesis of acute HIV infection, allowing establishment of infection and profound damage to innate as well as adaptive immune activities, not least in the GALT. Moreover, the central role played by chronic immune activation is being increasingly appreciated, and innate immune activation may play a pivotal role at this stage of infection.

It seems reasonable to assume that PRR-triggered inflammation and type I IFN production induced by HIV or opportunistic pathogens represent ample possibility for initiating and perpetuating this disadvantageous pathological immune activation leading to progressive immunodeficiency. It may be hypothesized that HIV evades innate immune recognition at early stages to establish chronic infection but allows some degree of innate PRR activation at later stages, where immune activation plays a detrimental role for the host.

Thus, the mechanisms of innate immune activation may be different in acute versus chronic infection, and elucidating either one may prove to be highly relevant. As described is this review, surprisingly few innate immune receptors have been implicated in HIV recognition. Alternatively, understanding the mechanisms by which HIV avoids immune recognition by PRRs may provide insight into pivotal aspects of HIV virology and possibly identify molecular targets for therapeutical interference with the viral life cycle.

Clearly, the search for innate immune receptors for HIV is still at an early stage, and this interesting subject is likely to lead to answers to central questions in HIV immunopathogenesis. Therefore, an integration of knowledge on the interactions between HIV and both innate and adaptive immunity is a prerequisite for gaining a more profound understanding of HIV immunopathogenesis, and ultimately for applying this knowledge into the development of novel treatment and vaccination strategies to clinical benefit for patients.

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