Differences in cellular immunity between humans and chimpanzees in relation to their relative resistance to aids
Rutjens, E.D.I.
Citation
Rutjens, E. D. I. (2011, February 3). Differences in cellular immunity between humans and chimpanzees in relation to their relative resistance to aids. Retrieved from
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General discussion
Introduction
Chimpanzees form the closest living relative to man and their experimental infection with HIV as well as the natural infection with SIVcpz has been used as a model for studying HIV pathogenesis. During the past 3 decades, a substantial number (more than 200) of chimpanzees have been experimentally infected with HIV-1 isolates and a large group of animals has been documented to be harboring a chronic SIVcpz infection, both in the wild as well as in captivity. Almost all animals infected with one of these lentiviruses have been living a healthy life without any symptoms of progression to AIDS (1,2) with the exception of one rare case of an animal that died of AIDS-like symptoms (3). The pathogenic variant, which emerged in this animal resulted form exposure to 3 different HIV-1 strains. Virological characterization of this variant showed this pathogenic strain to be a recombinant virus that emerged from at least 2 of the strains that were used to superinfect the animal. The relative resistance to disease progression, in an animal species so close to human, has become a major source of information about immunological differences between the susceptible Homo sapiens and non-susceptible Pan troglodytes.
SIVcpz infection in (HIV-1 pre-infected) chimpanzees
SIVcpz was found to be circulating in wild populations of Pt. troglodytes and Pt.
schweinfurthii, and molecular analysis of the virus in both subspecies of chimpanzees showed it to be closely related to HIV-1(4). This finding lead to the hypothesis that the HIV-1 epidemic arose from cross species transmission from chimpanzee to human, probably as a consequence of the hunting and consumption of chimpanzees in west-central Africa (5-7). In humans the routes of transmission from one person to another are well known and well understood (8), but for chimpanzees the route of virus transmission was not documented. In the study described in chapter 3, it is shown that in chimpanzee infection with SIVcpz can be achieved through intravenous as well as intravaginal or intrarectal exposure, similar to the human situation (9). The study also demonstrated that previous infection with HIV did not prevent secondary infection with SIVcpz when the virus was delivered via the intravenous or intrarectal route, while animals were protected against intravaginal SIVcpz exposure.
Although the mechanism of protection was not further investigated, induction of local immune responses, as also documented in HIV exposed seronegatives, could play a role. The
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second objective of this study was to investigate whether other chimpanzee subspecies, where SIVcpz infection has never been found, are intrinsically resistant to infection. For instance, it was shown that the Pt. subspecies show differences in their CD4 molecules, which could potentially lead to differences in susceptibility (10). However, we found that also Pt. verus subspecies can be experimentally infected with SIVcpz, which strengthens the idea that the lack of natural SIV infection in Pt. verus is related to the fact that it is living geographically isolated from the other subspecies. The data also could indicate that the introduction of SIVcpz in chimpanzees has occurred after sub-speciation of the chimpanzees.
Immune mechanisms involved in control of virus replication.
In contrast to HIV infected humans, chimpanzees infected with HIV-1 as well as SIVcpz maintain relatively high CD4 T-cell numbers as well as CD4 T-cell function. For instance, in chimpanzees both CD3 induced a well as specific responses to recall antigens are maintained and no increase in expression of activation markers or apoptosis is seen. (11-14).
Furthermore, high proliferative responses against HIV were reported (15,16). In chapter 4 we confirmed some of these earlier data and in addition showed that two key CD4 T-cell regulatory functions, namely CD3/CD28 triggered of IL2 production and CD154 upregulation, are maintained in chronically infected chimpanzees. This maintenance of CD4 T-cell function could either be an indirect effect of effective control of virus replication mediated by CTLs (17,18) or be caused by an intrinsic difference in susceptibility to the immune suppressive effects of HIV. Previous reports have shown important differences between humans and chimpanzees in CD4 amino acid sequence, especially in the HIV gp120 binding V1J1 domain (19,20). Since binding of HIV gp120 to CD4 in humans can negatively affect CD3 signaling and inhibit upregulation of CD154 (21-23), we investigated these effects in chimpanzees. We observed 1 to 2 fold lower levels of CD4 expression on T-cells in chimpanzees and although HIV gp120 could inhibit the upregulation of CD154 a four fold higher concentration of viral protein was needed. Chimpanzee CD4 T-cells are thus less sensitive to the immune-suppressive effects of low dose HIV, which may make no difference in the acute phase of the infection but could lead to a better preservation of immune function in the early chronic phase of the infection when virus replication is partially suppressed. This difference in CD154 induction may in turn, through cross talk between T-cells and Dendritic cells (DC’s), affect the innate immune system, i.e. CD154 interaction with CD40 on the DC’s induces DC maturation, upregulation of co-stimulatory molecules, enhancement of antigen
presenting capacity and production of IL-12 and thus boosts their T-cell stimulatory capacity and formation of effective T-helper as well as CTL responses. Although not investigated by us, similar differences in CD4 expression and consequential interaction with HIV could also be postulated for other CD4 expressing cells like macrophages and myeloid or plasmacytoid dendritic cells (pDC). Interestingly, differences in binding affinity of HIV to CD4 on pDC were recently shown to correlate directly with levels of IFN release (24), which in turns induces upregulation of TRAIL expression on macrophages, leading to death receptor 5 (DR5) mediated apoptosis of CD4 T cells exposed to either infectious or noninfectious HIV-1 (25-27). Binding of HIV to CD4 on human pDC is also known to induce expression of indoleamine 2,3-dioxygenase (IDO), resulting in altered tryptophan metabolism and reduced CD4 T-cell proliferation (28). Through these mechanisms a difference in CD4 expression level or interaction with HIV-gp120 may result in changes in antigen specific as well as bystander T-cell activation, which in HIV-1 patients could lead to chronic immune activation and exhaustion of immune function (29-32.), while inflicting different results in infected chimpanzees.
As stated above an alternative explanation for preserved CD4 T-cell function could be provided by effective CTL driven suppression of virus replication. In a previous publication by Balla et al. (33) it was shown that in HIV infected chimpanzees CTL activity against specific so called “conserved” HIV Gag epitopes can be detected, which are highly homologous to the peptides recognized by HLA-B27 and HLA-B57, found in HIV infected long term non progressors. In combination with the findings of de Groot et al. (34) that chimpanzees show a less broad repertoire of MHC class I alleles, the hypothesis of an evolutionary selective sweep arose. This hypothesis states that chimpanzees have passed through an epidemic of a pathogen (probably a lentivirus), resulting in selection of a small population with a limited MHC-class I repertoire that was highly efficient in recognizing specific epitopes and generating strong CTL responses to these antigenic structures.
Cytokines form one of the key regulatory molecules, acting on all lineages of lymphocytes, and dysfunction of this system will lead to effects on all cell types of the immune system.
Impaired IL-2 production, CD154 expression as well as IL-12 production could all affect NK cell function. Furthermore, binding of HIV-1 gp120 to NK cells suppresses NK cell proliferation and function and enhances apoptosis (35). Recent studies have shown that in HIV-1 patients the NK cell populations are functionally impaired with regards to killing of MHC negative cells. In HIV-1 patients a CD56-/CD16+ NK cell subset is found that has low
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or undetectable NCR (NKp30, NKp44, NKp46) expression, and increased HLA-DR and CD69 expression and increased iNKr expression (36-41). This increase of CD56-/CD16+NK cells in peripheral blood co-insides with the disappearance of the cytotoxic CD56dim/CD16+ NK subset, which is the predominant population in healthy humans. This observations lead to the conclusion that the human NK cell pool becomes exhausted and that the cytotoxic NK cell pool reaches an activation induced anergic state, which is irreversible. This loss of NK cell function could have a major impact on viral replication, since it would allow infected cells, that have downmodulated their MHC-I molecules through the action of the nef viral protein, to escape both CTL and NK mediated elimination. In addition, changes in NK cell function will directly impact on DC function, because the specific interaction between NKp30 and its ligand expressed on DCs leads to NK cell activation, immature DC maturation and immature DC killing by NK cells (42,43). Furthermore, recruitment of NK cells to lymph nodes was shown to enhance the induction of T-helper 1 responses via IFN secretion (44). Interestingly, Tomescu et al. (45) recently described that NK cell mediated killing of HIV-1 infected autologous CD4 T-cells is dependent on IFN mediated NK cell activation, which implies that potential differences in HIV-gp120-CD4 triggered IFN production by pDC, discussed above, could translate into reduced elimination of virus infected cells.
The important role of NK cells in immune regulation and the observed changes in HIV-1 patients lead us to further investigate NK cell phenotype and function in uninfected as well as HIV-1 or SIVcpz infected chimpanzees. Because of the limited information on NK cells in chimpanzees we started with the characterization of these cells. Chimpanzees have a clear CD3- / CD16+ lymphocyte population, but in contrast to humans, this population does not show any apparent CD56 expression. Peripheral chimpanzee NK cells were found to express functional NKp46, NKp80, NKG2D receptors, but they lack NKp30 expression, which is only induced (and functional) upon activation of the cells. NKp44 expression patterns show similarities with humans, meaning that it is not present on resting cells, but the protein is present on the surface of activated NK cells and also functional. One striking feature in chimpanzee however is that in resting NK cells the amount of mRNA encoding NKp44 is 5 times higher than its human counterpart, but both species do not express any protein in this stage. Upon activation NKp44 transcription is highly upregulated in human NK cells, but not in chimpanzee NK cells, leading to 12 fold lower mRNA levels in chimpanzees, as compared to humans. NKp44 protein levels are also (4 fold) lower on chimpanzee NK cells, which translates in less effective NKp44 triggered killing. One of the striking differences between
human and chimpanzee NK cells is that the majority of chimpanzee NK cells express CD8, whereas in humans this is only a minor population (46). Further analysis of the CD8 expressing and the CD8 negative subpopulations showed that cytotoxicity as well as cytokine production was largely confined to the CD8 expressing population and not seen in CD8 negative NK cells. The CD8+ NK cells clearly showed high expression of NCR’s and low HLA-DR, whereas the CD8 negative cells showed high HLA-DR and low NCR expression.
The data suggest that CD8 negative chimpanzee NK cells are functionally impaired, similar to the CD56 negative population described in humans. While HIV and SIVcpz infected chimpanzees had somewhat reduced NK cell numbers in the blood, the relative composition in CD8 positive and negative subsets was unaltered and also the patterns in NCR and inhibitory receptor expression were maintained. In conclusion, there are some striking differences between human and chimpanzee NK cells regarding expression of NCRs. NKp30 was found to be only expressed after activation. The role of this receptor in regulation of DC maturation and survival could translate into lower levels of virally induced cell activation, which is one of the hallmarks of pathogenic infection both in humans as well as in the SIV macaque models (47). Also the noted differences in NKp44 expression may be important in this regard, since the HIV-1 gp41 derived SWSNKS peptide was shown to induce NKp44L expression on CD4 T-cells making them susceptible targets for NKp44 mediated killing by NK cells (48).
While the development of highly active anti-retroviral therapy (HAART) has revolutionized the treatment of HIV patients, only a partial restoration of the immune compartment can be achieved (49-52). A better understanding of these deficits and key regulatory molecules may open new therapeutic possibilities that could support current anti-retroviral therapy. In this light the observations on differential expression of both NKp30 and NKp46 in chimpanzees, linked to the preservation of NK cell phenotype upon HIV infection could provide interesting clues that would warrant further investigations.
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