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
https://hdl.handle.net/1887/16435
Version: Corrected Publisher’s Version
License: Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden
Downloaded from: https://hdl.handle.net/1887/16435
Note: To cite this publication please use the final published version (if applicable).
Introduction
Introduction
In the early 1980’s a fast growing epidemic of fatal Karposi’s sarcoma (HHV8) and Pneumocytis carnii pneumonia was noted in gay communities in California and New York (1). These were atypical infections in middle aged individuals which in general are only observed in the elderly and in immuno-compromised persons. Further investigation revealed decreased immune function in these patients and occurrence of other opportunistic infections, neurological abnormalities, gastrointestinal disorders and malignancies. Because of these characteristics this disease was ultimately defined as Acquired Immuno-Deficiency Syndrome (AIDS). Within a few years after the onset of the epidemic, a retrovirus was isolated by F. Barré-Sinousis and L.
Montagnier at the institute Pasteur in Paris (2) and later by R.C. Gallo at the National Cancer Institute in Bethesda and J. Levy at UCSF (3), which was later designated as Human Immunodeficiency Virus (HIV) and over time confirmed as the primary etiological agent (4)
HIV
Retroviruses, literally, "reverse viruses" are a specialized subset of RNA viruses, characterized by several unique key enzymes encoded in the genetic material in the viral core, comprising a reverse transcriptase, integrase, and protease, essential for the virus's reproduction. The viral genetic material is reproduced in a process, which works in reverse of the normal cycle. Upon infection retroviruses release their RNA and core enzymes into the host cell. Viral RNA is copied into double-stranded DNA by the reverse transcriptase enzyme. The integrase transports the DNA copy of the virus to the cell nucleus, where the viral DNA copy is spliced directly into the host cell's DNA. As a result the virus is inherited by all the offspring of the cell. For production of new viral particles, the proviral DNA is transcribed into messenger RNA, which becomes the genetic core of a new virus particle. In addition, the mRNA is translated to produce the viral proteins that constitute the retroviral protein coat, the required enzymes that enable the packaging of new viral particles and the envelope protein. The viral core particles will subsequently migrate to the plasma membrane, where the new viruses bud off, encapsulating themselves in a lipid coat that also
contains the envelope protein. Subsequent infection of new target cells is mediated through the envelope protein that specifically binds to the CD4 receptor combined with chemokine receptors CCR5 or CXCR4. This results in the cascade of viral replication as described above (5) (6). HIV differs from many viruses in that it has a very high genetic variability. This diversity is a result of its fast replication cycle, with the generation of 109 to 1010 virions every day, coupled with a high mutation rate of approximately 3 x 10−5 per nucleotide base per cycle of replication (7).
HIV epidemic
Since its early emergence in the early 80’s HIV has spread rapidly leading to a world- wide epidemic. Since the mid 90’s effective therapeutics have become available. The most commonly used antiretroviral drugs are reverse transcriptase or protease inhibitors. However, these drugs are relatively expensive, cause severe side effects and are unable to eradicate the virus. At the moment an effective vaccine against HIV is still not available. Because of the high costs of the available treatments and difficulties to reach all communities in the world, the virus is still spreading. For 2008 the number of new infections is estimated at around 2,7 million, bringing the total amount of people infected in December 2008 at approximately 33,4 million worldwide. The majority of new infections (around 1,9 million in 2008) and AIDS related deaths (around 1,4 million in 2008) occur in sub Saharan Africa where a total population of 22,4 million people was infected in 2008.
HIV pathogenesis
Primary infection with HIV results in a profound peripheral viremia and a strong decrease in CD4 T-cells. After this primary burst of infection, the virus load decreases again as HIV specific CD8 T-cell responses appear (8-13). After a few weeks antibody responses are also strongly present (14), and these immunological parameters are comparable with the responses to other viral infections. However, HIV viremia never completely disappears and CD4 counts stay below the levels of before exposure. This ongoing infection is generally maintained at a low level for the duration of several years, mainly because of immune control by HIV specific CD8 T-
cell responses. However, due to the high mutation rate of the virus, escape from CD8 and antibody surveillance is likely to occur (15-17).
As virus levels rise, CD4 T-cell counts will slowly decrease during the chronic stage of infection. CD4 T-cells are a key role player in both adaptive and innate immune response.
Figure 1: Schematic representation of virus load, CD4 counts, anti HIV- CTL and anti-HIV Antibody responses during the course of HIV-1 infection in humans.
The current concept of induction of an immune response, entails that an antigen presenting cell first encounters a pathogen in the peripheral organs, which results in migration to the lymphoid system where this antigen loaded APC will induce an immune response. During this process CD4 T-cells play a role by mediating and enhancing signals between several components of the immune system. By means of specific signals that are transduced between the antigen presenting cell and the CD4 T-cell the type of response can be orchestrated towards a CTL or B-cell response.
Crosstalk between the APC and the CD4 T-cell is highly dependent of the activation state of both cell types (figure 2). Upon specific recognition of antigenic peptides, presented through the MHC-II molecule on the DC, CD4 T-cells are triggered to upregulate expression of activation markers and co-stimulatory molecules such as CD40L (CD154). Binding of CD154 to CD40 subsequently triggers induction of CD80, CD86, CD40 expression and redistribution of MHC-II molecules on the DC and enhances the production and secretion of IL12 (17-20). Subsequent binding of CD80 or CD86 to the CD28 receptor on the T-cell induces further T-cell activation, proliferation and cytokine production as well as maturation into effector and memory cells. Production of Th-1 cytokines, such as IL-2 and interferon- will stimulate the
1 2 4 8 16 32 64 128 256 512
Average # Weeks post infection
Course of HIV infection
Virusload CD4+T-cells HIV specific CTL Antibodies (ENV)
maturation, proliferation and activation of NK cells and cytotoxic T-cells (19). Once stimulated these cells are capable of inducing cell death of infected or neoplastic cells, either via interaction with antigenic peptides presented through the MHC-I receptor (CTL responses) or by triggering of cytotoxic response against cells that have down modulated MHC-I expression in order to evade CTL recognition (triggering NK responses) However these cells normally express other stress signals that are stimulating for NK cells through their NCRs.
Figure 2: Graphical representation of major interactions between key roleplayers in cellular immunity, with a central role for the Th cell.
In case the T-helper cell is stimulated to produce IL-4 and other Th-2 cytokines, predominantly B-cells are stimulated and antibody production is induced. These antibodies can serve to aid cytolytic responses via activation of the complement pathway or via Fc receptor mediated cell killing by NK cells, monocytes and eosinophils. Alternatively antibodies may be formed that directly inhibit virus binding to its target cell and thus prevent infection (neutralizing antibodies) (21, 22). In conclusion, the interaction between CD4 T-cells and antigen presenting DC forms the central orchestrating event, regulating induction of adaptive CD4, CD8 as well as B- cell responses, but also affect NK and DC or macrophage driven innate responses.
Therefore, the gradual decline of CD4 T cell numbers and function by relentless and chronic HIV infection over years, results in a less efficient immune response against invading pathogens and malignancies. The first signs of clinical disease are often skin
DC
Antigen in MHC II
Naive Th cell
Tcell receptor
Th-1 cell IFN-γ
Th-2 cell
B-cell
Antibodies CTL
IL-2 , IFN- γ, IL15
NK cell
CD40-CD40L CD80/86-CD28
IL-12
Tcell receptor
Antigen in MHC I
Cytotoxicity Cytotoxicity IL-2 , IFN- γ
Different stimuli:
CD40-CD40L IL-4 and IL-10
B-cell receptor encounters antigen Via B-cell receptor, interalises and presents to Th2 cell via MHCII
Tcell receptor Antigen in MHC II
rashes, respiratory infections and fungal infections of mucosal surfaces and emergence of specific tumors, of which Kaposi sarcoma (HHV8 infection) is the most characteristic. Further increases in virus production with reciprocal losses of CD4+ T cells ultimately leads to multiple opportunistic infections, cancers and death. Over the years, it has become more evident that indirect effects of this chronic infection play an important role in gradual loss of immune surveillance and ultimately immune exhaustion.
Following encounters with virus-infected or neoplastic cells, NK cells provide a first line of defence by antigen-independent recognition of specific triggering ligands which will, in the absence of inhibitory signals, result in cytotoxic activity (figure 3) and/or release of cytokines and chemokines which in turn can activate or recruit multiple cell types (23, 24). In addition, NK cells play a role in shaping of adaptive immune responses through interaction with antigen presenting dendritic cells (DC) as well as through the production of cytokines that enhance the induction of T-helper 1 responses (25-27).
Figure 3: Schematic representation of activation of NK cells. Upon recognition of a potential target cell by a (set of) activatory receptors (depicted by +) the NK cell will execute its lytic function (secretion of granules containing perforin and granzymes in combination with cytokines).
This activity will only take place once the potential target cell is not expressing inhibitory ligands. Ligation of inhibitory receptors (-) will result in an off-signal and the lytic cascade will be inhibited.
NK cells have a wide variety of activatory and inhibitory receptors (Table 1) that enable a highly specific set of responses. The best described NK cell response is the direct cytotoxic effect which is directed against cells that have downmodulated MHC-I in response to an infecting agent or as a result of a neoplastic transformation in the cell.
In this basic response, the NK cell recognises specific ligands on the surface of the potential target cell via Natural Cytotoxicity Receptors (NCRs) and costimulatory receptors (28, 29). The ligands for these receptors are common antigens expressed at low levels by most cell types, and are upregulated upon stress signalling due to infections or malignancies. In combination with activatory receptors, NK cells
Target cell
NK cell Target
cell
NK cell + -
+
Killing in absence of inhibitory signal
No response once inhibitory signal is present
express inhibitory receptors which mainly survey the cell surface for the expression of MHC-I. Upon recognition of these molecules (with or without antigen) the NK cell will withhold an otherwise lytic response. One of the NCRs (NKp30) is found to be also implicated in the regulation of DC maturation and the editing of immature DCs (30).
Table 1: Human NK cell receptors inducing/inhibiting cytotoxicity with their ligands. (reviewed in references 31, 32 and 33)
Receptor Name Inhibitory / Activatory
Ligand
CD16 Activatory Fc gamma chain
KIR2DL1 Inhibitory HLA-Cw2,4,5,6 K80
KIR2DL2 Inhibitory HLA-Cw1,3,7,8 N80
KIR2DL3 Inhibitory HLA-Cw1,3,7,8 N80
KIR3DL1 Inhibitory HLA-Bw4 I80
KIR3DL2 Inhibitory HLA-A3,A11
KIR2DS1 Activatory HLA-Cw2,4,5,6 K80
KIR3DS1 Activatory HLA-Bw4 I80
KIR2DL4 Activatory HLA-G
LILRB1 Inhibitory HLA class I (Low affinity)
HLA-F HLA-G
LILRB2 Inhibitory HLA-F HLA-G
NKG2A /CD94 complex Inhibitory HLA-E NKG2B/CD94 complex Inhibitory HLA-E NKG2C/CD94 complex Activatory HLA-E NKG2E/CD94 complex Activatory HLA-E
NKp46 (NCR1) Activatory HSPGs, vimentin, IV-HA, SV-HN, unknown
NKp44 (NCR2) Activatory HSPGs, IV-HA SV-HN,
unknown
NKp30 (NCR3) Activatory HSPGs, hCMV-PP65,
unknown
NKG2D Activatory MIC-A/B, ULBP1-5
NKp80 Co-Activatory AICL
DNAM1 Co-Activatory CD112, CD155
2B4 Co-Activatory
(inhibitory in patients with X-linked lymphoproliferative disease)
CD48,
NTB-A Co-Activatory
(inhibitory in patients with X-linked lymphoproliferative disease)
NTB-A
CS-1 Co-Activatory
(inhibitory in patients with X-linked lymphoproliferative disease)
CS-1
LAIR-1 Inhibitory Collagens
Siglec-7 Inhibitory Sacharides
In humans, two distinct circulating NK cell populations have been described, i.e. a CD56dim, CD16+ subset with strong cytolytic capacity and a CD56bright subset with propensity for IFN and TNF cytokine production (34, 35). Recently NK cell responses have been studied in greater detail in HIV infection, showing decreased NK cell cytolytic function and the emergence of an activated and dysfunctional CD56- CD16+HLA-DR+CD69+ subset (36, 37). The central role of NK cells in the orchestration of adaptive responses in combination with the observations of an exhausted population in HIV infected humans has lead us to investigate this versatile cell type in chimpanzees, an animal species that is relatively resistant to development of AIDS if infected with human adapted strains of HIV-1.
Natural infection with SIVcpz and HIV-1 infection in captive chimpanzees
Lentiviruses are found in many animal species in which they cause chronic infections.
They characteristically cause slow (lentus = slow in latin) degenerative diseases.
Since the time of the discovery of HIV as the causative agent of AIDS, similar viruses were found in several African primate species (38-46). The viruses found in chimpanzees and sooty mangabeys clearly showed a close relationship with the HIV strains found in the human population. The virus found in the western African chimpanzee Pan troglodytes troglodytes (SIVcpz) is closely related to the global epidemic HIV-1 that is causing AIDS (43). The virus found in Sooty mangabeys is similar to the less widespread and less pathogenic HIV-2 (42), which is mainly limited to western Africa. All infections with SIV in their natural host have been associated with a relatively apathological infection. Until recently this was the assumption in all African non-human primate species. Recent findings in wild chimpanzee populations indicate that the infection of chimpanzees with SIVcpz results in an AIDS like disease in Pan troglodytes schweinfurthii, as evidenced by higher mortality rate, and in one case, histopathological lesions similar to AIDS (38).
The slow rate of pathogenicity and the time to disease development for this type of infection has always made it difficult to study the development of disease in wild populations. This extensive study represents the first evidence of progression to AIDS in wild ranging African primate species which were considered to be resistant to this
disease (47). Until now there were only few cases of SIVcpz infected animals known in captivity, and none of these animals showed clinical evidence of immune deficiency, in some cases of over 20 years of follow-up. Next to these few SIVcpz infected animals, most information was limited to chimpanzees that had been experimentally infected with human derived HIV-1 strains.
During the earliest period of HIV (vaccine) research chimpanzees were found to be the only animal species that could be infected with (primary) HIV-1 strains. This lead to many early studies in this species, creating a large number of HIV-1 infected animals in several primate research facilities in the USA and Europe (48-53). Years of longitudinal follow-up of these infected animals showed that most animals stayed asymptomatically infected with HIV-1 for fifteen or more years. In the early course of infection, chimpanzees were found to respond in a similar way with a transient loss of CD4 T-cells and a peak viremia but then this was followed by suppression of HIV-1 replication. In contrast to the gradual persistent loss of CD4 T-cells in humans, which is associated with chronic immune activation, in chimpanzees the initial decrease in CD4 T-cells during primary infection was restored and during the chronic stage remained within normal values throughout the years. Previous reports have shown low levels of cell activation or proliferation, no increased sensitivity to apoptosis induction, with detectable CTL function, normal B-cell function and NK function, (ADCC activity) (54-57). Thus despite persistent infection immune function was found to be maintained in these animals (58). With the exception of a few animals (47) no clear clinical signs of AIDS development have been documented in HIV-1 infected chimpanzees during the past >25 years of research. It is for this reason, given their potential susceptibility, that we have used the term ‘relative resistance’ to AIDS compared to humans. This relevant resistance may be in part due to a relevantly longer exposure to retroviral-like pathogens in their natural habitat (59).
Scope of this thesis
In this thesis the main differences between human and chimpanzee immune responses will be further described in relation to chronic HIV-1 infection and the lack of immune cell dysfunction and overt loss of CD4 T-cells.
In the following chapter (chapter 2) the historical data concerning HIV/SIV infection in chimpanzees and their relative resistance to AIDS is reviewed. The historical data gathered in this chapter formed the basis for the research performed in this project.
The succeeding chapter (chapter 3) then elaborates further on SIVcpz transmission events into different subspecies of chimpanzees and the longitudinal follow-up of the first experimental SIVcpz transmission in chimpanzees. Susceptibility to infection was found not to be an issue and all animals studied showed no clinical signs of AIDS, consistent with numerous studies with HIV-1 strains in Chimpanzees.
Following these observations our attention focussed on the host’s immune response.
In chapter 4 the effect of the HIV-1 envelope protein on CD4 T-cell function will be compared to humans. In this chapter we report on evidence of lower immune suppressive effects of envelope glycoproteins on the function of chimpanzee CD4 T- cells as compared to humans.
The following 3 chapters compare NK phenotypes and function in both uninfected and HIV-1/SIVcpz infected chimpanzees as compared to humans (chapters 5, 6, 7).
Chapter 5 elaborates on the characterisation of chimpanzee NK cells with as the most striking feature, the inducible expression of NKp30 on chimpanzee NK cells and the maintenance of NCR expression in HIV-1/SIVcpz infected animals.
In chapter 6 the differences in expression and genetic structure of NKp44 in humans, chimpanzees and rhesus macaques are compared in which it is shown that expression and translation are differently regulated in the 3 species. The final chapter on NK cells deals with the unusual presence of CD8 on Chimpanzee NK cells, and compares the lack of CD8 on a small sub population. We propose that this is indicative for a non- functional NK cell pool, which could be comparable with the exhausted phenotype seen in humans. Interestingly, in contrast to humans this small population of non functional cells does not increase upon HIV infection in chimpanzees.
References
1. Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of a new acquired cellular immunodeficiency. Gottlieb MS, Schroff R, Schanker HM, Weisman JD, Fan PT, Wolf RA, Saxon A. N Engl J Med. 1981 Dec 10;305(24):1425-31.
2. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Barré-Sinoussi F, Chermann JC, Rey F, Nugeyre MT, Chamaret S, Gruest J, Dauguet C, Axler-Blin C, Vézinet-Brun F, Rouzioux C, Rozenbaum W, Montagnier L.
Science. 1983 May 20;220(4599):868-71.
3. Isolation of infectious human T-cell leukemia/lymphotropic virus type III (HTLV-III) from patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex (ARC) and from healthy carriers: a study of risk groups and tissue sources. Salahuddin SZ, Markham PD, Popovic M, Sarngadharan MG, Orndorff S, Fladagar A, Patel A, Gold J, Gallo RC. Proc Natl Acad Sci U S A. 1985 Aug;82(16):5530-4.
4. Human immunodeficiency viruses. Coffin J, Haase A, Levy JA, Montagnier L, Oroszlan S, Teich N, Temin H, Toyoshima K, Varmus H, Vogt P, et al. Science. 1986 May
9;232(4751):697
5. Mechanisms of enveloped virus entry into cells. Kielian M, Jungerwirth S. Mol Biol Med.
1990 Feb;7(1):17-31.
6. HIV and AIDS in relation to other pandemics. Weiss RA. EMBO Rep. 2003 Jun;4 Spec No:S10-4.
7. Recombination in AIDS viruses. Robertson DL, Hahn BH, Sharp PM. J Mol Evol. 1995 Mar;40(3):249-59
8. Primary human T-lymphotropic virus type III infection. Ho DD, Sarngadharan MG, Resnick L, Dimarzoveronese F, Rota TR, Hirsch MS. Ann Intern Med. 1985 Dec;103(6 ( Pt 1)):880-3.
9. Primary HIV infection: host responses and intervention strategies. Tindall B, Cooper DA.
AIDS. 1991 Jan;5(1):1-14.
10. Transient high levels of viremia in patients with primary human immunodeficiency virus type 1 infection. Daar ES, Moudgil T, Meyer RD, Ho DD. N Engl J Med. 1991 Apr 4;324(14):961- 4.
11. Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. Koup RA, Safrit JT, Cao Y, Andrews CA, McLeod G, Borkowsky W, Farthing C, Ho DD. J Virol. 1994 Jul;68(7):4650-5.
12. Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. Borrow P, Lewicki H, Hahn BH, Shaw GM, Oldstone MB. J Virol. 1994 Sep;68(9):6103-10.
13. Cytotoxic-T-cell responses, viral load, and disease progression in early human
immunodeficiency virus type 1 infection. Musey L, Hughes J, Schacker T, Shea T, Corey L, McElrath MJ. N Engl J Med. 1997 Oct 30;337(18):1267-74. Development of the anti-gp120 antibody response during seroconversion to human immunodeficiency virus type 1. Moore JP, Cao Y, Ho DD, Koup RA.
14. Virus escape from CTL recognition. Koup RA. J Exp Med. 1994 Sep 1;180(3):779-82.
15. Longitudinal phenotypic analysis of human immunodeficiency virus type 1-specific cytotoxic T lymphocytes: correlation with disease progression. Ogg GS, Kostense S, Klein MR, Jurriaans S, Hamann D, McMichael AJ, Miedema F. J Virol. 1999 Nov;73(11):9153-60.
16. Persistent numbers of tetramer+ CD8(+) T cells, but loss of interferon-gamma+ HIV-specific T cells during progression to AIDS. Kostense S, Vandenberghe K, Joling J, Van Baarle D, Nanlohy N, Manting E, Miedema F. Blood. 2002 Apr 1;99(7):2505-11.
17. Interleukin-12 production by dendritic cells. The role of CD40-CD40L interactions in Th1 T- cell responses. Kelsall BL, Stüber E, Neurath M, Strober W. Ann N Y Acad Sci. 1996 Oct 31;795:116-26.
18. The role of CD40 ligand in costimulation and T-cell activation. Grewal IS, Flavell RA.
Immunol Rev. 1996 Oct;153:85-106.
19. Analysis of the costimulatory requirements for generating human virus-specific in vitro T helper and effector responses. Blazevic V, Trubey CM, Shearer GM. J Clin Immunol. 2001 Jul;21(4):293-302.
20. CD80, CD86 and CD40 provide accessory signals in a multiple-step T-cell activation model.
Van Gool SW, Vandenberghe P, de Boer M, Ceuppens JL. Immunol Rev. 1996 Oct;153:47- 83.
21. Correlates of antibody-mediated protection against HIV infection. Sattentau Q. Curr Opin HIV AIDS. 2008 May;3(3):368-74.
22. Neutralizing and other antiviral antibodies in HIV-1 infection and vaccination. Montefiori DC, Morris L, Ferrari G, Mascola JR. Curr Opin HIV AIDS. 2007 May;2(3):169-176.
23. NK cell recognition. Lanier LL. Annu Rev Immunol. 2005;23:225-74. Review.
24. The dialogue between human natural killer cells and dendritic cells. Moretta A. Curr Opin Immunol. 2005 Jun;17(3):306-11.
25. Induced recruitment of NK cells to lymph nodes provides IFN-gamma for T(H)1 priming.
Martín-Fontecha A, Thomsen LL, Brett S, Gerard C, Lipp M, Lanzavecchia A, Sallusto F.
Nat Immunol. 2004 Dec;5(12):1260-5
26. NK-dependent DC maturation is mediated by TNFalpha and IFNgamma released upon engagement of the NKp30 triggering receptor.Vitale M, Della Chiesa M, Carlomagno S, Pende D, Aricò M, Moretta L, Moretta A.Blood. 2005 Jul 15;106(2):566-71.
27. Human dendritic cells activate resting natural killer (NK) cells and are recognized via the NKp30 receptor by activated NK cells. Ferlazzo G, Tsang ML, Moretta L, Melioli G, Steinman RM, Münz C. J Exp Med. 2002 Feb 4;195(3):343-51.
28. Natural killer cells, viruses and cancer. Cerwenka A, Lanier LL. Nat Rev Immunol. 2001 Oct;1(1):41-9
29. Human natural killer cells: their origin, receptors and function. Moretta L, Bottino C, Pende D, Mingari MC, Biassoni R, Moretta A. Eur J Immunol. 2002 May;32(5):1205-11
30. NK cells at the interface between innate and adaptive immunity. Moretta A, Marcenaro E, Parolini S, Ferlazzo G, Moretta L. Cell Death Differ. 2008 Feb;15(2):226-33
31. Human natural killer receptors, co-receptors, and their ligands. Biassoni R. Curr Protoc Immunol. 2009 Feb;Chapter 14
32. Up on the tightrope: natural killer cell activation and inhibition. Lanier LL. Nat Immunol.
2008 May;9(5):495-502.
33. NK cell receptors and their interactions with MHC. Biassoni R, Ugolotti E, De Maria A.Curr Pharm Des. 2009;15(28):3301-10
34. The small subset of CD56brightCD16- natural killer cells is selectively responsible for both cell proliferation and interferon-gamma production upon interaction with dendritic cells.Vitale M, Della Chiesa M, Carlomagno S, Romagnani C, Thiel A, Moretta L, Moretta A. Eur J Immunol. 2004 Jun;34(6):1715-22.
35. CD56bright natural killer cells are present in human lymph nodes and are activated by T cell- derived IL-2: a potential new link between adaptive and innate immunity. Fehniger TA, Cooper MA, Nuovo GJ, Cella M, Facchetti F, Colonna M, Caligiuri MA. Blood. 2003 Apr 15;101(8):3052-7.
36. Characterization of CD56-/CD16+ natural killer (NK) cells: a highly dysfunctional NK subset expanded in HIV-infected viremic individuals. Mavilio D, Lombardo G, Benjamin J, Kim D, Follman D, Marcenaro E, O'Shea MA, Kinter A, Kovacs C, Moretta A, Fauci AS. Proc Natl Acad Sci U S A. 2005 Feb 22;102(8):2886-91
37. NK cell function in HIV-1 infection. De Maria A, Moretta L. Curr HIV Res. 2008 Sep;6(5):433-40
38. Increased mortality and AIDS-like immunopathology in wild chimpanzees infected with SIVcpz. Brandon F. Keele, James Holland Jones, Karen A. Terio, Jacob D. Estes, Rebecca S.
Rudicell, Michael L. Wilson, Yingying Li, Gerald H. Learn, T. Mark Beasley, Joann Schumacher-Stankey, Emily Wroblewski, Anna Mosser, Jane Raphael, Shadrack Kamenya, Elizabeth V. Lonsdorf, Dominic A. Travis, Titus Mlengeya, Michael J. Kinsel, James G. Else, Guido Silvestri, Jane Goodall, Paul M. Sharp, George M. Shaw, Anne E. Pusey and Beatrice H. Hahn. Nature 2009 July;460 (7254):515-1939.
39. Simian immunodeficiency virus from African green monkeys. Daniel MD, Li Y, Naidu YM, Durda PJ, Schmidt DK, Troup CD, Silva DP, MacKey JJ, Kestler HW 3rd, Sehgal PK, et al. J Virol. 1988 Nov;62(11):4123-8.
40. Characterization of a novel simian immunodeficiency virus (SIV) from L'Hoest monkeys (Cercopithecus l'hoesti): implications for the origins of SIVmnd and other primate
lentiviruses. Hirsch VM, Campbell BJ, Bailes E, Goeken R, Brown C, Elkins WR, Axthelm M, Murphey-Corb M, Sharp PM. J Virol. 1999 Feb;73(2):1036-45.
41. Simian immunodeficiency virus (SIV) from sun-tailed monkeys (Cercopithecus solatus):
evidence for host-dependent evolution of SIV within the C. lhoesti superspecies. Beer BE, Bailes E, Goeken R, Dapolito G, Coulibaly C, Norley SG, Kurth R, Gautier JP, Gautier-Hion A, Vallet D, Sharp PM, Hirsch VM. J Virol. 1999 Sep;73(9):7734-44.
42. An African primate lentivirus (SIVsm) closely related to HIV-2. Hirsch VM, Olmsted RA, Murphey-Corb M, Purcell RH, Johnson PR. Nature. 1989 Jun 1;339(6223):389-92 43. Isolation and partial characterization of an HIV-related virus occurring naturally in
chimpanzees in Gabon. Peeters M, Honoré C, Huet T, Bedjabaga L, Ossari S, Bussi P, Cooper RW, Delaporte E. AIDS. 1989 Oct;3(10):625-30.
44. Isolation and characterization of simian immunodeficiency virus from mandrills in Africa and its relationship to other human and simian immunodeficiency viruses. Tsujimoto H, Cooper RW, Kodama T, Fukasawa M, Miura T, Ohta Y, Ishikawa K, Nakai M, Frost E, Roelants GE, et al. J Virol. 1988 Nov;62(11):4044-50.
45. Isolation and characterization of a new chimpanzee lentivirus (simian immunodeficiency virus isolate cpz-ant) from a wild-captured chimpanzee. Peeters M, Fransen K, Delaporte E, Van den Haesevelde M, Gershy-Damet GM, Kestens L, van der Groen G, Piot P. AIDS. 1992 May;6(5):447-51.
46. Human immunodeficiency viruses: SIV infection in wild gorillas. Van Heuverswyn F, Li Y, Neel C, Bailes E, Keele BF, Liu W, Loul S, Butel C, Liegeois F, Bienvenue Y, Ngolle EM, Sharp PM, Shaw GM, Delaporte E, Hahn BH, Peeters M. Nature. 2006 Nov 9;444(7116):164.
47. Development of AIDS in a chimpanzee infected with human immunodeficiency virus type 1.
Novembre FJ, Saucier M, Anderson DC, Klumpp SA, O'Neil SP, Brown CR 2nd, Hart CE, Guenthner PC, Swenson RB, McClure HM. J Virol. 1997 May;71(5):4086-91
48. Long-term persistence of HIV-1 vaccine-induced CD4+CD45RA-CD62L-CCR7- memory T- helper cells. Balla-Jhagjhoorsingh SS, Koopman G, Mooij P, Koornstra W, McCormack S, Weber J, Pantaleo G, Heeney JL. AIDS. 2004 Apr 9;18(6):837-48.
49. Human and simian immunodeficiency virus-infected chimpanzees do not have increased intracellular levels of beta-chemokines in contrast to infected humans. Ondoa P, Vereecken C, Fransen K, Colebunders R, van der Groen G, Heeney JL, Kestens L. J Med Virol. 2003 Mar;69(3):297-305.
50. The relative resistance of HIV type 1-infected chimpanzees to AIDS correlates with the maintenance of follicular architecture and the absence of infiltration by CD8+ cytotoxic T lymphocytes. Koopman G, Haaksma AG, ten Velden J, Hack CE, Heeney JL. AIDS Res Hum Retroviruses. 1999 Mar 1;15(4):365-73
51. Active and passive immunization against HIV type 1 infection in chimpanzees. Murthy KK, Cobb EK, Rouse SR, McClure HM, Payne JS, Salas MT, Michalek GR. AIDS Res Hum Retroviruses. 1998 Oct;14 Suppl 3:S271-6. Review.
52. Long-term observations of human immunodeficiency virus-infected chimpanzees. Johnson BK, Stone GA, Godec MS, Asher DM, Gajdusek DC, Gibbs CJ Jr. AIDS Res Hum Retroviruses. 1993 Apr;9(4):375-8.
53. Persistent infection of chimpanzees with human T-lymphotropic virus type
III/lymphadenopathy-associated virus: a potential model for acquired immunodeficiency syndrome. Fultz PN, McClure HM, Swenson RB, McGrath CR, Brodie A, Getchell JP, Jensen FC, Anderson DC, Broderson JR, Francis DP. J Virol. 1986 Apr;58(1):116-24.
54. Lack of chronic immune activation in HIV-infected chimpanzees correlates with the resistance of T cells to Fas/Apo-1 (CD95)-induced apoptosis and preservation of a T helper 1 phenotype.
Gougeon ML, Lecoeur H, Boudet F, Ledru E, Marzabal S, Boullier S, Roué R, Nagata S, Heeney J. J Immunol. 1997 Mar 15;158(6):2964-76.
55. Antibody-dependent cellular cytotoxicity to clinical isolates of HIV-1 and SIVcpz:
comparison of human and chimpanzees. Broliden K, Hinkula J, Tolfvenstam T, Niphuis H, Heeney J. AIDS. 1996 Sep;10(11):1199-204.
56. Immune strategies utilized by lentivirus infected chimpanzees to resist progression to AIDS.
Heeney J, Bogers W, Buijs L, Dubbes R, ten Haaft P, Koornstra W, Niphuis H, Nara P, Teeuwsen V. Immunol Lett. 1996 Jun;51(1-2):45-52.
57. The impact of HIV-1 infection on phenotypic and functional parameters of cellular immunity in chimpanzees. Ferrari G, Ottinger J, Place C, Nigida SM Jr, Arthur LO, Weinhold KJ. AIDS Res Hum Retroviruses. 1993 Jul;9(7):647-56.
58. Lentivirus infections and mechanisms of disease resistance in chimpanzees. Rutjens E, Balla- Jhagjhoorsingh S, Verschoor E, Bogers W, Koopman G, Heeney J. Front Biosci. 2003 Sep 1;8:d1134-45
59. Origins of HIV and the evolution of resistance to AIDS. Heeney JL, Dalgleish AG, Weiss RA.
Science. 2006 Jul 28;313(5786):462-6.
