Abstract
Immune pressure exerted by MHC class I-restricted cytotoxic T cells drives the development of viral escape mutations, thereby regulating HIV disease progression. Nonetheless, the relationship between host immunity and HIV central nervous system (CNS) disease remains poorly understood. The simian immunodeficiency virus (SIV) macaque model recapitulates key features of HIV infection including development of AIDS and CNS disease. To investigate cell-mediated immunity regulating SIV CNS disease progression, we compared the incidence of SIV encephalitis and the influence of MHC class I allele expression on the development of CNS disease in rhesus macaques (Macaca mulatta) versus pigtailed macaques (Macaca nemestrina). After inoculation with the immunosuppressive swarm SIV/DeltaB670 and the neurovirulent molecular clone SIV/17E-Fr, pigtailed macaques progressed more rapidly to AIDS, had higher plasma and cerebrospinal fluid (CSF) viral loads, and were more likely to progress to SIV-associated encephalitis (SIVE) compared to rhesus macaques. In addition, MHC class I alleles were neuroprotective in both species (Mamu-A*001 in rhesus macaques and Mane-A1*084:01:01 in pigtailed macaques); animals expressing these alleles were less likely to develop SIV encephalitis and correspondingly had lower viral replication in the brain. Species-specific differences in susceptibility to SIV disease demonstrated that cell mediated immune responses are critical to SIV CNS disease progression.
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Importance
Although advances in HIV treatment have reduced AIDS mortality and incidence of severe neurological complications including dementia, HIV-associated cognitive deficits still develop in patients receiving anti-retroviral therapy. The SIV macaque model recapitulates key features of HIV infection including development of AIDS and CNS disease. To investigate host factors regulating SIV CNS disease progression, we compared outcomes of SIV infection in two different species of Asian macaques commonly used to model HIV-associated diseases: rhesus macaques and pigtailed macaques. We found that pigtailed macaques had more rapid progression of disease and were more likely to progress to encephalitis. We also found that the expression of particular MHC class I alleles had a neuroprotective effect in each species. Differences in susceptibility to SIV disease development among species of Asian macaques demonstrate that host factors play critical roles in regulating SIV disease progression, including SIV CNS disease.
Introduction
Given the marked similarities between simian immunodeficiency virus (SIV) and HIV, SIV/macaque models have been extremely valuable for elucidating the pathogenesis of HIV, discovering therapeutics, and developing vaccines. The most widely used species for SIV studies include rhesus macaques (Macaca mulatta) and pigtailed macaques (Macaca nemestrina). Although SIV inoculation of Indian-origin rhesus macaques is the best characterized primate model of HIV infection, variable disease progression after SIV inoculation and limited availability of these animals have promoted interest in the use of alternate macaque species for SIV studies (Cohen 2000). In particular, pigtailed macaques have gained popularity as a primate model to study HIV pathogenesis because of their larger size, tractable temperament, and susceptibility to SIV infection (Klatt et al. 2012). Previous studies have suggested that SIV infection in pigtailed macaques more closely recapitulates HIV infection in humans and accelerates progression to SIV-induced encephalitis compared to SIV-inoculated rhesus macaques (Batten et al. 2006; Zink et al. 1997). Recently, HIV-1 was adapted to successfully induce AIDS in a CD8+ T cell-depleted pigtailed macaque model (Hatziioannou et al. 2014).
A great deal of evidence has identified cytotoxic lymphocyte-mediated MHC class I dependent immune responses as a crucial mechanism for HIV control (Limou and Zagury 2013; Pereyra et al. 2010). In particular, HLA-B*5701 and HLA-B*27 MHC class I alleles are overrepresented in individuals with delayed progression to AIDS (Blankson 2010; Goulder et al. 1996; Kaslow et al. 1996; Migueles et al. 2000; Schneidewind et al. 2007). Similar relationships have been identified in SIV/macaque models. MHC class I alleles of rhesus macaques (M. mulatta) have been especially well characterized in the context of SIV (Andrade et al. 2009; Goulder and Watkins 2008; Nakamura et al. 2011; Reed et al. 2011). The rhesus macaque MHC class I alleles Mamu-A1*001, Mamu-B*17, and Mamu-A*07 are associated with increased viral control and decreased progression to AIDS (Mothe et al. 2003; Muhl et al. 2002; O’Connor et al. 2003; Pal et al. 2002; Reed et al. 2011; Wu et al. 2011). Like humans and rhesus macaques, individual MHC class I alleles that present SIV peptides to cytotoxic T cells have also been identified in pigtailed macaques (Mankowski et al. 2008; Queen et al. 2011; Smith et al. 2005b). Of these, the pigtailed macaque MHC class I allele Mane-A*084:01 (formerly named Mane-A*10) has been associated with lower peak plasma viral load and slower progression to AIDS in animals inoculated with SIVmac251 (Klatt et al. 2012). In our well-characterized model of HIV CNS disease using pigtailed macaques inoculated with both SIV/17E-Fr and SIV/DeltaB670, we found that Mane-A*084:01 is a neuroprotective allele associated with decreased likelihood of progression to SIV CNS disease independent of influencing plasma viral load (Mankowski et al. 2008; Queen et al. 2011). Interestingly, Mane-A*084:01 recognizes an immunodominant SIV Gag epitope KP9 that is homologous to the HIV Gag epitope KF11, which is restricted by HLA-B*57:01 in humans (Smith et al. 2005a, b).
Few studies have directly compared SIV disease progression in rhesus and macaques and pigtailed macaques (Benveniste et al. 1988; Klatt et al. 2012; Polacino et al. 2008), and no studies have reported in detail whether the induction of SIV CNS disease varies between these two macaque species. Although advances in HIV treatment have dramatically reduced the incidence of HIV-associated dementia (HAD), neurocognitive defects in treated HIV-infected individuals persist, manifest as less severe HIV-associated neurocognitive deficits (HAND) (Spudich 2013). SIV/macaque models will be essential for establishing the causes of HAND and for testing compounds to effect virus eradication.
The accelerated consistent SIV pigtailed macaque model of CNS developed at Johns Hopkins recapitulates key features of HIV-associated neurologic disease, including high viral load in the cerebrospinal fluid (CSF) and encephalitis with abundant SIV replication in the brain (Clements et al. 2008; Zink et al. 1997; Zink et al. 1999), as well as PNS damage (Laast et al. 2007; Laast et al. 2011), and therefore serves as the basis for comparison with disease progression in rhesus macaques inoculated with the same SIV combination. To investigate whether host factors regulate SIV CNS disease progression, we compared the course of disease and the incidence of SIV encephalitis (SIVE) in rhesus and pigtailed macaques that were dual-inoculated with both SIV/DeltaB670, an immunosuppressive swarm, and SIV/17E-Fr, a neurovirulent molecular clone (Zink et al. 1997; Zink et al. 1999).
Methods
Animal studies
Forty-four pigtailed macaques (M. nemestrina) and 29 rhesus macaques (M. mulatta) were intravenously inoculated with both SIV/DeltaB670 (50 AID50) and SIV/17E-Fr (10,000 AID50) as previously described (Zink et al. 1997). Animals did not receive any treatment and were perfused with sterile saline at euthanasia to remove blood and circulating virus from brain. Animals were MHC class I typed by sequence-specific primer (SSP)-PCR (Mankowski et al. 2008). By design, pigtailed macaques were euthanized at approximately 84 days post-inoculation or at the onset of AIDS-defining illness (whichever came first) given consistent progression to AIDS at this time point (Zink et al. 1997; Zink et al. 1999). Initially, three rhesus macaques (RH25, RH26, and RH27) also were euthanized at day 84 post-inoculation to compare directly with pigtailed macaque study endpoints. As these three rhesus macaques did not develop either AIDS or CNS disease, the subsequent 26 rhesus macaques were euthanized at the onset of AIDS-defining illness, which ranged from 36 to 560 days post-inoculation. Animals were euthanized if any two of the following signs developed: weight loss greater than 15 % of baseline, clinical signs of organ-specific disease (i.e., CNS, lung, etc.), intractable diarrhea, or opportunistic infection. All animal procedures in this study were performed according to the principles set forth by the Institutional Animal Care and Use Committee at Johns Hopkins University and the National Research Council’s Guide for the care and use of laboratory animals.
Quantitation of SIV RNA
To measure ongoing viral replication in infected animals, SIV RNA in plasma, CSF, and tissues was measured by qRT-PCR using primers in the SIV gag region as previously described (Clements et al. 2002; Queen et al. 2011). The primers used to detect unspliced viral RNA were: forward primer, SGAG03, 5′-CAGGGAAIIAAGCAGATGAATTAG-3′; reverse primer, SGAG04, 5′-GTTTCACTTTCTCTTCTGCGTG-3′; and probe, pSUS05, 5′-(6-carboxyfluorescein [FAM])ATTTGGATTAGCAGAAAGCCTGTTGGAG (6-carboxytetramethylrhodamine [TAMRA])-3′ with cycle conditions of 50 °C for 30 min, 94 °C for 15 min to reverse transcribe RNA, which was followed by 45 cycles of PCR at 94 °C for 15 s, 55 °C for 15 s, and 60 °C for 30 s (detection limit 100 copies/mL) (Queen et al. 2011).
Quantitation of pro-inflammatory markers in the CSF
CSF samples were centrifuged to remove cells then stored at −80 C for subsequent analysis. CSF levels of IL-6 and CCL2 were measured by ELISA (R&D Systems, Minneapolis, MN) as previously described (Mankowski et al. 2004).
Histopathology
Sections of brain were scored for the presence of encephalitis as previously described (Mankowski et al. 2004). SIV-associated encephalitis was defined as multifocal perivascular accumulations of macrophages and multinucleated giant cells and glial nodules (Mankowski et al. 2004). Hematoxylin and eosin stained sections of frontal and parietal cortex, basal ganglia, thalamus, midbrain, and cerebellum were scored in a blinded fashion by two pathologists.
MHC class I allele genotyping
Expression of Mane-A1*084:04:01 in pigtailed macaques was determined by sequence-specific PCR as previously described (Mankowski et al. 2008). MHC class I genotyping in rhesus macaques was determined by multiple allele-specific PCR by the MHC Typing Service provided by David Watkins as previously described (Kaizu et al. 2007).
Statistical analysis
Survival curves for pigtailed macaques and rhesus macaques up to day 84 post-inoculation were compared by the Gehan-Breslow-Wilcoxon test. Similarly, groupwise comparisons of plasma and CSF viral load, CD4+ T cell counts, and CSF IL-6 and CCL2, and terminal tissue viral load were performed using the two sample nonparametric Mann–Whitney test. The Fisher’s exact test (one-sided) was used to identify associations between MHC class I allele expression versus development of SIV CNS disease.
Results
Accelerated progression to AIDS with a greater decline in CD4+ lymphocytes in pigtailed macaques compared to rhesus macaques
SIV-inoculated rhesus macaques survived significantly longer than pigtailed macaques (Fig. 1a). All pigtailed macaques developed AIDS-defining criteria and were euthanized by approximately three months p.i. (mean 78 days p.i.) with a steady decline in CD4+ T cells from day 45 post-inoculation onwards. In contrast, rapid progression to AIDS in rhesus macaques was much less common; although four rhesus macaques progressed rapidly (<60 days p.i.), most rhesus macaques developed AIDS and were euthanized between 120 and 350 days p.i. (mean 213 days p.i.; Table 1) Interestingly, rhesus macaques and pigtailed macaques had similar rates of progression to AIDS before 60 days p.i. (Fig. 1b); however, between 60 and 80 days p.i., pigtailed macaques progressed to AIDS at a more rapid rate than rhesus macaques. By design, all pigtailed macaque studies were terminated by 90 days p.i. due to uniforn progression to AIDS defining criteria.
To compare kinetics of immunosuppression after SIV infection, we measured CD4+ T cell counts in blood longitudinally in all animals, revealing a greater decline from baseline levels of CD4+ T cells in pigtailed macaques compared to rhesus macaques throughout the course of infection (Fig. 1c). There was no significant difference between absolute CD4+ T cell counts at 84 p.i. in rhesus macaques compared to pigtailed macaques; however, rhesus macaques had a significantly lower terminal absolute CD4+ lymphocyte count (median 169 cells/μL) than pigtailed macaques (median 337 cells/μL; P = 0.0003, Mann–Whitney, data not shown). The nadir median CD4+ cell count in rhesus was reached at >300 days p.i. consistent with a more protracted course of disease progression in rhesus macaques than pigtailed macaques.
Pigtailed macaques consistently developed higher viral loads in both plasma and cerebrospinal fluid than rhesus macaques
SIV RNA was measured in both the plasma and CSF of all animals throughout the course of infection (Fig. 2a, b). Pigtailed macaques had a significantly higher viral load than rhesus macaques at day 84 p.i. in both plasma (Fig. 2c; P = 0.0002, Mann–Whitney) and CSF (Fig. 2d; P = 0.0093, Mann–Whitney t test). Even with the longer duration of infection in rhesus macaques compared to pigtailed macaques, terminal viral loads were higher in pigtailed macaques in both the plasma (P = 0.009, Mann–Whitney t test) and CSF (P = 0.062, Mann–Whitney).
Pigtailed macaques developed SIV-induced CNS disease more frequently than rhesus macaques
To quantify the incidence and severity of SIV-induced CNS disease, the CNS of all animals were scored for the presence of SIV encephalitis, defined by presence of multifocal glial nodules and perivascular cuffs of macrophages and multinucleated giant cells. By these established criteria, pigtailed macaques developed SIV encephalitis more frequently than rhesus macaques. (Table 2; P = 0.068, one-sided Fisher’s exact test). Correspondingly, pigtailed macaques had higher levels of CCL2 (MCP-1) in the CSF than rhesus macaques during both acute (Fig. 3b; P = <0.0001 at d7 p.i, Mann–Whitney) and chronic phases of infection (P = 0.046 at d84 p.i. Mann–Whitney). In addition, when terminal CSF CCL2 levels were compared, CCL2 was significantly higher (P = 0.045, Mann–Whitney t test) in pigtailed macaques compared to rhesus macaques. Although CSF IL-6 levels in pigtailed macaques were slightly higher than rhesus macaques in acute and chronic stages of infection, these differences were not significant (P = 0.13 and 0.22, respectively; Mann–Whitney). There was no species difference in terminal CSF IL-6 levels (P = 0.92, Mann–Whitney).
Comparable terminal tissue SIV RNA levels in pigtailed macaques and rhesus macaques
To compare the extent of virus replication in peripheral tissues and the CNS at terminal time points, we measured SIV RNA levels in the spleen and basal ganglia (Fig. 4a, b) from rhesus macaques and pigtailed macaques. While viral RNA levels were higher in both the spleen and basal ganglia of pigtailed macaques compared to rhesus macaques, there was not a significant difference between the two groups.
MHC class I alleles play an important role in the development of SIV-encephalitis in both pigtailed macaques and rhesus macaques
To determine whether host genetics contribute to the progression of neurologic disease across macaque species, we genotyped all animals for expression of MHC class I alleles previously associated with lower plasma viral loads including Mamu-A1*001 in rhesus macaques and Mane-01*084:01:01 in pigtailed macaques. Five of 29 (17 %) of rhesus macaques expressed Mamu-A1*001; 14 of 44 (32 %) of the pigtailed cohort expressed Mane-01*084:01:01 (Table 3). In pigtailed macaques, Mane-01*084:01:01 expression was not associated with either altered plasma or CSF viral loads (Fig. 5a, c). In contrast, rhesus macaques that expressed Mamu-A1*001 had significantly lower terminal plasma viral loads (Fig. 5b; P = 0.0190, Mann–Whitney), but viral load in the CSF was not associated with this MHC class I allele (Fig. 5d; P = 0.3710, Mann–Whitney). Neither allele was associated with altered levels of CSF CCL2 or IL-6 (data not shown). However, both pigtailed macaques expressing Mane-01*084:01:01 and rhesus macaques expressing Mamu-A1*001 had lower levels of SIV RNA (P = 0.057 and P = 0.011, respectively, Mann–Whitney) in the brain consistent with MHC class I-mediated neuroprotection (Fig. 5e and f).
Discussion
Rhesus macaques and pigtailed macaques have proven to be valuable animal models of HIV due to their susceptibility to SIV; however, few studies have directly compared SIV outcomes in these different macaque species. Over the last 20 years, we have studied a large number of both pigtailed macaques and rhesus macaques that were inoculated with the same SIV combination, allowing a large retrospective comparative study. Based on our observations and other reports (Klatt et al. 2012; Zink et al. 1997), we hypothesized that rhesus macaques would progress to AIDS more slowly and develop SIV CNS disease less frequently. In addition, we examined whether the MHC class I allele Mamu-A1*001 would show similar neuroprotective effects in rhesus macaques as previously shown for the Mane-A1*084:01:01 MHC class I allele in pigtailed macaques (Mankowski et al. 2008).
SIV-infected pigtailed macaques progressed more rapidly than rhesus macaques, with shorter survival time post-inoculation, a greater decline in CD4+ cells, and higher longitudinal plasma and CSF viral load compared to rhesus macaques. In addition, at terminal time points, plasma and CSF viral loads as well as SIV RNA levels in the spleen and brain were higher in pigtailed macaques than rhesus macaques. Overall, pigtailed macaques died or were euthanized due to AIDS-defining illness much earlier than rhesus macaques. Although we initially suspected that rhesus macaques would exhibit a similar course of infection as pigtailed macaques, when the first three rhesus macaques were euthanized at three months post-infection (the time point by which all pigtailed macaques had progressed to AIDS), none of the rhesus macaques developed encephalitis or AIDS-defining illnesses. Thus, subsequent rhesus macaques were allowed to progress until the development of AIDS-defining illness, which in many animals did not occur until after 200 days post inoculation.
Consistent with previous findings in both rhesus and pigtailed macaques (Benveniste et al. 1988; Klatt et al. 2012; Kneitz et al. 1993; Letvin and King 1990; McClure et al. 1989), we found decreases in CD4+ T cell levels in both species after SIV inoculation; however, there was a much greater decrease in CD4+ T cells from pre-inoculation baseline levels in pigtailed macaques. Pigtailed macaques showed a classic pattern of acute CD4+ T cell decrease followed by a slight rebound then a progressive loss of CD4+ T cells over time. Conversely, rhesus macaques had an initial drop that was sustained over 84-days post-inoculation. The median CD4+ T cell levels then continued to decline over time as animals progressed past 500 days, consistent with rhesus macaques progressing more slowly to end-stage disease than pigtailed macaques despite comparable acute viremia.
Rhesus macaques did not develop neurologic disease as frequently as pigtailed macaques. With the dual-inoculum of the neurovirulent molecular clone SIV/17E-Fr and the immunosuppressive swarm SIV/B670, 64 % of pigtailed macaques developed SIVE compared to 42 % of rhesus macaques, although the mean time to euthanasia for rhesus macaques (213 days) was substantially longer than pigtailed macaques (78 days). We also compared several well-defined biomarkers predictive of SIV CNS disease including CSF IL-6 and CCL2 (Mankowski et al. 2004). Pigtailed macaques had higher IL-6 and CCL2 in the CSF at acute (d10 p.i.) and chronic (d42 p.i. to terminal) time points. Terminal CSF IL-6 levels in rhesus macaques were similar to pigtailed macaque values, consistent with prolonged disease progression in rhesus macaques. In contrast, terminal CSF CCL2 levels were significantly higher in pigtailed macaques than rhesus macaques.
Recently, Klatt et al. performed a retrospective study that compared SIVmac239 infection in rhesus macaques versus pigtailed macaques. Although pigtailed macaques developed AIDS more rapidly than rhesus macaques, they did not have a correspondingly higher plasma viral load in contrast to our findings in this report (Klatt et al. 2012). Previously, Polacino et al. compared SHIVSF162 P4 infection in pigtailed macaques versus rhesus macaques and concluded that pigtailed macaques had significantly higher peak and set-point (100+ days p.i.) plasma viral loads as well as a significantly higher proportion of animals that showed persistent viremia (Polacino et al. 2008). Similar to the findings of Polacino et al. our group of SIV-inoculated pigtailed macaques had higher viral loads in both plasma and CSF than rhesus macaques. Additional important differences between our study and previous reports include persistent viremia with much higher plasma viral loads, and uniform progression to AIDS-defining illness in all pigtailed macaques in a relatively short time frame. This is likely due to the specific inoculum used in our cohort; all animals in our cohort were dual-inoculated with a macrophage-tropic, neurovirulent clone as well as an immunosuppressive swarm, as opposed to single inoculation with cloned SIVmac239 used in the aforementioned studies.
Another study compared the neuropathogenesis of simian-human immunodeficiency virus (SHIV)(KU-2) infection of rhesus macaques versus pigtailed macaques and found that 21 of 22 pigtailed macaques failed to develop SHIV-associated neurologic disease or productive CNS viral replication. While the virus was macrophage tropic in rhesus macaques, leading to effective CNS viral replication in most animals, the lack of neurologic disease in pigtailed macaques was attributed to the inherent failure of the SHIV to replicate in pigtailed macaque macrophages (Buch et al. 2002). Macrophage tropism has been well established as a prerequisite for SIV or SHIV strains to cause lentiviral-associated neurologic disease in both rhesus and pigtailed macaques (Buch et al. 2002; Czub et al. 1996; Mankowski et al. 1997; Stephens et al. 1997).
This is the first study to directly compare the pathogenesis of rhesus macaques and pigtailed macaques specifically challenged with a neurovirulent SIV inoculum. To examine the effects of host genetics on disease progression, we focused on the most well-characterized MHC class I allele in each macaque species: Mamu-A1*001 in rhesus macaques and Mane-A*084:01:01 in pigtailed macaques. Although there is a large amount of variation in Mamu-A1*001 expression between different wild and captive populations of rhesus macaques, 31.8 % of the pigtailed macaques in this study expressed Mane-A*084:01:01 which is similar to prevalence reported in other studies (Pratt et al. 2006). Of our rhesus, 18.5 % expressed Mamu-A1*001 which falls within the range of reported frequency of Mamu-A1*001 expression that varies from <1 to 33 % depending on the population and country of origin (Kanthaswamy et al. 2010; Kyes et al. 2006; Muhl et al. 2002).
In this study, expression of the Mamu-A1*001 allele in rhesus macaques was associated with a lower plasma viral load, consistent with previously reported findings (Lim et al. 2010; Mothe et al. 2003; Muhl et al. 2002; Pal et al. 2002). Surprisingly, this difference seen in the peripheral virus did not translate to the CSF, a compartment in which levels of viral RNA were not associated with expression of this MHC class I allele. We nonetheless found lower levels of SIV RNA and less inflammation in the brains of rhesus macaques that expressed Mamu-A1*001, demonstrating that Mamu-A1*001 is neuroprotective. This suggests that MHC class I-mediated viral control in the brain differs from control in the periphery, underscoring the unique nature of CTL efficacy in the central nervous system. While there was no difference in either plasma or CSF viral loads of pigtailed macaques associated with expression of Mane-A*084:01:01, both SIV RNA and inflammation in the brain were lower in pigtailed macaques that expressed Mane-A*084:01:01.
This study illustrates the marked differences in SIV disease progression that develop in genetically distinct species after inoculation with an identical neurovirulent inoculum. In addition, the lack of appreciable difference in plasma viral loads between pigtailed macaques and rhesus macaques at acute infection (d10 p.i. P = 0.16, Mann–Whitney) implies that intrinsic or innate immune responses are not playing a major role in species differences. Rather, adaptive immune responses, in particular cell-mediated immunity, are the likely major determinant of species differences in disease outcome to SIV. Clearly, the relationship between MHC class I alleles and disease outcome is complex and multifactorial, and no single MHC class I allele will define the whole immunologic outcome. Thus, deeper and more comprehensive MHC class I haplotyping of different macaque species will be critical to understand the relationship between host immunogenetics and viral immunity. This is an important consideration for preventive and therapeutic vaccine development because vaccination against one single SIV epitope is unlikely to be completely effective. Furthermore, cytotoxic T cell responses do not develop in isolation from other associated inflammatory responses and may be linked to macrophage and microglial immune activation in the CNS; additional study of these potential relationships will clarify casual interactions betweem CTLs and more generalized CNS inflammatory responses. To understand the differences between individual responses to HIV-1 infection, we must try to understand the differences observed in primate models of lentiviral disease, the best animal models available to study HIV pathogenesis.
References
Andrade MC, Leite JP, Cabello PH (2009) Frequency of the major histocompatibility complex Mamu-A*01 allele in a closed breeding colony of rhesus monkey (Macaca mulatta) from Brazil. J Med Primatol 38:39–41
Batten CJ, De Rose R, Wilson KM, Agy MB, Chea S, Stratov I, Montefiori DC, Kent SJ (2006) Comparative evaluation of simian, simian-human, and human immunodeficiency virus infections in the pigtail macaque (Macaca nemestrina) model. AIDS Res Hum Retroviruses 22:580–8
Benveniste RE, Morton WR, Clark EA, Tsai CC, Ochs HD, Ward JM, Kuller L, Knott WB, Hill RW, Gale MJ et al (1988) Inoculation of baboons and macaques with simian immunodeficiency virus/Mne, a primate lentivirus closely related to human immunodeficiency virus type 2. J Virol 62:2091–101
Blankson JN (2010) Control of HIV-1 replication in elite suppressors. Discov Med 9:261–6
Buch SJ, Villinger F, Pinson D, Hou Y, Adany I, Li Z, Dalal R, Raghavan R, Kumar A, Narayan O (2002) Innate differences between simian-human immunodeficiency virus (SHIV)(KU-2)-infected rhesus and pig-tailed macaques in development of neurological disease. Virology 295:54–62
Clements JE, Babas T, Mankowski JL, Suryanarayana K, Piatak M Jr, Tarwater PM, Lifson JD, Zink MC (2002) The central nervous system as a reservoir for simian immunodeficiency virus (SIV): steady-state levels of SIV DNA in brain from acute through asymptomatic infection. J Infect Dis 186:905–13
Clements JE, Mankowski JL, Gama L, Zink MC (2008) The accelerated simian immunodeficiency virus macaque model of human immunodeficiency virus-associated neurological disease: from mechanism to treatment. J Neurovirol 14:309–17
Cohen J (2000) AIDS research. Vaccine studies stymied by shortage of animals. Science 287:959–60
Czub S, Muller JG, Czub M, Muller-Hermelink HK (1996) Impact of various simian immunodeficiency virus variants on induction and nature of neuropathology in macaques. Res Virol 147:165–70
Goulder PJ, Watkins DI (2008) Impact of MHC class I diversity on immune control of immunodeficiency virus replication. Nat Rev Immunol 8:619–30
Goulder PJ, Bunce M, Krausa P, McIntyre K, Crowley S, Morgan B, Edwards A, Giangrande P, Phillips RE, McMichael AJ (1996) Novel, cross-restricted, conserved, and immunodominant cytotoxic T lymphocyte epitopes in slow progressors in HIV type 1 infection. AIDS Res Hum Retroviruses 12:1691–8
Hatziioannou T, Del Prete GQ, Keele BF, Estes JD, McNatt MW, Bitzegeio J, Raymond A, Rodriguez A, Schmidt F, Mac Trubey C, Smedley J, Piatak M Jr, KewalRamani VN, Lifson JD, Bieniasz PD (2014) HIV-1-induced AIDS in monkeys. Science 344:1401–5
Kaizu M, Borchardt GJ, Glidden CE, Fisk DL, Loffredo JT, Watkins DI, Rehrauer WM (2007) Molecular typing of major histocompatibility complex class I alleles in the Indian rhesus macaque which restrict SIV CD8+ T cell epitopes. Immunogenetics 59:693–703
Kanthaswamy S, Kou A, Satkoski J, Penedo MC, Ward T, Ng J, Gill L, Lerche NW, Erickson BJ, Smith DG (2010) Genetic characterization of specific pathogen-free rhesus macaque (Macaca mulatta) populations at the California National Primate Research Center (CNPRC). Am J Primatol 72:587–99
Kaslow RA, Carrington M, Apple R, Park L, Munoz A, Saah AJ, Goedert JJ, Winkler C, O’Brien SJ, Rinaldo C, Detels R, Blattner W, Phair J, Erlich H, Mann DL (1996) Influence of combinations of human major histocompatibility complex genes on the course of HIV-1 infection. Nat Med 2:405–11
Klatt NR, Canary LA, Vanderford TH, Vinton CL, Engram JC, Dunham RM, Cronise HE, Swerczek JM, Lafont BA, Picker LJ, Silvestri G, Brenchley JM (2012) Dynamics of simian immunodeficiency virus SIVmac239 infection in pigtail macaques. J Virol 86:1203–13
Kneitz C, Kerkau T, Muller J, Coulibaly C, Stahl-Hennig C, Hunsmann G, Hunig T, Schimpl A (1993) Early phenotypic and functional alterations in lymphocytes from simian immunodeficiency virus infected macaques. Vet Immunol Immunopathol 36:239–55
Kyes RC, Jones-Engel L, Chalise MK, Engel G, Heidrich J, Grant R, Bajimaya SS, McDonough J, Smith DG, Ferguson B (2006) Genetic characterization of rhesus macaques (Macaca mulatta) in Nepal. Am J Primatol 68:445–55
Laast VA, Pardo CA, Tarwater PM, Queen SE, Reinhart TA, Ghosh M, Adams RJ, Zink MC, Mankowski JL (2007) Pathogenesis of simian immunodeficiency virus-induced alterations in macaque trigeminal ganglia. J Neuropathol Exp Neurol 66:26–34
Laast VA, Shim B, Johanek LM, Dorsey JL, Hauer PE, Tarwater PM, Adams RJ, Pardo CA, McArthur JC, Ringkamp M, Mankowski JL (2011) Macrophage-mediated dorsal root ganglion damage precedes altered nerve conduction in SIV-infected macaques. Am J Pathol 179:2337–45
Letvin NL, King NW (1990) Immunologic and pathologic manifestations of the infection of rhesus monkeys with simian immunodeficiency virus of macaques. J Acquir Immune Defic Syndr 3:1023–40
Lim SY, Chan T, Gelman RS, Whitney JB, O’Brien KL, Barouch DH, Goldstein DB, Haynes BF, Letvin NL (2010) Contributions of Mamu-A*01 status and TRIM5 allele expression, but not CCL3L copy number variation, to the control of SIVmac251 replication in Indian-origin rhesus monkeys. PLoS Genet 6:e1000997
Limou S, Zagury JF (2013) Immunogenetics: genome-wide association of Non-progressive HIV and viral load control: HLA genes and beyond. Front Immunol 4:118
Mankowski JL, Flaherty MT, Spelman JP, Hauer DA, Didier PJ, Amedee AM, Murphey-Corb M, Kirstein LM, Munoz A, Clements JE, Zink MC (1997) Pathogenesis of simian immunodeficiency virus encephalitis: viral determinants of neurovirulence. J Virol 71:6055–60
Mankowski JL, Queen SE, Clements JE, Zink MC (2004) Cerebrospinal fluid markers that predict SIV CNS disease. J Neuroimmunol 157:66–70
Mankowski JL, Queen SE, Fernandez CS, Tarwater PM, Karper JM, Adams RJ, Kent SJ (2008) Natural host genetic resistance to lentiviral CNS disease: a neuroprotective MHC class I allele in SIV-infected macaques. PLoS One 3:e3603
McClure HM, Anderson DC, Fultz PN, Ansari AA, Lockwood E, Brodie A (1989) Spectrum of disease in macaque monkeys chronically infected with SIV/SMM. Vet Immunol Immunopathol 21:13–24
Migueles SA, Sabbaghian MS, Shupert WL, Bettinotti MP, Marincola FM, Martino L, Hallahan CW, Selig SM, Schwartz D, Sullivan J, Connors M (2000) HLA B*5701 is highly associated with restriction of virus replication in a subgroup of HIV-infected long term nonprogressors. Proc Natl Acad Sci U S A 97:2709–14
Mothe BR, Weinfurter J, Wang C, Rehrauer W, Wilson N, Allen TM, Allison DB, Watkins DI (2003) Expression of the major histocompatibility complex class I molecule Mamu-A*01 is associated with control of simian immunodeficiency virus SIVmac239 replication. J Virol 77:2736–40
Muhl T, Krawczak M, Ten Haaft P, Hunsmann G, Sauermann U (2002) MHC class I alleles influence set-point viral load and survival time in simian immunodeficiency virus-infected rhesus monkeys. J Immunol 169:3438–46
Nakamura M, Takahara Y, Ishii H, Sakawaki H, Horiike M, Miura T, Igarashi T, Naruse TK, Kimura A, Matano T, Matsuoka S (2011) Major histocompatibility complex class I-restricted cytotoxic T lymphocyte responses during primary simian immunodeficiency virus infection in Burmese rhesus macaques. Microbiol Immunol 55:768–73
O’Connor DH, Mothe BR, Weinfurter JT, Fuenger S, Rehrauer WM, Jing P, Rudersdorf RR, Liebl ME, Krebs K, Vasquez J, Dodds E, Loffredo J, Martin S, McDermott AB, Allen TM, Wang C, Doxiadis GG, Montefiori DC, Hughes A, Burton DR, Allison DB, Wolinsky SM, Bontrop R, Picker LJ, Watkins DI (2003) Major histocompatibility complex class I alleles associated with slow simian immunodeficiency virus disease progression bind epitopes recognized by dominant acute-phase cytotoxic-T-lymphocyte responses. J Virol 77:9029–40
Pal R, Venzon D, Letvin NL, Santra S, Montefiori DC, Miller NR, Tryniszewska E, Lewis MG, VanCott TC, Hirsch V, Woodward R, Gibson A, Grace M, Dobratz E, Markham PD, Hel Z, Nacsa J, Klein M, Tartaglia J, Franchini G (2002) ALVAC-SIV-gag-pol-env-based vaccination and macaque major histocompatibility complex class I (A*01) delay simian immunodeficiency virus SIVmac-induced immunodeficiency. J Virol 76:292–302
Pereyra F, Jia X, McLaren PJ, Telenti A, de Bakker PI, Walker BD, Ripke S, Brumme CJ, Pulit SL, Carrington M, Kadie CM, Carlson JM, Heckerman D, Graham RR, Plenge RM, Deeks SG, Gianniny L, Crawford G, Sullivan J, Gonzalez E, Davies L, Camargo A, Moore JM, Beattie N, Gupta S, Crenshaw A, Burtt NP, Guiducci C, Gupta N, Gao X, Qi Y, Yuki Y, Piechocka-Trocha A, Cutrell E, Rosenberg R, Moss KL, Lemay P, O’Leary J, Schaefer T, Verma P, Toth I, Block B, Baker B, Rothchild A, Lian J, Proudfoot J, Alvino DM, Vine S, Addo MM, Allen TM, Altfeld M, Henn MR, Le Gall S, Streeck H, Haas DW, Kuritzkes DR, Robbins GK, Shafer RW, Gulick RM, Shikuma CM, Haubrich R, Riddler S, Sax PE, Daar ES, Ribaudo HJ, Agan B, Agarwal S, Ahern RL, Allen BL, Altidor S, Altschuler EL, Ambardar S, Anastos K, Anderson B, Anderson V, Andrady U, Antoniskis D, Bangsberg D, Barbaro D, Barrie W, Bartczak J, Barton S, Basden P, Basgoz N, Bazner S, Bellos NC, Benson AM, Berger J, Bernard NF, Bernard AM, Birch C, Bodner SJ, Bolan RK, Boudreaux ET, Bradley M, Braun JF, Brndjar JE, Brown SJ, Brown K, Brown ST et al (2010) The major genetic determinants of HIV-1 control affect HLA class I peptide presentation. Science 330:1551–7
Polacino P, Larsen K, Galmin L, Suschak J, Kraft Z, Stamatatos L, Anderson D, Barnett SW, Pal R, Bost K, Bandivdekar AH, Miller CJ, Hu SL (2008) Differential pathogenicity of SHIV infection in pig-tailed and rhesus macaques. J Med Primatol 37(Suppl 2):13–23
Pratt BF, O’Connor DH, Lafont BA, Mankowski JL, Fernandez CS, Triastuti R, Brooks AG, Kent SJ, Smith MZ (2006) MHC class I allele frequencies in pigtail macaques of diverse origin. Immunogenetics 58:995–1001
Queen SE, Mears BM, Kelly KM, Dorsey JL, Liao Z, Dinoso JB, Gama L, Adams RJ, Zink MC, Clements JE, Kent SJ, Mankowski JL (2011) Replication-competent simian immunodeficiency virus (SIV) Gag escape mutations archived in latent reservoirs during antiretroviral treatment of SIV-infected macaques. J Virol 85:9167–75
Reed JS, Sidney J, Piaskowski SM, Glidden CE, Leon EJ, Burwitz BJ, Kolar HL, Eernisse CM, Furlott JR, Maness NJ, Walsh AD, Rudersdorf RA, Bardet W, McMurtrey CP, O’Connor DH, Hildebrand WH, Sette A, Watkins DI, Wilson NA (2011) The role of MHC class I allele Mamu-A*07 during SIV(mac)239 infection. Immunogenetics 63:789–807
Schneidewind A, Brockman MA, Yang R, Adam RI, Li B, Le Gall S, Rinaldo CR, Craggs SL, Allgaier RL, Power KA, Kuntzen T, Tung CS, LaBute MX, Mueller SM, Harrer T, McMichael AJ, Goulder PJ, Aiken C, Brander C, Kelleher AD, Allen TM (2007) Escape from the dominant HLA-B27-restricted cytotoxic T-lymphocyte response in Gag is associated with a dramatic reduction in human immunodeficiency virus type 1 replication. J Virol 81:12382–93
Smith MZ, Dale CJ, De Rose R, Stratov I, Fernandez CS, Brooks AG, Weinfurter J, Krebs K, Riek C, Watkins DI, O’Connor DH, Kent SJ (2005a) Analysis of pigtail macaque major histocompatibility complex class I molecules presenting immunodominant simian immunodeficiency virus epitopes. J Virol 79:684–95
Smith MZ, Fernandez CS, Chung A, Dale CJ, De Rose R, Lin J, Brooks AG, Krebs KC, Watkins DI, O’Connor DH, Davenport MP, Kent SJ (2005b) The pigtail macaque MHC class I allele Mane-A*10 presents an immundominant SIV Gag epitope: identification, tetramer development and implications of immune escape and reversion. J Med Primatol 34:282–93
Spudich S (2013) HIV and neurocognitive dysfunction. Curr HIV/AIDS Rep 10:235–43
Stephens EB, Galbreath D, Liu ZQ, Sahni M, Li Z, Lamb-Wharton R, Foresman L, Joag SV, Narayan O (1997) Significance of macrophage tropism of SIV in the macaque model of HIV disease. J Leukoc Biol 62:12–9
Wu Y, Gao F, Liu J, Qi J, Gostick E, Price DA, Gao GF (2011) Structural basis of diverse peptide accommodation by the rhesus macaque MHC class I molecule Mamu-B*17: insights into immune protection from simian immunodeficiency virus. J Immunol 187:6382–92
Zink MC, Amedee AM, Mankowski JL, Craig L, Didier P, Carter DL, Munoz A, Murphey-Corb M, Clements JE (1997) Pathogenesis of SIV encephalitis. Selection and replication of neurovirulent SIV. Am J Pathol 151:793–803
Zink MC, Suryanarayana K, Mankowski JL, Shen A, Piatak M Jr, Spelman JP, Carter DL, Adams RJ, Lifson JD, Clements JE (1999) High viral load in the cerebrospinal fluid and brain correlates with severity of simian immunodeficiency virus encephalitis. J Virol 73:10480–8
Acknowledgments
This work was supported by NIH grants R01 NS089482, R01 NS077869, RO1 HL078479, P40 OD013117, and T32 OD011089.
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The authors declare they have no conflict of interest.
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Beck, S.E., Kelly, K.M., Queen, S.E. et al. Macaque species susceptibility to simian immunodeficiency virus: increased incidence of SIV central nervous system disease in pigtailed macaques versus rhesus macaques. J. Neurovirol. 21, 148–158 (2015). https://doi.org/10.1007/s13365-015-0313-7
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DOI: https://doi.org/10.1007/s13365-015-0313-7