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. Author manuscript; available in PMC: 2009 Aug 18.
Published in final edited form as: J Med Primatol. 2008 Dec;37(Suppl 2):13–23. doi: 10.1111/j.1600-0684.2008.00325.x

Differential Pathogenicity of SHIVSF162 P4 Infection in Pig-tailed and Rhesus Macaques

Patricia Polacino 1, Kay Larsen 1, Lindsey Galmin 2, John Suschak 2, Zane Kraft 3, Leonides Stamatatos 3,4, David Anderson 1, Susan W Barnett 5, Ranajit Pal 2, Kristen Bost 6, A H Bandivdekar 7, Christopher J Miller 6, Shiu-Lok Hu 1,8,*
PMCID: PMC2728750  NIHMSID: NIHMS131315  PMID: 19187427

Abstract

Background

Differential pathogenicity has been observed in cynomolgus and rhesus macaques following primate lentivirus infection. However, little is known about the comparative susceptibility of pig-tailed macaques to lentivirus infection and diseases.

Methods

We compared the in vivo infectivity and pathogenicity of a CCR5-tropic SHIVSF162 P4 after intravenous, intravaginal or intrarectal inoculation in rhesus and pig-tailed macaques. Plasma viral load, peripheral blood CD4+ T cell counts and clinical signs were monitored.

Results

Both rhesus and pig-tailed macaques are similarly susceptible to SHIVSF162 P4 infection by intravenous and mucosal routes. However, SHIV replication was significantly more robust in pig-tailed macaques than in rhesus, resulting in persistent viremia in 9/21 pig-tails vs. 2/24 rhesus (p<0.013) and severe CD4+ T-cell depletion in 2/21 pig-tails (vs. none in rhesus).

Conclusions

Together with earlier observations, our findings underscore the importance of considering host genetic and immunological factors when comparing vaccine efficacy in different macaque species.

Keywords: Plasma viremia, AIDS vaccine, intravenous, intrarectal, intravaginal

Introduction

Due to their propensity to develop AIDS-like diseases resulting from primate lentivirus infection, Asian macaques have been widely used for HIV vaccines and pathogenesis studies [24, 27, 32, 52]. Among macaque species, rhesus (Macaca mulatta), cynomolgus (M. fascicularis) and pig-tailed (M. nemestrina) macaques are most commonly used. However, in part because of the considerable logistics required, only a limited number of studies have been undertaken to examine the relative infectivity and pathogenicity of primate lentiviruses among these macaque species. The paucity of comparative data, coupled with the variability of challenge stocks prepared from different laboratories, makes it difficult to interpret divergent findings from even similar vaccine approaches evaluated in different macaque models.

Substantial differences in susceptibility to primate lentivirus-induced diseases have been observed between different species, or subspecies, of macaques. ten Haaft et al. [55] compared early plasma viral load in cynomolgus and rhesus macaques infected with different strains of SIVmac or SHIV89.6P inoculated via intravenous or various mucosal routes. After SIV infection, cynomolgus macaques had lower setpoint viral load than rhesus macaques. However, no such difference was observed in animals infected with SHIV89.6P, or among animals inoculated via different routes. Rhesus macaques of Chinese origin infected intravenously with SIVmac239 [33], or intravaginally with SIVmac251 [35], have significantly lower plasma viral load than rhesus macaques of Indian origin [33, 35]. Among the IV inoculated animals, disease progression was more rapid in rhesus monkeys of Chinese origin than those of Indian origin. Reimann et al. [48] compared pathogenicity of intravenous SHIV89.6P or SIVmac251 infection in cynomolgus macaques, and in rhesus macaques of Chinese or Indian origins. In contrast to the findings reported by ten Haaft et al. [55], they observed lower plasma viral load following either SIVmac251 or SHIV89.6P infection in cynomolgus and Chinese rhesus, as compared to Indian rhesus. The attenuated pathogenicity in cynomolgus macaques was associated with higher frequency of viral antigen specific cellular and neutralizing antibody responses.

On the other hand, little is known about lentivirus infection in pig-tailed macaques relative to these other species. Pig-tailed macaques are of interest, not only because they are more distantly related to rhesus and cynomolgus macaques [20, 56], but also because they may be more susceptible to primate lentivirus-induced diseases than rhesus macaques. Rosenberg et al. [50] demonstrated increased susceptibility of pig-tailed as compared to rhesus macaques to the early gastrointestinal distress and death resulting from SIVPBj-14 infection. Persistent infection and/or AIDS-like disease progression have also been observed in pig-tailed macaques inoculated with primary isolates of HIV-2 [37, 43], in contrast to the common observation of transient infection and lack of pathogenicity in HIV-2 infected rhesus macaques [11, 16]. Hirsch et al. [26] passaged SIVagm in pig-tailed macaques and observed species-specific variations in pathogenicity correlating with the extent of in vivo replication. Chen et al. [12] observed enhanced infectivity, but no pathogenicity, after serial passages of an R5-tropic subtype C SHIV in pig-tailed macaques. Despite these early indications, information is still lacking on the comparative susceptibility of pig-tailed and rhesus macaques to a pathogenic primate lentivirus commonly used for vaccine studies.

SHIVSF162P is one of the few existing CCR5-tropic chimeric viruses capable of establishing persistent infection in rhesus macaques [58]. Infection causes an early and dramatic loss of CD4+ T cells in the gut-associated lymphoid tissue compartment, followed by a gradual decline of CD4+ T cells in peripheral blood [25]. However, post-acute phase plasma viral load varies significantly after SHIVSF162P infection in rhesus macaques and AIDS-like diseases progression remains rare [30]. Different passages of SHIVSF162P have been established and used in a number of vaccine challenge studies, primarily with rhesus macaques [2, 8, 9, 13, 14, 59]. In an attempt to develop a more robust model for the evaluation of vaccine efficacy in a macaque model, we compared the in vivo infectivity and pathogenicity of a standard challenge stock of SHIVSF162P4 after intravenous (IV), intrarectal (IR) or intravaginal (IVag) inoculation in rhesus and pig-tailed macaques.

Materials and Methods

Animals

A total of 27 rhesus macaques (of Indian, Chinese, or hybrid origin) and 22 pig-tailed macaques, all tested negative for simian type D retrovirus by serology and polymerase chain reaction (PCR), were used in this study. Animals were inoculated with the same challenge virus (see below) via different routes as summarized in Table 1 and described in further details under Results. Procedures for IV, IR and IVag inoculations were as previously described [2, 31, 34, 38]. Studies with pig-tailed macaques were performed at the Washington National Primate Research Center (WaNPRC), the IV and IR studies with rhesus macaques at the California National Primate Research Center (CNPRC), and the IVag studies with rhesus at Advanced BioScience Laboratories, Inc. (ABL). Peripheral blood was collected by venipuncture and analyzed for viral load and lymphocyte subsets as described below. Animals were monitored for general health, body weight and temperature by routine physical examinations. All animals were cared for in accordance with established guidelines and the experimental procedures performed under approval from the respective Institutional Animal Care and Use Committees.

Table 1.

In vivo infectivity of SHIVSF162 P4 in rhesus and pig-tailed macaques:

Route Rhesus Macaques Pig-tailed Macaques
TCID50 Infected/total TCID50 Infected/total
IV 36 – 3.6 4/4 360-0.036 10/10
IR 1,800
360		 6/6
5/6		 1,800
360		 6/6
5/6
IVag 3,600
1,800		 6/7
3/4		 ND ND
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Virus stock

A macaque-passaged stock SHIVSF162 P3, was originally established in Dr. Cecilia Cheng-Mayer's laboratory [25]. Lymph node cells and PBMC from a macaque infected with SHIVSF162 P3 collected at 2 weeks after infection were amplified in human PBMC to generate a SHIVSF162 P4 stock. This virus shares the same env gp120 sequences as HIV-1SF162 and similar neutralization susceptibility (data not shown). A standardized stock of SHIVSF162 P4 was prepared in rhesus peripheral blood mononuclear cells (PBMC) at ABL for vaccine challenge studies. Briefly, 0.5 ml of plasma from a SHIV162P4-infected macaque (from Dr. L. Stamatatos) was injected intravenously into a naive Indian rhesus macaque. Following infection, blood (10 ml) and bone marrow (5 ml) of this macaque were injected into a second naïve animal. At the peak level of infection as evident from plasma viremia, PBMCs of the second macaque were collected, depleted of CD8+ T cells, activated with phytohemagglutinin (PHA) and a virus stock was isolated by co-culturing with PHA-activated PBMCs from naïve macaques. The in vitro infectivity of this stock as determined by 50% tissue culture infectious dose (TCID50) was 3.6 × 103/ml on rhesus PBMC.

Plasma viral load

Viral load was determined by one of the following methods: real-time reverse transcription (RT)-PCR [15, 46, 54] was used for samples from all pig-tailed macaques at WaNPRC; branched-chain DNA (bDNA) [39] for samples from rhesus at CNPRC, and nucleic acid sequence based amplification (NASBA) [49] for samples from rhesus at ABL.

Hematology and immunophenotype analysis

Absolute numbers of peripheral blood CD3+/4+ cells were determined by flow cytometry according to regulations from the Centers for Disease Control and Prevention and described in further details in by Polacino et al. [46].

Results

Study design

Twenty-seven rhesus macaques and 22 pig-tailed macaques were enrolled in this study at three performance sites (Table 1). All animals were inoculated with a single dose of the same challenge stock of SHIVSF162 P4 virus prepared in rhesus macaque PBMC. Ten pigtailed macaques were inoculated by intravenous inoculation, with 2 animals each at 10-fold serial dilutions from 360 to 0.036 TCID50. Similarly, two rhesus macaques each were inoculated at 36 or 3.6 TCID50. For IR inoculations, six rhesus and six pig-tailed macaques each were inoculated at 1,800 or 360 TCID50. In addition, seven rhesus macaques were inoculated intravaginally with 3,600 TCID50 and four at 1,800 TCID50. Plasma viral load, CD4+ T cell counts and disease progression were monitored for up to 24 weeks. Plasma RNA load data of four of the seven macaques inoculated intravaginally with 3,600 TCID50 were presented in an earlier study [2].

Similar in vivo infectivity of SHIVSF162 P4 in rhesus and pig-tailed macaques

All rhesus and pigtailed macaques inoculated intravenously were infected, including those that received only 0.036 TCID50 dose of SHIVSF162 P4, indicating the in vivo infectivity of this stock was >30-fold greater than its in vitro titers measured in rhesus PBMC. The mean peak viral load for intravenously infected pigtailed and rhesus macaques was 3.2 × 107 and 4.2 × 106 copies/ml (p<0.036) of plasma at wk 2 after infection (Fig. 1A-B). There was no correlation between peak viral load, or the time to peak viremia, with the amount of virus inoculum.

Fig. 1.

Fig. 1

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Plasma viral load in rhesus (left panels) and pig-tailed (right panels) macaques after SHIVSF162 P4 inoculation. Panels A and B: Numbers in parenthesis refer to the IV inoculum dose expressed in TCID50. Panels C and D: Animals in the top line of the legend received an inoculum of 1,800 TCID50 via the IR route and those in the bottom line received 360 TCID50. Panel E: Open symbols indicate animals that received an inoculum of 1,800 TCID50 via IVag route and the rest received 3,600 TCID50. RNA load of macaque M632 following challenge with 1,800 TCID50 and rechallenge with 3,600 TCID50 was shown respectively as M632 and M632R. Panel F and G: Summary of all viral load data from all infected animals. Please note that different symbols are used in these panels: open symbols denote viral load in animals inoculated by mucosal (IR or IVag) route and closed symbol, those inoculated by IV route. Solid lines represent the geometric mean values of viral load from all infected animals.

Similar infectivity was also observed in rhesus and pigtailed macaques inoculated via mucosal routes. Regardless of the species tested, all six animals inoculated IR with 1,800 TCID50 and five out of six macaques inoculated with 360 TCID50 became infected. In a parallel study, six of seven rhesus macaques inoculated IVag at 3,600 TCID50 and three of four inoculated at 1,800 TCID50 became infected (Table 1). One of the animals (M632) initially inoculated with 1,800 TCID50 resisted infection as evident from the lack of plasma viremia, tissue proviral DNA and anti-SIV antibodies in serum (data not shown). Following re-inoculation with 3,600 TCID50, this macaque was clearly infected (Fig 1E). The mean peak viral load in IR or IVag infected rhesus (1. 7 × 107 and 1. 2 × 107 copies/ml of plasma, respectively; Fig. 1C and E) was not significantly different from that in IV or IR inoculated pigtailed macaques (3.2 × 107 and 2.1 × 107 copies/ml of plasma, respectively; Fig. 1B and D). There was also no discernable difference in the time to reach peak viremia (two weeks after inoculation) in IV or IR inoculated pig-tailed macaques (Fig. 1B and D). However, we did observe a difference in the proportion of animals that showed a delay in the time to reach peak viremia among IVag infected rhesus macaques as compared to IV inoculated pig-tailed macaques. Among rhesus macaques, viral load peaked at three weeks, rather than two, after IVag inoculation in seven of nine infected animals (Fig. 1E), as compared to 1/10 IV (p<0.0055), or 2/11 IR (p<0.0216) infected pig-tailed macaques (Fig. 1B and D). Unfortunately, samples were not available from IV or IR inoculated rhesus to ascertain whether this delay was shared among rhesus macaques, or only in IVag inoculated animals.

Differential control of plasma viremia in rhesus and pig-tailed macaques infected with SHIVSF162 P4

Despite the similarity in infectivity and peak plasma viral load between rhesus and pig-tailed macaques inoculated with SHIVSF162 P4, significant differences were observed in the persistence of viremia in the post-acute phase of infection. Plasma viremia remained >103 copies/ml in five of 10 IV inoculated pig-tailed macaques (Fig. 1B). The mean plasma viral load was >5.3 × 104 copies/ml between wks 16-24. In contrast, none of the four similarly inoculated Indian rhesus macaques showed persistent viremia beyond the acute phase (Fig. 1A).

Among IR inoculated animals, four of the 11 infected pig-tailed macaques showed persistent viremia with a mean plasma viral load of 1.5-5.2 × 105/ml between wks 16-24 after infection (Fig. 1D). In contrast, none of the 11 similarly inoculated rhesus macaques showed persistent viremia (Fig. 1C). Among IVag inoculated rhesus macaques, two of the nine infected animals showed persistent plasma viral load of 105-106/ml between wks 14-24 after infection (Fig. 1E). However, differences in the proportion of IR or IVag infected rhesus with persistent viremia (0/11 vs. 2/9, respectively) did not reach statistical significance.

Taken together, SHIVSF162 P4-infected pig-tailed macaques showed significantly higher peak (p<0.025) and setpoint (p<0.003) plasma viral load than similarly infected Indian rhesus macaques (Fig. 2A). Using a value of <103 copies/ml of mean plasma viral load between weeks 12-24 as an indication of control of infection, a significantly higher proportion of infected pig-tailed macaques showed persistent viremia after SHIVSF162 P4 infection, as compared to similarly infected rhesus macaques (p<0.013) (Fig. 2B).

Fig. 2.

Fig. 2

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Differential control of SHIVSF162 P4 replication in rhesus and pig-tailed macaques. Panel A: Horizontal lines indicate the mean plasma viral load at peak (week 2 or 3) or setpoint (between week 16 and 24) after infection. Individual values for all infected animals, regardless of the route of inoculation, are represented. P-value was determined by two-sided non-parametric Mann-Whitney U test. Panel B: Proportion of animals controlling infection, as defined by setpoint viremia <103 copies/ml (indicated by the shaded area in Panel A) is indicated in the solid bars. P-value was determined by two-sided Fisher's exact test.

Peripheral blood CD4 T-cell depletion in SHIVSF162 P4-infected pig-tailed macaques

Peripheral blood CD4+ T cell level was monitored for all animals. Two of the 21 infected pig-tailed macaques (K03388 inoculated IV and J04009 inoculated IR) showed precipitous and irreversible CD4+ T-cell depletion beginning at 12 weeks after infection (Fig. 3G). In addition, one animal (K02305 inoculated IR, Fig. 3D) showed CD4+ T cell level at approx. 200/microliter from week 12 to 24 after infection. Animal J04009 also developed anemia and failed to gain weight. All animals were euthanized at the end of the study period of 24 weeks.

Fig. 3.

Fig. 3

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Peripheral blood CD4+ T cells numbers in rhesus (left panels) and pig-tailed (right panels) macaques after SHIVSF162 P4 inoculation. Symbols are the same as described in the legend for Fig. 1. CD4+ T cell counts of macaque M632 following challenge with 1,800 TCID50 (M632) and 3,600 TCID50 (M632 R) are shown separately in Fig. 3E. Solid lines in Panels F and G show animals that developed CD4+ T cell decline.

In contrast, none of the 15 similarly infected rhesus macaques showed persistent viremia or CD4+ T-cell depletion in peripheral blood within the study period of 20 to 24 weeks (Fig. 3F). One of the nine IVag infected rhesus macaques did show significant decline in peripheral blood CD4+ T cell level (M367, Fig. 3E), which remained at approx. 200/microliter from week 6 to week 14 after infection. However, differences between rhesus and pig-tailed macaques in the proportion of animals showing severe CD4+ T-cell depletion did not reach statistical significance. None of the infected rhesus showed any other clinical sign throughout the study period of 24 weeks.

Discussion

This study documents the similar infectivity, but differential control of primate lentivirus replication in pig-tailed versus rhesus macaques. To our knowledge, this is the first report of a comparative study with different macaque species inoculated with a CCR5-tropic SHIV developed for the evaluation of HIV vaccine candidates.

Results from this study allow us to draw several major conclusions. First, SHIVSF162 P4 showed similar infectivity in pig-tailed and rhesus macaques following IV and IR inoculations. Second, inoculum dose had no effect on the peak or setpoint plasma viral load in infected animals, in agreement with previous observations [17, 21,51]. Third, the route of inoculation did not significantly affect the peak or setpoint viral load among infected pig-tailed or rhesus macaques. Fourth, the time to peak viral load was delayed by a week in vaginally infected animals as compared to IV infected ones, similar to previously reported observations [1, 21, 34]. Finally and importantly, our results showed significantly higher setpoint plasma viremia and lower proportion of animals controlling infection in SHIVSF162 P4-infected pig-tailed macaques as compared to similarly infected rhesus macaques. Unfortunately, the study duration was too short to fully document disease progression among infected animals. Nevertheless, about 10% (2/21) of infected pig-tailed showed severe and irreversible peripheral CD4+ T cell depletion within the first three months after infection, which is rarely observed in similarly infected rhesus macaques [2, 30]. In a parallel vaccine study, among 11 naïve pig-tailed macaque infected with the same stock of SHIVSF162 P4, three showed peripheral blood CD4+ T cell depletion (one at week 8 and two at week 28 after inoculation), two of which developed AIDS-like clinical signs and were euthanized at weeks 22 and 42 (data not shown). Taken together, these findings indicate increased susceptibility of pig-tailed macaques to lentiviral induced disease as compared to the commonly used Indian rhesus macaques. The proportion of SHIVSF162 P4-infected pig-tailed macaques developing CD4+ T cell depletion (5/32 in 7 months from two studies combined) and the rapid onset of AIDS-like disease (2/32 within 7 months) are comparable to SIVmac251-infected Indian rhesus macaques [48], which represents one of the more virulent models of lentivirus infection in macaque species.

Findings from this study are in line with earlier observations suggesting an increased susceptibility of pig-tailed macaques to lentivirus induced diseases. Rosenberg et al. [50] showed that pig-tailed are more susceptible than rhesus macaques to death resulting from gastrointestinal distress following SIVPBj-14 infection. Buch et al. [7] demonstrated innate differences between rhesus and pig-tailed macaques infected with SHIV KU-2 in the development of neutrological diseases. Persistent and pathogenic infection of primary isolates of HIV-2 has been observed in pig-tailed macaques [37, 43]. Infection of pig-tailed macaques with SHIV HXBc2 (IIIB) vpu+, a CXCR4-tropic virus generally considered as non-pathogenic in rhesus macaques, lead to CD4+ T cell depletion in 20% of infected animals [28]. Passage of SHIV HXBc2 (IIIB) in pig-tailed macaques resulted in a highly pathogenic virus, SHIV 229, which induces rapid and irreversible peripheral CD+ T cell depletion and AIDS [19]. Findings here provide a direct comparison between pig-tailed and rhesus macaques for their susceptibility and ability to control primate lentivirus infections.

The basis for the differences observed between these two macaque species remains not clear. Pig-tailed macaques have been found to be defective in the host restriction factor TRIM5α [6], used by rhesus macaques to restrict replication by certain retroviruses, such as HIV-1 [53]. However, this is not likely to explain our observations here, because SHIVSF162 P4 has the same capsid as SIVmac, which is not susceptible to rhesus TRIM5α restriction. Although target cell abundance and replenishment may play a role [29, 42, 44, 45], the similar levels of plasma viral load in pig-tailed and rhesus macaques in the acute phase infection indicate that SHIVSF162 P4 replicates and disseminates to establish systemic infection equally well in the two macaque species. The fact that the major difference observed between these two species is their ability to control viral replication in chronic infection (and possibly the resulting disease progression) indicates that differences in host antiviral immune responses, innate or adaptive, may be involved.

Comparative studies of pathogenic SIV infection in rhesus versus non-pathogenic infection their natural host sooty mangabeys have revealed the important role of inflammatory responses and cellular activation in lentivirus induced diseases [3, 5, 18, 22; 29; 32, 36, 40, 42, 47, 57]. Pathogenic SIVmac infection in rhesus results in inflammatory cytokine responses and CD4+ T cell activation, leading to increased target cell availability, decreased repopulation of central memory T cells and apoptosis. While comparative studies between susceptible macaque species, such as rhesus and pig-tailed macaques, have yet to be performed on these parameters, early studies of Rosenberg et al. [50] have indicated that PBMC from pig-tailed macaques, unlike those from rhesus, have reduced CD4+/CD8+ T-cell ratios and a skewing of T cells towards CD45RAhi expression. Increased level of pre-activated CD4+ T-cells thus could lead to enhanced viral replication. Whether and how increased cellular activation contributes to the persistence of plasma viremia in pig-tailed macaques will need to be addressed by future studies.

Adaptive responses may also contribute to the differential control of viral replication. Reimann et al. [48] reported that the reduced pathogenicity in SIVmac251- or SHIV89.6P-infected cynomolgus macaques, as compared to Indian rhesus, was in part due to the higher frequency of Gag- and Env-specific gamma interferon-positive T cells and virus neutralizing antibody responses. Results from our studies indicate that pig-tailed macaques are fully capable of mounting gamma interferon-positive T cell and antibody responses, including virus neutralizing antibodies against the challenge virus, SHIVSF162 P4 (unpublished data). This notion is also supported by the fact that about 50% of the infected pig-tailed macaques were able to control acute infection and reduce the mean peak viremia from >107 copies/ml to the setpoint viral load of <104 copies/ml. However, considerable differences in post-acute viral load indicate that intra-species variation in host factors, such as relative effectiveness of various major histocompatibility complex genes alleles to present viral antigens, may play a significant role in the uncontroled lentivirus replication found in pig-tailed macaques, as has been demonstrated in humans and other macaque species [4, 10, 23, 41]. Further comparative studies of host factors contributing to the innate and adaptive responses of macaque species to lentivirus infection will be needed.

Non-human primates provide the only experimental models available to-date for the assessment of the effectiveness of candidate AIDS vaccines. However, in part because of the lack of efficacy data from human vaccine trials, the predictive value of any particular animal model cannot be taken for granted. It is therefore risky to rely on any single non-human primate model to “rank-order” candidate vaccines for clinical development. Results from the present study indicate that efficacy in any vaccine trial may depend not only on the immunogen, vaccination regimen and the challenge virus, but also the species of macaques used. Comparative infectivity and pathogenicity data from different macaque species and better understanding of the factors contributing to these differences may result in more informed use of macaque models for HIV vaccine development.

Acknowledgments

We thank Dr. Nancy Miller (DAIDS, NIAID) for her support and coordination, Heather Mack, Valerie Teske, Ryan Wallerstedt, Ding Lu, Roxanna Colon, and Lara Compton for expert technical assistance, Dr. Steve Kelly and staff at WaNPRC and Dr. Deborah Weiss at ABL for veterinary care of animals housed at the respective sites. This study is supported in part by NIH grants and contracts N01 AI060005 and N01 A130057 (ABL), P51 RR0165 (CNPRC), P01 AI066314 and U19 AI51596 (CJM), N01 AI060006 and P51 RR0166 (WaNRPC), and P01 AI05456 (SLH).

This work was supported in part by NIH grants and contracts N01 AI060005 and N01 A130057 (ABL), P51 RR0165 (CNPRC), P01 AI066314 and U19 AI51596 (CJM), N01 AI060006 and P51 RR0166 (WaNPRC), and P01 AI05456 (SLH).

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