Studies in nonhuman primates are recognized as playing a critical role in advancing our understanding of HIV-1 transmission, pathogenesis, and basic vaccine, prevention, and treatment concepts.1–4 Experimental infection of Asian macaques with simian or simian–HIVs (SIV and SHIV, respectively) have provided important information on the early host events and kinetics of virus transmission and replication, the dynamics of CD4+ T-cell homeostasis during virus infection, the mechanisms of disease induction, and host immune responses.5–9 In particular, we have used infection of Indian rhesus macaques (RMs) (Macaca mulatta) with pathogenic CXCR4 (X4) and CCR5 (R5)-tropic SHIVs to study the impact of tropism on AIDS pathogenesis10–14 and have evaluated the ability of topical microbicides used alone or in combination with vaccines to prevent virus transmission using this model.15,16 Because the majority of HIV-1 transmitted/founder viruses are CCR5 tropic, with neutralization susceptibility profiles that are typical of primary viruses,17,18 we focused on developing an R5 SHIV infection model that recapitulates key features of HIV-1 infection in humans. We showed that infection of Indian-origin RMs via the intravenous, intrarectal (ir), or intravaginal (ivg) route with R5 SHIVSF162P3N resulted in acute CD4+ T-cell depletion in the gut, uncontrolled replication, and progression to AIDS, with switch in coreceptor preference toward CXCR4 in ∼50% of intravenous- and ir-infected animals.19–21 This model therefore mimics the type of transmission route in the majority of HIV-1–infected patients, allowing studies of viral selection through mucosal transmission, and late-stage coreceptor switch that is also seen in chronically infected HIV individuals not on treatment. Furthermore, development of giant cell SIV-induced encephalitis was observed in ∼30% of monkeys with symptoms of AIDS, with neuropathology mirroring that of HIV-1–associated encephalitis in infected patients (SW, CH, ZK, AG, JB and CCM, unpublished observations, 2012), providing an important model to study neuropathogenesis.
Several features of infection in Indian RMs, however, differ from that of HIV-1–infected individuals. These include a faster rate of progression to AIDS,22 high plasma virus levels, and a rapid and sustained loss of circulating and mucosal CD4+ CCR5+ memory T cells that is not seen in HIV-1–infected patients.23–25 This raises the concern that the Indian RM infection models may not fully reproduce the immunopathogenic events occurring during HIV-1 infection. Accordingly, and because Indian RMs were often in short supply, alternative macaque species such as cynomolgus, pig-tailed, or RMs from different geographic origin were used as models of HIV infection and AIDS.26 Several groups have reported that the slower course of infection and reduced risk of progression to AIDS in SIV/SHIV-infected Chinese-origin RMs are closer to HIV-1 infections in untreated adult humans than infection of Indian RMs.27–31 Moreover, similar to HIV-1–infected patients, the levels of immune activation in SIV-infected Chinese RMs are markers of disease progression.32,33 These findings led to the suggestion that SIV/SHIV infection of Chinese-origin rhesus is a more relevant model of AIDS outcomes than Indian RMs.28,34
In the present study, we evaluated mucosal transmissibility and pathogenesis of R5 SHIVSF162P3N in Chinese RMs and compared infection outcomes with those observed in Indian RMs. We found that the transmission efficiency, magnitude, and kinetics of early virus dissemination were similar in the 2 macaque subspecies after ir inoculation, but transmission and early virus spread with ivg challenge seemed to be more efficient in the Chinese than Indian RMs. Consistent with findings for SIV, mucosal infection of Chinese RMs with R5 SHIVSF162P3N resulted in attenuated pathogenicity when compared with infection in Indian RMs, as evidenced by lower levels of set point viremia and prolonged survival. Understanding these subspecies differences in response to R5 SHIVSF162P3N should guide the use of this virus in nonhuman primate studies of HIV-1 transmission and prevention, resistance to infection, and progression to pathology.
Animal Inoculation and Clinical Assessments
All ir or ivg inoculations were carried out in adult rhesus monkeys (M. mulatta) of Chinese origin housed at the Tulane National Primate Research Center in compliance with the Guide for the Care and use of Laboratory Animals. Chinese-origin rhesus were 5–10 years old and were confirmed to be serologically and virus negative for simian-type D retrovirus and serologically negative for SIV and simian T-cell lymphotropic virus before infection. The males were born and raised at Tulane National Primate Research Center, whereas the females were purchased from an outside vendor, the latter were used without Depo-provera treatment and randomized with regard to the stage of the menstrual cycle at the time of ivg challenge. Macaques received a single 104 50% tissue culture infectious dose of the cell-free challenge stock SHIVSF162P3N.10 Whole blood from the inoculated animals was collected weekly for the first 8–11 weeks, biweekly for another 16 weeks, and monthly thereafter. Surgery was performed during acute [2–3 weeks postinfection (wpi)] and chronic (12–18 wpi) phase of infection for tissue collection. These include the colonic, mesenteric, iliac, and/or inguinal lymph nodes for lymphoid cell isolation and immunohistological examination, and ∼20 cm of the jejunum for processing of laminar propria (LP) lymphocytes, with ileum and colon wedge biopsies for immunohistological analysis. Animals were euthanized at the end of study period (∼50 weeks for ivg and >60 weeks for ir) by intramuscular administration of telazol and buprenorphine followed by an overdose of sodium pentobarbital. Euthanasia was considered to be AIDS related if the animal exhibited peripheral blood CD4+ T-cell depletion (<200/mm3), greater than 25% loss of body weight, or combinations of the following conditions: diarrhea unresponsive to treatment, opportunistic infections, peripheral lymph node atrophy, and abnormal hematology. Plasma viremia was quantified by branched DNA analysis (Siemens Medical Solutions Diagnostic Clinical Laboratory, Emeryville, CA), and absolute CD4+ and CD8+ cell counts were monitored in TruCount tubes (BD Biosciences, Palo Alto, CA). The percentages of CD4+ T cells in the tissue cells were analyzed by flow cytometry (FACScalibur) using CD3–fluorescein isothiocyanate, CD4–phycoerythrin, and CD8–peridinin chlorophyll protein antibodies. Except for CD3–fluorescein isothiocyanate (BioSource, Camarillo, CA), all antibodies were obtained from BD Biosciences. Comparative data from Indian-origin rhesus monkeys were obtained from other pathogenesis studies, in which the animals received the same virus inoculum dose.21 The cohort of Indian female rhesus monkeys used was similarly randomized with respect to the menstrual cycle.
Plasma virus loads were transformed to log10 copies per milliliter before all analyses. Peak viral load was the highest recorded value (2–4 wpi), and baseline CD4+ T-cell count was measured at preinfection. Plateau (set point) viremia and CD4+ T-cell counts were calculated as the median of all values between days 56 and 168 postinfection, with differences examined using Mann–Whitney U tests. Changes in the percentage of tissue CD4+ T lymphocytes over time were also determined using Mann–Whitney U tests. Disease-free survival curves for the ir- and ivg-infected macaques were estimated using the Kaplan–Meier method, and statistical significance of the differences in the survival curves was determined by log-rank test. A P value less than 0.05 was considered statistically significant.
Efficient Mucosal Transmission of R5 SHIVSF162P3N in Chinese RMs
To determine mucosal transmissibility and pathogenicity of R5 SHIVSF162P3N in the RMs of Chinese origin, we inoculated 6 males ir and 6 females ivg with 10,000 50% tissue culture infectious dose virus. All animals in the ir- and ivg-inoculated groups became infected, with seroconversion at 4–5 wpi. Peak viremia of 6–8 log10 RNA copies per milliliter plasma was detected in both the ir- and ivg-infected macaques (Figs. 1A, B), with no significant difference in magnitude between the 2 groups (Fig. 1C). The kinetics of virus spread was also comparable among the 2 inoculation groups, with plasma viremia detected at 1 wpi in 6 of 6 ir- and 4 of 6 ivg-infected RMs, reaching the peak 1 week later in all except GL26, an ir-inoculated animal that peaked at 3 wpi (Fig. 1D). Viral load subsequently declined, with greater control in the ivg- than the ir-infected macaques. Virus replication reached undetectable levels (<165 RNA copies per milliliter plasma) in all the 6 ivg-infected Chinese RMs between 8 and 16 wpi, with partial rebound to <4 log10 RNA copies per milliliter plasma in 3 of the 6 animals. In comparison, only 1 ir-infected Chinese RM (FV03) suppressed plasma viremia below the level of detection. Accordingly, viral set point was significantly higher in the ir- than the ivg-infected Chinese-origin RMs (Fig. 1C, P = 0.015). The difference in viral control between the 2 inoculation groups suggests a route-dependent effect on SHIVSF162P3N replication in Chinese RMs and is consistent with our previous findings of route dependency in infection outcome of Indian-origin rhesus monkeys with this virus.21
All the infected animals experienced transient peripheral CD4+ T-cell loss with the onset of viremia. The absolute number of this T-cell subset decreased by approximately 15% during the first 2 weeks of infection in the ir-infected animals (from a median baseline value of 1037 at day 0 to 877 CD4+ cells per microliter blood) and by approximately 30% in the ivg-infected monkeys (from a median baseline value of 1409 at day 0 to 998 CD4+ cells per microliter blood) (Figs. 1A, B). Peripheral CD4+ T-cell count stabilized or fluctuated thereafter in 6 of the 6 ivg- and 3 of the 6 ir-infected animals. The exceptions were the ir-infected rhesus GL26, GB30, and GP22 where a gradual decline in CD4+ T lymphocytes was seen despite a viral load that is <104 RNA copies per milliliter plasma in the latter 2 animals. We concluded therefore that R5 SHIVSF162P3N transmits efficiently across mucosal surfaces in Chinese RMs, but infection is frequently controlled. Because the level of set point viremia is a strong predictor for disease progression in HIV-1–infected humans and SIV-infected Indian RMs,35,36 the 2 ir-infected Chinese macaques with sustained viremia >104 RNA copies per milliliter plasma for over 40 weeks of infection (GL26 and GB40) were followed for AIDS development.
Disease Progression in ir-Infected Chinese RM
GB40 was euthanized at 97 wpi for AIDS-unrelated causes. Viral load in this animal at the time of euthanasia was ∼3 log10 copies per milliliter plasma, with a peripheral CD4+ T-cell count of 578 cells per microliter blood. In contrast, GL26 developed clinical symptoms consistent with AIDS, including chronic diarrhea and weight loss, and was euthanized at 99 wpi with a CD4+ T-cell count of 226 cells per microliter blood. Histological examination revealed secondary and mycobacterial (Mycobacterim avium) infection. Peak viremia in this macaque reached 6–7 log10 RNA copies per milliliter plasma but dropped ∼2 log thereafter, reaching a plateau of 4–5 log10 RNA copies per milliliter (Fig. 1E). A rise in viremia to a near peak plasma viral load level, however, was seen toward end-stage disease. Examination of the mucosal and lymph node CD4+ T cells during the course of infection showed severe acute depletion of the gut CD4+ T cells (90%; 2 wpi), with minimal loss in the lymph node compartments. Gut CD4+ T-cell loss was sustained during chronic infection (17 wpi) and at the time of necropsy (99 wpi), with ∼50% preservation of this lymphocyte subset in the lymph node compartments at end-stage disease. R5 SHIVSF162P3N, therefore, can induce AIDS in Chinese-origin rhesus in a manner similar to HIV-1 infection in humans.
R5 SHIVSF162P3N Infection Is Attenuated in Mucosally Infected Chinese RMs in Comparison with Indian RMs
SIV infection in Chinese RMs had been reported to be more attenuated compared with RMs of Indian origin.27–31 Because an objective of this study is to assess the utility of R5 SHIVSF162P3N infection of Chinese-origin RMs in studies of HIV-1 transmission and pathogenesis, we compared the virologic and immunologic parameters in ir- and ivg-infected Chinese RMs with those observed previously in Indian RMs.21 We found that the peak viremia was of similar magnitude in the Chinese (n = 6) and Indian (n = 11) ir-infected RMs (Figs. 2A, B, P > 0.05). However, although a range in set point viremia was seen in both the subspecies hosts, the median steady state viremia was significantly lower in the Chinese rhesus than in the Indian-origin monkeys (Fig. 2B, P = 0.0075). This result is consistent with findings with SIV that the differences between the subspecies appear in the chronic phase.
There was no significant difference in baseline peripheral CD4+ T-cell counts between the Chinese- and the Indian-origin ir-infected animals (P > 0.05), but the Indian-origin ir-infected RMs displayed greater loss of peripheral CD4+ T cells during acute infection than the Chinese-origin ir-inoculated monkeys (Fig. 2A). The Indian ir-infected animals suffered a 33% drop in median peripheral CD4+ T-cell count (from 635 to 427 CD4+ cells per microliter blood at 2 wpi), whereas the ir-infected Chinese rhesus only lost 15% of this lymphocyte subset (from 1037 to 877 CD4+ cells per microliter blood) at the corresponding time postinfection. The peripheral CD4+ T-cell loss of the 2 subspecies remained divergent during the chronic phase of infection, consistent with the differences in viral load. CD4+ T lymphocyte count declined steadily in the ir-infected Indian but varied widely among the ir-infected Chinese RMs. Severe depletion of CD4+ T lymphocytes in the LP of the gut occurred in both the Indian- and Chinese-origin ir-infected RMs (Fig. 2B). However, the dynamics of this loss varied between the 2 macaque subspecies. CD4+ T cells constituted less than 10% of total gut CD3+ T lymphocytes in the ir-infected Chinese RMs as compared with 20% in the ir-infected Indian RMs at 2 wpi, despite similar peak viremia. Accordingly, the depletion of CD4+ T lymphocytes in the LP was highly significant during peak viremia (P = 0.0009) in the Chinese and only approached significance in the Indian RMs (P = 0.062). Further analysis of the percentage of CD4+ T lymphocytes in the LP during the chronic phase of infection (12–18 wpi) revealed continued diminution of CD4+ T cells in the Indian RMs, resulting in a loss that is now significant. The percentage of CD4+ T lymphocytes in the LP of the Chinese ir-infected RMs rose during the chronic phase, suggestive of gut CD4+ T-cell reconstitution,37 but is still significantly lower than the uninfected controls.
As in the ir-inoculated RMs, peak viremia was of similar magnitude in the Chinese- (n = 6) and Indian (n = 8)-origin RMs exposed ivg to the same inoculum dose (Fig. 3A, P > 0.05). But whereas a greater range in set point plasma viral load was found among the Indian-origin ivg-infected animals, the median set point viremia in this subspecies host was significantly higher compared with animals of Chinese origin (Fig. 3B, P = 0.02). The subspecies difference in SHIVSF162P3N chronic phase viremia therefore is route independent. With the onset of viremia, peripheral CD4+ T counts declined substantially in both the Indian- and Chinese-origin ivg-inoculated RMs (Fig. 3A). The median peripheral CD4+ T-cell count dropped by 30% in the ivg-infected Chinese RMs (from 1409 to 998 CD4+ cells per microliter blood) and by 47% in the ivg-infected Indian rhesus monkeys (from 1097 to 576 CD4+ cells per microliter blood) during peak viremia. However, 5 of the 6 ivg-infected Chinese RMs were able to recover their blood CD4+ T-cell loss postpeak, whereas only 4 of 8 ivg-inoculated Indian RMs showed a rebound in peripheral CD4+ T-cell levels. Unlike the ir-infected RMs, both macaque subspecies infected by the ivg route experienced only moderate gut CD4+ T-cell loss during acute infection (30%–40%; Fig. 3B), and only during the chronic phase (12–18 wpi) did the percentages of CD4+ T cells plummet, with more severe depletion in the Indian (>90%) than the Chinese origin RMs (>75%).
R5 SHIVSF162P3N Is Minimally Pathogenic in Chinese Rhesus Monkeys
Ten of the 11 ir-infected Indian-origin RMs (91%) progressed to disease over a 1- to 1.5-year infection period as compared with 1 of 6 ir-infected Chinese RMs (16.7%), with an RP phenotype in 4 of the 11 ir-infected Indian RMs (36.4%) and none of the ir-infected macaques of Chinese origin (Table 1). Kaplan–Meier analysis of disease progression showed statistically significant difference in the rate of disease progression between the 2 macaque subspecies (Fig. 4A, P = 0.0009; log-rank test). The percentage of animals AIDS free at 60 wpi was 27.3% for the ir-infected Indian-origin macaques and 100% for the ir-infected macaques of Chinese origin. In comparison, there was no statistically significant difference in the rate of disease progression between the ivg-infected Chinese and Indian RMs (P > 0.05), with 75% and 100% of animals AIDS free at 40 wpi in the ivg-infected Indian- and Chinese-origin rhesus, respectively. However, whereas all the 6 Chinese-origin RMs were infected after a single high-dose ivg exposure, only 8 of the 12 Indian RMs challenged ivg with the same inoculum dose established systemic infection (Table 1). Furthermore, the observation that the kinetics of early virus spread in the ivg- and ir-infected Chinese RMs was similar (Fig. 1D) contrasts with our findings with this virus in the Indian RMs,21 prompting us to compare early SHIVSF162P3N dissemination in the 2 subspecies hosts. We found that the time to peak viremia overlapped in the ir-infected Indian and Chinese RMs but varied by geographic origin for the ivg-infected animals (Fig. 4B). Peak virema was week 2 in all 6 ivg-infected Chinese rhesus, but it took 3–4 weeks to reach peak viremia in 2 of the 8 ivg-infected Indian-origin macaques, with one showing no evidence of systemic infection until 3 wpi. These results of ivg inoculation suggest that the Chinese-origin monkeys may be more susceptible to SHIVSF162P3N vaginal infection than Indian-origin animals.
In developing AIDS models of HIV-1 infection using different nonhuman primate species or RMs of different geographic origin with SIVs or SHIVs, it is important to understand the characteristics of infection with each virus in the various animal hosts to guide the rational design and optimal use of the models. In this study, we established that R5 SHIVSF162P3N transmits efficiently across the rectal and vaginal/cervical mucosa of Chinese-origin RMs, modeling the type of transmission route in the majority of HIV-1 patients. This model therefore allows for studies of viral selection through mucosal transmission and evaluation of the effectiveness of vaccines and pharmacological agents to block virus acquisition. However, a large number of the SHIVSF162P3N ir- and ivg-infected Chinese-origin animals controlled their infection, with undetectable plasma viremia found more frequently in the ivg- than the ir-infected animals, and AIDS development in only 1 of the 6 ir-infected Chinese rhesus after 99 weeks of infection. The variability in chronic viremia and limited pathogenicity of SHIVSF162P3N in Chinese-origin rhesus may restrict the utility of this model in understanding the mechanisms of HIV-1 disease development, in dissecting cellular and humoral immune responses over the course of infection from the time of inoculation to the development of fatal immunodeficiency, and in evaluating vaccines and antiretrovirals that aim at reducing viral loads postinfection and delaying AIDS progression.
Consistent with reports with SIV,27–31 peak viremia was similar but viral load postinfection was lower and survival was longer in the SHIVSF162P3N-infected Chinese RMs compared with Indian-origin macaques. The lack of a rapid progressor phenotype and sustained peripheral CD4+ T-cell levels in the infected Chinese-origin monkeys provided further evidence that the clinical course of SHIVSF162P3N infection differs in the 3 macaque subspecies. Several hypotheses have been proposed to explain the divergent outcome of SIV/SHIV chronic infection in RMs of Chinese and Indian origin. It has been suggested that because the inoculating virus was passaged and recovered from Indian RMs, it is better adapted and replicate more successfully in the Indian RM immune environment than in the "foreign" Chinese RM immune milieu.28,30 SHIVSF162P3N was also passaged and recovered from the Indian RMs, providing a plausible explanation for the differences in pathogenesis we observed between the 2 macaque subpopulations. Genetic differences including factors governing CCR5 expression, cellular molecules that restrict viral replication, and adaptive immunity could also affect the biological consequences of viral infections in the 2 monkey subspecies.34,38–40 The animals used in this study were genotyped for TRIM5α, with results showing that genetic polymorphism at this locus cannot explain the difference in R5 SHIVSF162P3N infection of Indian and Chinese RMs. Among the Chinese-origin macaques used in the current study, 33.3% of the males (2 of 6) and females (2 of 6) expressed restrictive homozygous TFP/TFP allele compared with 72.2% of the male (8 of 11) and 37.5% of the female (3 of 8) Indian rhesus monkeys (data not shown). CD8 T-cell–mediated immunity has been suggested to play a role in the spontaneous control of chronic viremia in Chinese-origin rhesus.37 Very little is known about the degree to which class 1 alleles in the Chinese rhesus population confer protection for SIV/SHIV challenges. Recent advances in identifying major histocompatibility complex alleles for Chinese-origin macaques41–45 will be important for studying cellular immunology in this monkey subpopulation and its impact on SIV/SHIV replication.
All 6 Chinese-origin macaques not treated with progesterone were infected with one high-dose SHIVSF162P3N ivg challenge, a rate of infection that is similar to that achieved after ir inoculation (Figs. 1A, B). This finding contrasts early studies in Indian RMs using nonphysiological high doses of SIVs and SHIVs, including SHIVSF162P3N, showing that the infection rate was lower after inoculation by the ivg than by ir route.21,46–50 Moreover, the kinetics of early virus spread was similar in Chinese RMs infected by the ir and ivg routes (Fig. 1D), differing from observations of slower kinetics of virus dissemination and greater variability in RNA levels in Indian-origin monkeys infected by the ivg route than those infected by the ir route.48,51,52 Baseline peripheral CD4+ T-cell counts were significantly higher in the ivg-inoculated Chinese RMs than the Indian RMs (P = 0.0080). If this observation in peripheral blood translates into the genital mucosa, the greater number of CD4+ T cells and targets could provide a possible explanation for the successful ivg transmission and rapid spread of virus in the Chinese-origin animals. Alternatively, and because the differences in the rate of infection and kinetics of early dissemination in the 2 macaque subspecies were only seen with ivg and not ir inoculation, differential host response to exposure at the genital mucosa with an Indian RM-adapted virus may have favored vaginal transmissibility and the initial wave of viral replication in the Chinese RMs. Studies in a larger number of animals will be required to confirm and understand the differences in SHIVSF162P3N vaginal transmission in Chinese and Indian RMs.
In summary, our findings with R5 SHIVSF162P3N in Chinese- and Indian-origin RMs further illustrate that the subspecies differences in pathogenicity after SIV/SHIV infection is independent of the route of inoculation and the virus strain used. The ease of mucosal transmission with SHIVSF162P3N in Chinese RMs suggests that this model will be suitable for prevention, early host events, and kinetics of virus replication studies. In particular, it will be of interest to determine if transmission of different viral variants and/or local host responses influenced the observed subspecies differences in SHIVSF162P3N genital mucosal infection. However, the finding that a significant fraction of the SHIVSF162P3N-infected Chinese-origin animals, especially those infected ivg, controlled virus replication to levels that are intermittent or below conventional detection highlights the limitation of this model for vaccine and therapeutic trials aimed at reducing set point viremia and HIV-1 disease progression.
The authors thank Wendy Chen for help with the graphics.
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Keywords:© 2013 Lippincott Williams & Wilkins, Inc.
SHIV; rhesus macaque subspecies; mucosal transmission; AIDS