In an effort to identify other sources of macaques that may serve as useful animal models for AIDS vaccine studies, we characterized the course of infection of SIVmac251 and SHIV-89.6P in cynomolgus and Chinese rhesus macaques. When compared to Indian rhesus macaques, the pathogenicity of both viruses was moderately attenuated in Chinese rhesus macaques and markedly attenuated in cynomolgus macaques. Manifestations of attenuated pathogenicity included lower levels of plasma viremia, preservation of CD4+
T-cell number, preservation of both cellular and humoral immune responses, and increased survival time. We note, however, that cynomolgus macaques used in our study were of Mauritian origin. The pathogenicity of these viruses may differ in cynomolgus macaques from different Asian locations. However, the consequences of lentiviral infection we report in Chinese rhesus macaques and Mauritian cynomolgus macaques are in agreement with those reported in other studies of Chinese rhesus macaques and cynomolgus macaques that evaluated different viruses or employed other measures of pathogenicity (7
No existing nonhuman primate AIDS model is ideal for testing the efficacy of candidate HIV vaccines. Marked antigenic differences exist between the envelope glycoproteins of the SIVs and HIV-1. Infection of Indian-origin rhesus macaques with most SIVs also results in levels of plasma virus well above those seen in HIV-1 infection of humans. Alternatively, chimeric SHIVs share envelope composition with HIV-1. Infection with some SHIVs also results in an acute CD4 T lymphocytopenia that can serve as an additional experimental endpoint not available in SIV models. However, for some SHIVs such as SHIV-89.6P, the coreceptor usage and acute pathogenicity also differs from that seen in natural HIV-1 infection. Thus, infection of macaques with these chimeric viruses has also been criticized as a suboptimal model for AIDS vaccine testing (4
Our results and those previously reported by others clearly indicate that the alternate nonhuman primate models such as cynomolgus or Chinese rhesus macaques macaque infected with SIV develop plasma virus levels and an attenuated disease course that approximates those seen in HIV infection (10
). However, it is crucial that the nonhuman primate models used to evaluate vaccine efficacy provide experimental endpoints, such as plasma virus level or changes in CD4+
T-cell number, that have sufficient power to detect differences in vaccine effect while utilizing reasonable group sizes. It is readily apparent, based on the present data, that vaccine challenge studies utilizing cynomolgus macaques are not feasible since a large fraction of animals naturally control SIV or SHIV replication to levels that are below conventional detection; such studies would need to be very large to have reasonable power to detect a treatment-induced effect. Chinese rhesus macaques may be somewhat more useful in this regard. Although levels of plasma virus were lower than those seen in Indian rhesus macaques, SIV and SHIV viremia remained detectable in most animals.
Of particular interest in this study was the rapid and strong gamma interferon ELISPOT responses observed after both SHIV and SIV inoculation of cynomolgus macaques. These early virus-specific cellular immune occurred well before the generation of neutralizing antibodies, consistent with the hypothesis that attenuation of pathogenicity was due to immune control of virus replication mediated by T cells. If this relationship is causal, the present observation provides further evidence for the importance of the control of primary viremia as a determining factor in disease course.
Alternatively, SIV and SHIV may have inherently low replication rates in the lymphocytes and macrophages of cynomolgus macaques due to virus-host interactions unrelated to the immune responses induced by viral infection. Thus, viral dynamics in cynomolgus macaques may have resulted in reduced virally induced cytopathicity giving rise to better preservation of immune responses and, ultimately, an attenuation of disease course compared to that seen in Indian rhesus macaques. Indeed, there is evidence that pathogenicity of other viral, bacterial, and parasitic microbes is also attenuated in cynomolgus macaques (5
However, three observations support a role for early T-cell immune responses in the attenuation of viral pathogenicity in cynomolgus macaques. First, attenuation of disease was observed after infection with both SIV and SHIV—viruses that infect different CD4+
T-cell subsets (15
). Second, the early and strong ELISPOT responses also occurred in cynomolgus macaques infected with either SIV or SHIV. Finally, the trend toward a negative correlation between the magnitude of the cellular immune response and level of viremia 2 weeks postinoculation seen in cynomolgus macaques infected with either virus suggests that the reduction in virus replication may have resulted from the early cellular immune response.
Both SIVmac251 and SHIV-89.6P viruses used in these studies were either isolated from or propagated by serial in vivo passage in rhesus macaques of Indian origin (2
). Propagation or serial passage of viral stocks in Indian rhesus macaques may have resulted in the selection of viral variants adapted for more efficient replication and/or enhanced pathogenicity these animals compared to other cynomolgus or Chinese rhesus macaques. Indeed, not all chimeric SHIVs show such a large variation in pathogenicity when inoculated into different macaque species as we observed in this study (3
). Therefore, serial in vivo passage of these two viruses in cynomolgus or Chinese rhesus macaques might result in virus isolates that replicate to higher levels and are more pathogenic in macaques of this species or geographic origin.
While these studies do not definitively elucidate the mechanism responsible for SIV and SHIV attenuation in cynomolgus and Chinese rhesus macaques, they do provide further evidence that therapeutic interventions or vaccination aimed at limiting lentivirus replication during primary infection have the potential to modulate disease progression later in the course of infection. Understanding the limitations of each nonhuman primate AIDS model is essential for the rational and efficient design of vaccine challenge studies.