Repeated Low-Dose Mucosal Simian Immunodeficiency Virus SIVmac239 Challenge Results in the Same Viral and Immunological Kinetics as High-Dose Challenge: a Model for the Evaluation of Vaccine Efficacy in Nonhuman Primates

Simian immunodeficiency virus (SIV) challenge of rhesus macaques provides a relevant model for the assessment of human immunodeficiency virus (HIV) vaccine strategies. To ensure that all macaques become infected, the vaccinees and controls are exposed to large doses of pathogenic SIV. These nonphysiological high-dose challenges may adversely affect vaccine evaluation by overwhelming potentially efficacious vaccine responses. To determine whether a more physiologically relevant low-dose challenge can initiate infection and cause disease in Indian rhesus macaques, we used a repeated low-dose challenge strategy designed to reduce the viral inoculum to more physiologically relevant doses. In an attempt to more closely mimic challenge with HIV, we administered repeated mucosal challenges with 30, 300, and 3,000 50% tissue culture infective doses (TCID(50)) of pathogenic SIVmac239 to six animals in three groups. Infection was assessed by sensitive quantitative reverse transcription-PCR and was achieved following a mean of 8, 5.5, and 1 challenge(s) in the 30, 300, and 3,000 TCID(50) groups, respectively. Mortality, humoral immune responses, and peak plasma viral kinetics were similar in five of six animals, regardless of challenge dose. Interestingly, macaques challenged with lower doses of SIVmac239 developed broad T-cell immune responses as assessed by ELISPOT assay. This low-dose repeated challenge may be a valuable tool in the evaluation of potential vaccine regimes and offers a more physiologically relevant regimen for pathogenic SIVmac239 challenge experiments

Rapid and slow progressors differ by a single MHC class I haplotype in a family of MHC-defined rhesus macaques infected with SIV

Highly polymorphic HLA class I molecules may influence rates of disease progression of HIV-infected individuals. Recent evidence suggests that individuals who mount vigorous CTL responses to multiple HIV-1 epitopes have reduced viral loads, and survive longer than individuals that make a less robust or less diverse CTL response. It has been difficult, however, to define associations between particular HLA class I alleles and rates of disease progression. This may be due, in part, to the uncontrolled variables associated with naturally acquired HIV infections. Studies using MHC-defined, non-human primates infected with well characterized viral stocks should help to clarify this relationship. To explore the possibility that MHC class I polymorphism can influence disease progression, we infected four Mamu-DRB-identical individuals from a family of MHC-defined rhesus macaques intravenously with 40 TCID 50SIV mac239. Two of these macaques developed severe wasting and were euthanized within 80 days of infection, while the other two survived for more than 400 days without showing any symptoms of disease. Since all four of these macaques were Mamu-DRB-identical, we were able to exclude the MHC class II DRB loci as determinant of disease progression. Interestingly, both of the slow progressors made CTL responses to the same three SIV CTL epitopes, which were restricted by two molecules (Mamu-B*03 and B*04) encoded by their common maternal haplotype. The two rapid progressors did not share this haplotype with the slow progressors, and we were unable to detect CTL responses in these two siblings. These observations implicate products of the Mamu-B*03 and B*04 alleles in resistance to disease progression in this family of SIV-infected macaques, and provide additional evidence that certain MHC class I-restricted CTL responses may play a significant role in delaying the onset of AIDS