Impact of Viral Dose and Major Histocompatibility Complex Class IB Haplotype on Viral Outcome in Mauritian Cynomolgus Monkeys Vaccinated with Tat upon Challenge with Simian/Human Immunodeficiency Virus SHIV89.6P

Abstract

The effects of the challenge dose and major histocompatibility complex (MHC) class IB alleles were analyzed in 112 Mauritian cynomolgus monkeys vaccinated (n ‫؍‬ 67) or not vaccinated (n ‫؍‬ 45) with Tat and challenged with simian/human immunodeficiency virus (SHIV) 89.6P cy243. In the controls, the challenge dose (10 to 20 50% monkey infectious doses [MID 50 ]) or MHC did not affect susceptibility to infection, peak viral load, or acute CD4 T-cell loss, whereas in the chronic phase of infection, the H1 haplotype correlated with a high viral load (P ‫؍‬ 0.0280) and CD4 loss (P ‫؍‬ 0.0343). Vaccination reduced the rate of infection acquisition at 10 MID 50 (P < 0.0001), and contained acute CD4 loss at 15 MID 50 (P ‫؍‬ 0.0099). Haplotypes H2 and H6 were correlated with increased susceptibility (P ‫؍‬ 0.0199) and resistance (P ‫؍‬ 0.0087) to infection, respectively. Vaccination also contained CD4 depletion (P ‫؍‬ 0.0391) during chronic infection, independently of the challenge dose or haplotype.Advances in typing of the major histocompatibility complex (MHC) of Mauritian cynomolgus macaques (14,20,26) have provided the opportunity to address the influence of host factors on vaccine studies (13). Retrospective analysis of 22 macaques vaccinated with Tat or a Tat-expressing adenoviral vector revealed that monkeys with the H6 or H3 MHC class IB haplotype were overrepresented among aviremic or controller animals, whereas macaques with the H2 or H5 haplotype clustered in the noncontrollers (12). More recently, the H6 haplotype was reported to correlate with control of chronic infection with simian immunodeficiency virus (SIV) mac251, regardless of vaccination (18).Here, we performed a retrospective analysis of 112 Mauritian cynomolgus macaques, which included the 22 animals studied previously (12), to evaluate the impact of the challenge dose and class IB haplotype on the acquisition and severity of simian/human immunodeficiency virus (SHIV) 89.6P cy243 infection in 45 control monkeys and 67 monkeys vaccinated with Tat from different protocols (Table 1).Study description. All animals were challenged intravenously with 10 (n ϭ 29), 15 (n ϭ 68), or 20 (n ϭ 15) monkey infectious doses (MID 50 ) of SHIV86.6P cy243 derived from a cynomolgus macaque inoculated with the original SHIV89.6P stock from rhesus monkeys (3, 5) ( Table 1). The SIV RNA load in plasma and CD4 T-cell counts were determined as described previously (23).MHC allele predictions were generated on the basis of the microsatellite profiles (26), with the alleles for class I and class II regions being inferred on the basis of established haplotypeallele associations (20,26). As shown in Fig. 1A, the distribution of the seven major haplotypes (haplotypes H1 to H7) in vaccinated and control animals was balanced. Due to the presence of the H7 haplotype in only 3 out of 112 monkeys, it was excluded from the analyses.As the factors investigated in this study may affect susceptibility to acute (1 to 4 weeks) or chronic (16 to 52 weeks) infection differently, these wer...

Variable Prevalence and Functional Diversity of the Antiretroviral Restriction Factor TRIMCyp in Macaca fascicularis

“…Although data from our phylogenetic analysis are consistent with this finding, we were not able to resolve the relationships among TRIMCyp-negative M. fascicularis macaques due to the limited sequence data available. Because of the low genetic diversity in the Mauritian M. fascicularis population, these animals are of particular interest as an AIDS model (4,9,19,38). The finding that these animals uniformly lack TRIMCyp, which could be a confounding factor in infection studies, indicates the potential for additional advantages of working with this model.…”

Development of a novel AIDS vaccine: the HIV-1 transactivator of transcription protein vaccine

“…Overall, the results obtained with the Tat vaccine in monkeys and in humans indicate that Tat is critical in HIV-1 life cycle, as, when targeted either during natural infection or upon vaccination, it contains viral replication with no/low progression, whereas in vaccinated macaques protection appears to confine the virus at the portal of entry (Figure 3) [58] or grant sterilizing immunity [77,82]. Of note, data from the T-002 therapeutic trial indicate that targeting Tat in successfully cART-treated individuals reduces immune activation, as indicated by the homeostatic recovery and balancing of all lymphocyte populations and functional subsets, which we interpret as an immunological 'reset and restart', conceivably occurring upon removal of extracellular Tat from tissues.…”

“…Of importance, vaccination also contained CD4 + T-cell depletion (p = 0.0391) during chronic infection, irrespective of the challenge dose [82].…”

Paradigm Changes and the Future of HIV Vaccine Research: A Summary of a Workshop Held in Baltimore on 20 November 2013

“…Anti-Tat Abs, which are infrequently produced upon natural infection, are able to restore and increase HIV neutralization that would normally be impaired by extracellular Tat [24]. Since vaccination with Tat decreases the proviral DNA load (Ensoli et al submitted), slows down the progression to AIDS and can lead to complete or partial protection from infection [19,[24][25][26], the accumulated evidence supports a novel paradigm that views HIV-1 Tat as an important vaccine candidate either on its own or as part of a multicomponent vaccine [19,[24][25][26].…”