A recombinant vaccine containing Aventis Pasteur’s canarypox vector (ALVAC)–HIV and gp120 alum decreased the risk of HIV acquisition in the RV144 vaccine trial. The substitution of alum with the more immunogenic MF59 adjuvant is under consideration for the next efficacy human trial. We found here that an ALVAC–simian immunodeficiency virus (SIV) and gp120 alum (ALVAC–SIV + gp120) equivalent vaccine, but not an ALVAC–SIV + gp120 MF59 vaccine, was efficacious in delaying the onset of SIVmac251 in rhesus macaques, despite the higher immunogenicity of the latter adjuvant. Vaccine efficacy was associated with alum-induced, but not with MF59-induced, envelope (Env)-dependent mucosal innate lymphoid cells (ILCs) that produce interleukin (IL)-17, as well as with mucosal IgG to the gp120 variable region 2 (V2) and the expression of 12 genes, ten of which are part of the RAS pathway. The association between RAS activation and vaccine efficacy was also observed in an independent efficacious SIV-vaccine approach. Whether RAS activation, mucosal ILCs and antibodies to V2 are also important hallmarks of HIV-vaccine efficacy in humans will require further studies.

T follicular regulatory cells (TFR) are a suppressive CD4+ T cell subset that migrates to germinal centers (GC) during antigen presentation by up-regulating the chemokine receptor CXCR5. In the GC, TFR control T follicular helper cells (TFH) expansion and modulate the development of high-affinity antigen specific responses. Here we identified and characterized TFR as CXCR5+ CCR7−-“follicular” T regulatory cells (TREG) in lymphoid tissues of healthy rhesus macaques, and we studied their dynamic throughout infection in a well-defined animal model of HIV pathogenesis. TFR were infected by SIVmac251 and had comparable levels of SIV-DNA to CXCR5− CCR7+-“T-zone” TREG and TFH. Contrary to the SIV-associated TFH expansion in the chronic phase of infection, we observed an apparent reduction of TFR frequency in cell suspension, as well as a decrease of CD3+ Foxp3+ cells in the GC of intact lymph nodes. TFR frequency was inversely associated with the percentage of TFH and, interestingly, with the avidity of the antibodies that recognize the SIV-gp120 envelope protein. Our findings show changes in the TFH/TFR ratio during chronic infection and suggest possible mechanisms for the unchecked expansion of TFH cells in HIV/SIV infection.

TRIM5␣ is a natural resistance factor that binds retroviral capsid proteins and restricts virus replication. The B30.2/SPRY domain of TRIM5␣ is polymorphic in rhesus macaques, and some alleles are associated with reduced simian immunodeficiency virus (SIV) SIV mac251 and SIV smE543 replication in vivo. We determined the distribution of TRIM5␣ alleles by PCR and sequence analysis of the B30.2/SPRY domain in a cohort of 82 macaques. Thirty-nine of these macaques were mock vaccinated, 43 were vaccinated with either DNA-SIV/ ALVAC-SIV/gp120, ALVAC-SIV/gp120, or gp120 alone, and all were exposed intrarectally to SIV mac251 at one of three doses. We assessed whether the TRIM5␣ genotype of the macaques affected the replication of challenge virus by studying the number of SIV variants transmitted, the number of exposures required, the SIV mac251 viral level in plasma and tissue, and the CD4 ؉ T-cell counts. Our results demonstrated that TRIM5␣ alleles, previously identified as restrictive for SIV mac251 replication in vivo following intravenous exposure, did not affect SIV mac251 replication following mucosal exposure, regardless of prior vaccination, challenge dose, or the presence of the protective major histocompatibility complex alleles (MamuA01 ؉ , MamuB08 ؉ , or MamuB017 ؉ ). The TRIM5␣ genotype had no apparent effect on the number of transmitted variants or the number of challenge exposures necessary to infect the animals. DNA sequencing of the SIV mac251 Gag gene of the two stocks used in our study revealed SIV mac239 -like sequences that are predicted to be resistant to TRIM5␣ restriction. Thus, the TRIM5␣ genotype does not confound results of mucosal infection of rhesus macaques with SIV mac251 .The simian immunodeficiency virus (SIV) SIV mac251 macaque model is widely used to evaluate the relative efficacy of human immunodeficiency virus (HIV) vaccine candidates in macaques. Thus, understanding the natural factors that confer resistance to SIV mac251 replication in rhesus macaques is important in order to minimize the overestimation of vaccine efficacy. HIV-1 does not infect macaques, and the restriction of HIV replication in Old World monkeys occurs at the postentry level (6,22,29) and is mediated, in part, by the interaction of TRIM5␣ and the viral capsid protein (10, 23). TRIM5␣ is an interferon-inducible gene that is conserved across species and encodes a cytoplasmic (4, 5) protein. Species-specific TRIM5␣ polymorphisms (22) that affect the efficiency of SIV replication in vitro and in vivo have been characterized in rhesus macaques (30). TRIM5␣ antiretroviral activity is mediated by the RING domain, which through its E3 ubiquitin ligase activity, polyubiquitinates TRIM5␣ itself. The polyubiquitinated TRIM5␣ binds to the viral capsid protein via the B30.2 (SPRY) domain, and the protein complex is degraded by the proteasome (7, 27). However, the disruption of the RING domain, the modulation of the expression of E1 ubiquitin-activating enzyme, or the inhibition of the proteasome activity only partially affe...

In the version of this article initially published online, an affiliation for Luca Schifanella was omitted and there was an error in the description of the phenotypic analyses of plasmablasts in the Online Methods. The error has been corrected for the print, PDF and HTML versions of this article.