Profound early control of highly pathogenic SIV by an effector memory T-cell vaccine

Abstract

The AIDS-causing lentiviruses HIV and SIV effectively evade host immunity, and once established, infections with these viruses are only rarely controlled by immunologic mechanisms1-3. However, the initial establishment of infection in the first few days after mucosal exposure, prior to viral dissemination and massive replication, may be more vulnerable to immune control4. Here, we report that SIV vaccines that include rhesus cytomegalovirus (RhCMV) vectors5 establish indefinitely persistent, high frequency, SIV-specific effector-memory T cell (TEM) responses at potential sites of SIV replication in rhesus macaques (RM) and stringently control highly pathogenic SIVmac239 infection early after mucosal challenge. Thirteen of 24 RM receiving either RhCMV vectors alone or RhCMV vectors followed by adenovirus 5 (Ad5) vectors (vs. 0 of 9 DNA/Ad5-vaccinated RM) manifested early complete control of SIV (undetectable plasma virus), and in 12/13 of these RM, we observed long-term (≥1 year) protection characterized by: 1) occasional blips of plasma viremia that ultimately waned; 2) predominantly undetectable cell-associated viral load in blood and lymph node mononuclear cells; 3) no depletion of effector site CD4+ memory T cells; 4) no induction or boosting of SIVenv-specific antibodies (Abs); and 5) induction and then loss of T cell responses to an SIV protein (vif) not included in the RhCMV vectors. Protection correlated with the magnitude of the peak SIV-specific CD8+ T cell responses in the vaccine phase, and occurred without anamnestic T cell responses. Remarkably, long-term RhCMV vector-associated SIV control was insensitive to either CD8+ or CD4+ lymphocyte depletion, and at necropsy, cell-associated SIV was only occasionally measurable at the limit of detection with ultrasensitive assays, observations suggesting the possibility of eventual viral clearance. Thus, persistent vectors such as CMV and their associated TEM responses might significantly contribute to an efficacious HIV/AIDS vaccine.

The (gradual) rise of memory inflation

“…These fit well with the slightly updated version of the definition included in this review. For the rhesus macaque‐based cytomegaloviruses, there are a series of additional modifications regarding immune evasion and, interestingly, cellular targeting which can have quite profound impacts on the specificities observed, some of which are unconventional (eg, HLA‐E restricted) and can have potentially potent antiviral properties 86, 87, 88. Overall—even in settings where more conventional CD8 + T‐cell responses are induced—there is evidence that these responses can provide protection against viruses and cancers 2, 43.…”

Gag and env conserved element CE DNA vaccines elicit broad cytotoxic T cell responses targeting subdominant epitopes of HIV and SIV Able to recognize virus-infected cells in macaques

“…The inability of Gag-specific T cells alone to control virus acquisition has been shown in other studies. 88–91 Martins et al 88 reported that vaccine regimens that did not contain Gag, or Env or a combination of both were largely inefficient in reducing viremia, suggesting that the synergy between Gag-specific T cell responses and antibodies targeting Env were an important requirement in the effective control of the virus, an observation also supported by others. 92 , 93 Roederer et al 89 reported that vaccination with mosaic Gag DNA as prime followed by rAd5 as a booster immunization did not protect from infection but showed reduction of viremia.…”

“…92 , 93 Roederer et al 89 reported that vaccination with mosaic Gag DNA as prime followed by rAd5 as a booster immunization did not protect from infection but showed reduction of viremia. On the other hand, Hansen et al 90 , 91 reported no protection from virus acquisition but found robust control of viremia in ∼half of the rCMV (SIV Gag) immunized macaques. A fundamental difference between our and the rCMV vaccine is that DNA vaccination induces T cell immunity using canonical MHC molecules, while certain rCMV vectors are able to elicit T cell immunity through the non-canonical MHC-E, 94 , 95 a feature that makes the rCMV vector induced responses unique.…”

Polyvalent vaccine approaches to combat HIV‐1 diversity

“…A novel CMV vector developed by Louis Picker et al 31, 32, 33. has elicited unusual and protective T‐cell responses in rhesus macaques.…”

“…By using rhesus CMV vectors that lacked particular genes (Rh157.5, Rh157.4, and Rh157.6), a prolific T‐cell response was generated, and a very high density of epitopes was targeted in the SIVmac Gag protein that was included in the vaccine. The responses were restricted either by class II major histocompatibility complex (MHC) molecules,32 or by the conserved, non‐classical, ubiquitously expressed MHC‐E protein 33. The MHC‐E presented epitopes were non‐canonical, meaning that they generally did not contain previously defined MHC‐E anchor motifs 33.…”