Activated CD4 ⁺ CCR5 ⁺ T cells in the rectum predict increased SIV acquisition in SIVGag/Tat-vaccinated rhesus macaques

Abstract

An effective T-cell–based AIDS vaccine should induce strong HIV-specific CD8+ T cells in mucosal tissues without increasing the availability of target cells for the virus. Here, we evaluated five immunization strategies that include Human adenovirus-5 (AdHu5), Chimpanzee adenovirus-6 (AdC6) or -7 (AdC7), Vaccinia virus (VV), and DNA given by electroporation (DNA/EP), all expressing Simian immunodeficiency virus group specific antigen/transactivator of transcription (SIVmac239Gag/Tat). Five groups of six rhesus macaques (RMs) each were vaccinated with DNA/EP-AdC6-AdC7, VV-AdC6-AdC7, DNA/-EP-VV-AdC6, DNA/EP-VV-AdC7, or AdHu5-AdHu5-AdHu5 and were challenged repeatedly with low-dose intrarectal SIVmac239. Upon challenge, there were no significant differences among study groups in terms of virus acquisition or viral load after infection. When taken together, the immunization regimens did not protect against SIV acquisition compared with controls but did result in an ∼1.6-log decline in set-point viremia. Although all immunized RMs had detectable SIV-specific CD8+ T cells in blood and rectal mucosa, we found no correlation between the number or function of these SIV-specific CD8+ T cells and protection against SIV acquisition. Interestingly, RMs experiencing breakthrough infection showed significantly higher prechallenge levels of CD4+C-C chemokine receptor type 5 (CCR5)+HLA-DR+ T cells in the rectal biopsies (RB) than animals that remained uninfected. In addition, among the infected RMs, the percentage of CD4+CCR5+Ki-67+ T cells in RBs prechallenge correlated with higher early viremia. Overall, these data suggest that the levels of activated CD4+CCR5+ target T cells in the rectal mucosa may predict the risk of SIV acquisition in RMs vaccinated with vectors that express SIVGag/Tat.

Molecular Signatures of Immune Activation and Epithelial Barrier Remodeling Are Enhanced during the Luteal Phase of the Menstrual Cycle: Implications for HIV Susceptibility

“…Indeed, the shared chemotactic activities of these neutrophil granule-derived proteins could be the driving force behind the immune cell recruitment and the corresponding epithelial barrier disruption observed during the luteal phase in the present study, which may contribute to the overall vulnerability to HIV infection observed during this time. It is possible that the HIV target cell populations and/or phenotypes, which can impact HIV acquisition risk due to an increased expression of HIV coreceptors (54), varied at the mucosal surface of these luteal-phase samples; however, we were unable to confirm this in our study since matching cytobrush and/or biopsy samples were not collected for this purpose. A longitudinal study assessing these immune cell populations in parallel with these molecular signatures would help answer this question.…”

Balancing Trained Immunity with Persistent Immune Activation and the Risk of Simian Immunodeficiency Virus Infection in Infant Macaques Vaccinated with Attenuated Mycobacterium tuberculosis or Mycobacterium bovis BCG Vaccine

“…One study showed that PBMC IFN-␥ enzyme-linked immunosorbent spot assay (ELISPOT) responses inversely correlated with the number of SIV exposures needed to establish infection in adult macaques (72). Another study comparing various vaccine modalities showed that regardless of the vaccine strategy, the number of activated CD4 ϩ T cells in the rectal mucosa predicted early viremia and risk for rectal SIV infection (73). Both studies established a link between immune activation at the time of challenge and SIV exposure risk, although a statistically significant difference in challenge outcome between the groups was not demonstrated (72,73).…”

“…Another study comparing various vaccine modalities showed that regardless of the vaccine strategy, the number of activated CD4 ϩ T cells in the rectal mucosa predicted early viremia and risk for rectal SIV infection (73). Both studies established a link between immune activation at the time of challenge and SIV exposure risk, although a statistically significant difference in challenge outcome between the groups was not demonstrated (72,73). Similarly, in a recent low-dose rectal SIV infection study, animals with higher numbers of Ki67-positive CD4 ϩ T cells in the colorectal mucosa required fewer SIV exposures to become infected (74).…”

Protocol of a randomised controlled trial characterising the immune responses induced by varicella-zoster virus (VZV) vaccination in healthy Kenyan women: setting the stage for a potential VZV-based HIV vaccine

“…[26][27][28][29][30][31] In this study, we aim to characterise mucosal immunity before and after vaccination with a commercial live-attenuated VZV vaccine with respect to immune activation state, mucosal homing properties and VZV-specific effector immune responses in Kenyan women at low risk for HIV acquisition and with preimmunity to VZV through natural infection. Characterising VZV responses in this study setting is highly relevant, since Kenya, along with other African countries, is among the countries which can derive the greatest benefit with an HIV vaccine.…”