Persistent Low-Level Replication of SIVΔnef Drives Maturation of Antibody and CD8 T Cell Responses to Induce Protective Immunity against Vaginal SIV Infection

Abstract

Defining the correlates of immune protection conferred by SIVΔnef, the most effective vaccine against SIV challenge, could enable the design of a protective vaccine against HIV infection. Here we provide a comprehensive assessment of immune responses that protect against SIV infection through detailed analyses of cellular and humoral immune responses in the blood and tissues of rhesus macaques vaccinated with SIVΔnef and then vaginally challenged with wild-type SIV. Despite the presence of robust cellular immune responses, animals at 5 weeks after vaccination displayed only transient viral suppression of challenge virus, whereas all macaques challenged at weeks 20 and 40 post-SIVΔnef vaccination were protected, as defined by either apparent sterile protection or significant suppression of viremia in infected animals. Multiple parameters of CD8 T cell function temporally correlated with maturation of protection, including polyfunctionality, phenotypic differentiation, and redistribution to gut and lymphoid tissues. Importantly, we also demonstrate the induction of a tissue-resident memory population of SIV-specific CD8 T cells in the vaginal mucosa, which was dependent on ongoing low-level antigenic stimulation. Moreover, we show that vaginal and serum antibody titers inversely correlated with post-challenge peak viral load, and we correlate the accumulation and affinity maturation of the antibody response to the duration of the vaccination period as well as to the SIVΔnef antigenic load. In conclusion, maturation of SIVΔnef-induced CD8 T cell and antibody responses, both propelled by viral persistence in the gut mucosa and secondary lymphoid tissues, results in protective immune responses that are able to interrupt viral transmission at mucosal portals of entry as well as potential sites of viral dissemination.

Impact of Poxvirus Vector Priming, Protein Coadministration, and Vaccine Intervals on HIV gp120 Vaccine-Elicited Antibody Magnitude and Function in Infant Macaques

“…In vaccine studies with adult macaques, the avidities of anti-Env serum IgG measured by NaSCN displacement ELISA have been correlated with the levels of ADCC activity (35) and protection against rectal or vaginal SHIV or SIV challenge (30,31,36,37). In the current study, the avidity indices of C.1086 gp120-specific IgG measured in the NaSCN ELISA did not show evidence of differences between groups.…”

“…We have previously shown that oral vaccine priming followed by systemic boosting in infants generates salivary or intestinal IgA responses that, albeit not protective against infection, correlate with control of viremia after oral SIV exposure (20,29). Similarly, vaccine-mediated induction of Env-specific mucosal IgA responses at sites of SIV or SHIV challenge has been associated with protection, delayed rates of infection, or control of viremia in adult macaques (30,36,37,42). Consistent with the induction of mucosal gp120-specific IgA, gp120-specific B cells in intestinal tissues were only detected in the extended-interval group.…”

Modified Vaccinia Virus Ankara Vector Induces Specific Cellular and Humoral Responses in the Female Reproductive Tract, the Main HIV Portal of Entry

“…We confirm that CD4 + and CD8 + T cells express memory markers in the FRT (17), whereas naive cells were primarily found in blood and LNs. Among the memory T cells, resident memory lymphocytes have been described in tissues such as the vagina (18). Our analyses performed in one vaccinated animal showed that CD8 + resident memory T cells were primarily present in the vagina (39.8% among effector memory T cells) and in the cervix (22.2% among effector memory T cells) and were less frequent in the uterus (2.5% among effector memory T cells) (data not shown).…”

IL-15 Complexes Induce Migration of Resting Memory CD8 T Cells into Mucosal Tissues

“…Vaccine strategies that promote the establishment of T RM cells within the mucosal tissues hold promise for limiting early dissemination of virus infections such as HIV-1 and Influenza [7, 51]. We demonstrated that CD8 T cells depend on mTORC1 signaling to specifically accumulate with mucosal tissues.…”