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 SIVnef and then vaginally challenged with wild-type SIV. directly correlates with the concentration of JNJ-28312141 TCLA neutralizing antibodies in serum within group 20 (p = 0.031) and group 40 (p = 0.029) (two-tailed Spearman correlation).(EPS) ppat.1006104.s002.eps (66K) GUID:?B15A75A8-D205-448B-80B6-A32AAB217A13 S3 Fig: Anti-Env IgA antibody titers do not correlate with post-challenge peak viremia. (A) Anti-Env IgA antibody titers in the serum at day of challenge showed no relationship to peak SIVmac251 viremia post-challenge. (B) Anti-Env IgA specific activity in the vaginal mucosa at day of challenge did not correlate with peak SIVmac251 viremia post-challenge.(EPS) ppat.1006104.s003.eps (140K) GUID:?E9F6A819-0D9A-4A6F-A01B-D243AB8E81CF S4 Fig: No decrease in the CD4 T cell population of the gut mucosa after SIVmac251 challenge. (A) No decrease of the memory CD4 T cell populace (CD95+CD4+) as a percentage of total CD3+ T cells in the gut, including the jejunum, the colon and the mesenteric lymph nodes. (B) No difference in the memory CD4 T cell populace as a percentage of total CD3+ T cells in the gut of sterilely guarded (uninfected) and partially protected (infected) animals at day 14 post-challenge with SIVmac251.(EPS) ppat.1006104.s004.eps (133K) GUID:?61787265-223B-4357-8FEC-6F80DCC44183 S5 Fig: Low proliferation of SL8-specific CD8 T cells at week 20 post-SIVnef vaccination. SL8-specific CD8 T cells express significantly lower Ki-67 (p<0.0045) in peripheral blood, secondary lymphoid tissues and the gut mucosa at week 20 than at week 5 (two-tailed unpaired t test).(EPS) ppat.1006104.s005.eps (130K) GUID:?2643F4CE-68FE-41B9-B783-59E9F1F9B673 S1 Table: MHC class I genotypes of longitudinal study animals. MHC class I alleles were determined by sequence specific PCR .(DOCX) ppat.1006104.s006.docx (103K) GUID:?320606DB-5BB7-4C9D-8574-3CB4921E02C6 Data Availability StatementAll relevant data are within the paper and its Supporting Information files. Abstract Defining the correlates of immune protection conferred by SIVnef, the most effective vaccine against SIV challenge, could enable the design of a protective vaccine against HIV contamination. Here we provide a comprehensive assessment of immune responses that protect against SIV contamination through detailed analyses of cellular and humoral immune responses in the blood and tissues of rhesus macaques vaccinated with SIVnef 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 computer virus, whereas all macaques challenged at weeks 20 and 40 post-SIVnef vaccination were protected, as defined by either apparent sterile protection or significant suppression of viremia in infected animals. Multiple parameters JNJ-28312141 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 populace of SIV-specific CD8 T cells Rabbit Polyclonal to ARSE in the vaginal mucosa, which was dependent on ongoing low-level antigenic activation. Moreover, we show that vaginal and serum antibody titers inversely correlated with post-challenge peak viral weight, and we correlate the accumulation and affinity maturation of the antibody response to the duration of the vaccination period as well as to the SIVnef antigenic weight. In conclusion, maturation of SIVnef-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. Author Summary Annually, more than two million people worldwide are infected with HIV, the computer virus that causes AIDS. Rhesus macaques can be infected with SIV, a close relative and ancestor of HIV, resulting in simian AIDS, recapitulating key aspects of human HIV contamination. SIVnef, a live attenuated form of SIV, protects rhesus macaques from subsequent challenge with pathogenic SIV and is widely viewed as the most effective SIV vaccine. Here we demonstrate that SIVnef persistence during the vaccination period drives both cell-mediated and humoral immune response maturation. During the vaccination period, cell-mediated immune responses elicited by SIVnef target more conserved regions of the computer virus rendering immune escape more difficult. Furthermore, JNJ-28312141 the localization of the cell-mediated immune responses is usually shifted over time from peripheral blood to sites of viral production that are rich in uninfected SIV target cells, thereby positioning cell-mediated immune responses where they are most needed after wild-type SIV challenge. Similarly, SIVnef persistence during the vaccination period also prospects to the accumulation and maturation of the humoral immune response. Our findings spotlight the unique capacity of prolonged vaccines to elicit durable and effective immune responses against wild-type SIV challenge. Introduction Despite the considerable resources committed to developing an effective HIV vaccine over the past three decades, this objective remains elusive. Recent failures of HIV vaccine trials to demonstrate protection against contamination [1, 2] and the.