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Mucosal-associated invariant T (MAIT) cells help combat opportunistic infections. Thus, MAIT cells are of interest in HIV/SIV vaccination and infection. We investigated MAIT cell dynamics and function in rhesus macaque blood and bronchoalveolar lavage (BAL) following mucosal adenovirus (Ad)-SIV recombinant priming, intramuscular SIV envelope boosting and infection following repeated low-dose intravaginal SIV exposures. Increased frequencies of blood MAIT cells over the course of vaccination were observed, which were maintained even 12-weeks post-SIV infection. BAL MAIT cells only increased after the first Ad immunization. Vaccination increased MAIT cell levels in blood and BAL expressing the antiviral cytokine IFN-γ and TNF-α and the proliferation marker Ki67. Upon T cell-specific α-CD3, α-CD28 stimulation, MAIT cells showed a greater capacity to secrete cytokines/chemokines associated with help for B cell activation, migration and regulation compared to CD3 + MR1 − cells. Culture of MAIT cell supernatants with B cells led to greater tissue like memory B cell frequencies. MAIT cell frequencies in blood and BAL correlated with SIV-specific antibody levels in rectal secretions and with SIV-specific tissue resident memory B cells. Overall, SIV vaccination influenced MAIT cell frequency and functionality. The potential for MAIT cells to provide help to B cells was evident during both vaccination and infection.

HIV infected individuals have been shown to be pre-disposed to pulmonary infections even while receiving anti-retroviral therapy. Alveolar macrophages (AMs) play a critical role in lung innate immunity, but contradictory results have been reported regarding their functionality following HIV infection. Here, using the SIV rhesus macaque model, we document the effect of SIV infection on the phenotypic and functional properties of AMs. Following infection with SIV , AMs in bronchoalveolar lavage (BAL) sampled over 2- to 20-weeks post-infection (wpi) were compared to those in BAL samples from naïve macaques. AM expression of proinflammatory cytokines TNF-α, IL-6, IL-1β, and chemokine RANTES drastically increased 2-wpi compared to AMs of naïve macaques ( < 0.0001 for all), but dropped significantly with progression to chronic infection. Phagocytic activity of AMs 2-and 4-wpi was elevated compared to AMs of naive animals ( = 0.0005, = 0.0004, respectively) but significantly decreased by 12-wpi ( = 0.0022, = 0.0019, respectively). By 20-wpi the ability of AMs from chronically infected animals to perform SIV-specific antibody-dependent phagocytosis (ADP) was also diminished ( = 0.028). Acute SIV infection was associated with increased FcγRIII expression which subsequently declined with disease progression. Frequency of FcγRIII AMs showed a strong trend toward correlation with SIV-specific ADP, and at 2-wpi FcγRIII expression negatively correlated with viral load ( = -0.6819; = 0.0013), suggesting a contribution to viremia control. Importantly, PD-1 was found to be expressed on AMs and showed a strong trend toward correlation with plasma viral load ( = 0.8266; = 0.058), indicating that similar to over-expression on T-cells, PD-1 expression on AMs may also be associated with disease progression. Further, AMs predominantly expressed PD-L2, which remained consistent over the course of infection. PD-1 blockade enhanced SIV-specific ADP by AMs from chronic infection indicating that the PD-1/PD-L2 pathway may modulate functional activity of AMs at that stage. These findings provide new insight into the dynamics of SIV infection leading to AM dysfunction and alteration of pulmonary innate immunity. Our results suggest new pathways to exploit in developing therapies targeting pulmonary disease susceptibility in HIV-infected individuals.

T follicular helper (T FH ) cells are pivotal in lymph node (LN) germinal center (GC) B cell affinity maturation. Circulating CXCR5 + CD4 + T (cT FH ) cells have supported memory B cell activation and broadly neutralizing antibodies in HIV controllers. We investigated the contribution of LN SIV-specific T FH and cT FH cells to Env-specific humoral immunity in female rhesus macaques following a mucosal Ad5hr-SIV recombinant priming and SIV gp120 intramuscular boosting vaccine regimen and following SIV vaginal challenge. T FH and B cells were characterized by flow cytometry. B cell help was evaluated in T FH -B cell co-cultures and by real-time PCR. Vaccination induced Env-specific T FH and Env-specific memory (ESM) B cells in LNs. LN Env-specific T FH cells post-priming and GC ESM B cells post-boosting correlated with rectal Env-specific IgA titers, and GC B cells at the same timepoints correlated with vaginal Env-specific IgG titers. Vaccination expanded cT FH cell responses, including CD25 + Env-specific cT FH cells that correlated negatively with vaginal Env-specific IgG titers but positively with rectal Env-specific IgA titers. Although cT FH cells post-2 nd boost positively correlated with viral-loads following SIV challenge, cT FH cells of SIV-infected and protected macaques supported maturation of circulating B cells into plasma cells and IgA release in co-culture. Additionally, cT FH cells of naïve macaques promoted upregulation of genes associated with B cell proliferation, BCR engagement, plasma cell maturation, and antibody production, highlighting the role of cT FH cells in blood B cell maturation. Vaccine-induced LN T FH and GC B cells supported anti-viral mucosal immunity while cT FH cells provided B cell help in the periphery during immunization and after SIV challenge. Induction of T FH responses in blood and secondary lymphoid organs is likely desirable for protective efficacy of HIV vaccines.

Vaccine strategies targeting the mucosal portal of entry may prevent HIV acquisition and systemic infection. Macrophages in cervicovaginal compartments are one of the first cell types to encounter virus upon vaginal exposure. Their activation can lead to recruitment of additional macrophages and CD4  T-cells susceptible to viral infection. However, they are also critical in providing early protection against invading pathogens. Therefore, understanding their response to immunization is important for vaccine design. We immunized rhesus macaques twice mucosally with replicating adenovirus (Ad) SIV recombinants, followed by two intramuscular boosts with SIV gp120 protein. Macaques were subsequently challenged intravaginally with repeated low doses of SIV . Using flow cytometry, we evaluated responses of cervicovaginal macrophages (CVM) and alveolar macrophages (AM) in bronchoalveolar lavage as initial immunization was to the upper respiratory tract. The frequency of CVM increased over the course of immunization; however, CCR5 expression significantly decreased. Significantly increased expression of the chemokines CCL3 (p < 0.01), CCL4, CCL5, and CXCL8 (p < 0.0001 for all) on CVM was seen post-1 Ad but their expression significantly decreased post-2 boost. CD4  T-cell frequency in the cervical mucosa remained unchanged. CVM FcγRIII expression was significantly increased at all time points post-immunization compared to naïve animals. FcγRIII expression post-2 Ad positively correlated with the number of challenges needed for infection (r = 0.68; p = 0.0051). Vaccination increased AM FcγRIII expression which post-2 boost correlated with antibody-dependent phagocytosis. Activation of AMs was evident by increased expression of CD40 and CD80 post-2 Ad compared to naïve macaques. APRIL expression also significantly increased post-2 Ad and correlated with B cell frequency in bronchoalveolar lavage (BAL) (r = 0.73; p = 0.0019) and total IgG in BAL-fluid (r = 0.53; p = 0.047). B cells cultured with SIV gp120-stimulated AM supernatant from vaccinated macaques exhibited significant increases in B cell activation markers CD38 and CD69 compared to B cells cultured alone or with AM supernatant from unvaccinated macaques. Overall, the vaccine regimen did not induce recruitment of susceptible cells to the vaginal mucosa but increased CVM FcγRIII expression which correlated with delayed SIV acquisition. Further, immunization induced expression of AM cytokines, including those associated with providing B cell help.

Effective CD8 T-cell responses play an important role in determining the course of SIV/HIV viral infection. Here we identified a unique population of dysfunctional CD8 T-cells in lymphoid tissues and bronchoalveolar lavage (BAL) of rhesus macaques with chronic SIV infection characterized by co-expression of CD6 and PD-1. The frequency of CD6 and PD-1 co-expressing CD8 T-cells was significantly increased in lymphoid tissues and BAL during chronic SIV infection compared to pre-infection levels. These CD6 PD-1 CD8 T-cells displayed impaired proliferation, cytokine secretion and cytotoxicity compared to their CD6 PD-1 CD8 T cell counterparts. The frequency of CD8 PD-1 and CD8 CD6 PD-1 T-cells in the lymph node and bone marrow did not correlate with SIV viral load, whereas the frequency of CD8 CD6 PD-1 T-cells positively correlated with SIV viral load in these tissues highlighting the contribution of CD6 to disease progression. CD6 PD-1 CD8 T-cells expressed elevated levels of SHP2 phosphatase compared to CD6 PD-1 CD8 T-cells providing a potential mechanism by which CD6 may induce T-cell dysfunction during chronic SIV infection. Combined targeting of CD6 and PD-1 effectively revived the CD8 T-cell proliferative response suggesting a strategy for potential therapeutic benefit.

B1 cells spontaneously produce protective natural antibodies which provide the first line of defense against a variety of pathogens. Although these natural antibodies share similar autoreactive features with several HIV-1 broadly neutralizing antibodies, the role of B1 cells in HIV/SIV disease progression is unknown. We report the presence of human-like B1 cells in rhesus macaques. During chronic SIV infection, we found that the frequency of splenic CD11b B1 cells positively correlated with plasma SIV viral load and exhausted T cells. Mechanistically, we discovered that splenic CD11b B1 cells express PD-L2 and IL-10, and were able to induce PD-1 upregulation on CD4 T cells . These findings suggest that splenic CD11b B1 cells may contribute to the regulation of SIV plasma viral load by enhancing T cell exhaustion. Therefore, understanding the mechanisms that govern their function in rhesus macaques may lead to novel therapeutic strategies for impeding HIV/SIV disease progression.

Marburg virus (MARV) is a virus of high human consequence with a case fatality rate of 24–88%. The global health and national security risks posed by Marburg virus disease (MVD) underscore the compelling need for a prophylactic vaccine, but no candidate has yet reached regulatory approval. Here, we evaluate a replication-defective chimpanzee adenovirus type 3 (ChAd3)-vectored MARV Angola glycoprotein (GP)-expressing vaccine against lethal MARV challenge in macaques. The ChAd3 platform has previously been reported to protect against the MARV-related viruses, Ebola virus (EBOV) and Sudan virus (SUDV), and MARV itself in macaques, with immunogenicity demonstrated in macaques and humans. In this study, we present data showing 100% protection against MARV Angola challenge (versus 0% control survival) and associated production of GP-specific IgGs generated by the ChAd3-MARV vaccine following a single dose of 1 × 1011 virus particles prepared in a new clinical formulation buffer designed to enhance product stability. These results are consistent with previously described data using the same vaccine in a different formulation and laboratory, demonstrating the reproducible and robust protective efficacy elicited by this promising vaccine for the prevention of MVD. Additionally, a qualified anti-GP MARV IgG ELISA was developed as a critical pre-requisite for clinical advancement and regulatory approval.

The emergence of Marburg virus (MARV) in Guinea and Ghana triggered the assembly of the MARV vaccine “MARVAC” consortium representing leaders in the field of vaccine research and development aiming to facilitate a rapid response to this infectious disease threat. Here, we discuss current progress, challenges, and future directions for MARV vaccines.

The human immunodeficiency virus epidemic continues in sub-Saharan Africa, and particularly affects adolescent girls and women who have limited access to antiretroviral therapy. Here we report that the risk of vaginal simian immunodeficiency virus (SIV) mac251 acquisition is reduced by more than 90% using a combination of a vaccine comprising V1-deleted (V2 enhanced) SIV envelope immunogens with topical treatment of the zinc-finger inhibitor SAMT-247. Following 14 weekly intravaginal exposures to the highly pathogenic SIV mac251 , 80% of a cohort of 20 macaques vaccinated and treated with SAMT-247 remained uninfected. In an arm of 18 vaccinated-only animals without microbicide, 40% of macaques remained uninfected. The combined SAMT-247/vaccine regimen was significantly more effective than vaccination alone. By analysing immune correlates of protection, we show that, by increasing zinc availability, SAMT-247 increases natural killer cytotoxicity and monocyte efferocytosis, and decreases T-cell activation to augment vaccine-induced protection. Topical microbicide combined with vaccine effectively prevents infection of female macaques with simian immunodeficiency virus.