Effects of persistent modulation of intestinal microbiota on SIV/HIV vaccination in rhesus macaques

Abstract

An effective vaccine to prevent HIV transmission has not yet been achieved. Modulation of the microbiome via probiotic therapy has been suggested to result in enhanced mucosal immunity. Here, we evaluated whether probiotic therapy could improve the immunogenicity and protective efficacy of SIV/HIV vaccination. Rhesus macaques were co-immunized with an SIV/HIV DNA vaccine via particle-mediated epidermal delivery and an HIV protein vaccine administered intramuscularly with Adjuplex™ adjuvant, while receiving daily oral Visbiome® probiotics. Probiotic therapy alone led to reduced frequencies of colonic CCR5+ and CCR6+ CD4+ T cells. Probiotics with SIV/HIV vaccination led to similar reductions in colonic CCR5+ CD4+ T cell frequencies. SIV/HIV-specific T cell and antibody responses were readily detected in the periphery of vaccinated animals but were not enhanced with probiotic treatment. Combination probiotics and vaccination did not impact rectal SIV/HIV target populations or reduce the rate of heterologous SHIV acquisition during the intrarectal challenge. Finally, post-infection viral kinetics were similar between all groups. Thus, although probiotics were well-tolerated when administered with SIV/HIV vaccination, vaccine-specific responses were not significantly enhanced. Additional work will be necessary to develop more effective strategies of microbiome modulation in order to enhance mucosal vaccine immunogenicity and improve protective immune responses.

Intestinal microbial communities andHoldemanellaisolated from HIV+/− men who have sex with men increase frequencies of lamina propria CCR5+CD4+T cells

“… 22 A more recent study also supported a link between the gut microbiome and gut CCR5 expression by showing that probiotic intake reduced CCR5 expression on CD4 + T cells in the gut of macaques. 23 These studies together support that MSM-microbiome mediated increases in CD4 + CCR5 + T cells in the rectum has potential implications for increased risk of HIV transmission and that the gut microbiome may be a viable target for disease prevention. More work will be needed, however, to validate that the gut microbiome of MSM actually induces increased transmission of HIV in vivo and the particular microbes and mechanisms involved.…”

“…The concept that an altered microbiome can influence rectal HIV transmission via induction of CCR5 expression on CD4 + T cells is supported by two recent studies in macaques. 22 , 23 Specifically, rhesus macaques from two different sources had significantly different rates of infection against repeated low-dose SHIV intrarectal challenge, and this was associated with an altered gut microbiome and an increase in activated CD4 + CCR5 + Ki67 + T cells in the rectal mucosa of the susceptible group. 22 A more recent study also supported a link between the gut microbiome and gut CCR5 expression by showing that probiotic intake reduced CCR5 expression on CD4 + T cells in the gut of macaques.…”

Microbiome Studies in Non-human Primates

“…After probiotic administration, the authors observed significant increases in colonic and lymph node myeloid cells, IgA + B-cells, increased LN TFH cells and intestinal innate lymphocyte type 3 s, and decreased activation of colonic CD4 + T-cells. Similarly, Klatt et al observed that co-administration of probiotic Visbiome with adjuvanted SIV Gag and HIV Env DNA/HIV gp140 trimer protein vaccination strategy, decreased target cell frequency, increased SIV gag-specific CD4 + and CD8 + T-cell responses, and increased IgA + LN B-cells [ 114 ].…”

“…Though widely reported to have beneficial effects on gastrointestinal immunity, oral probiotic therapy in macaques has not been shown to extensively remodel the intestinal microbiome [ 47 , 114 ] perhaps suggesting the potential for a finite number of taxa to influence susceptibility to SIV or HIV. In an effort to create a gastrointestinal pathogen-free ( Campylobacter spp.…”

“…Where comprehensively analyzed, the probiotic and antibiotic therapies described above do not reveal an obvious reciprocal commensal:pathogen dichotomy suggesting that immunological benefits of these therapies may be associated with a recalibration of the metabolic networks shaped by the intestinal microbial ecosystem, more so than the presence or absence of specific taxa [ 41 , 47 , 114 , 115 •]. Indeed, observational studies that have described an association between the macaque or human rectal microbiome and lentiviral acquisition did not identify the taxa utilized in the pre-therapeutic studies described here [ 30 , 31 , 44 ••].…”