During HIV/SIV infection, mucosal immune system dysfunction and systemic immune activation are associated with progression to AIDS; however, it is unclear to what extent pre-existing gastrointestinal damage relates to disease progression postinfection. Pigtail macaques (PTM) are an excellent model in which to assess mucosal dysfunction in relation to HIV/SIV pathogenesis, as the majority of these animals have high levels of gastrointestinal damage, immune activation, and microbial translocation prior to infection, and rapidly progress to AIDS upon SIV infection. In this study, we characterized the mucosal immune environment prior to and throughout SIV infection in 13 uninfected PTM and 9 SIV-infected PTM, of which 3 were slow progressors. This small subset of slow progressors had limited innate immune activation in mucosal tissues in the periphery, which was associated with a more intact colonic epithelial barrier. Furthermore, we found that preinfection levels of microbial translocation, as measured by LPS-binding protein, in PTM correlated with the rate of progression to AIDS. These data suggest that pre-existing levels of microbial translocation and gastrointestinal tract dysfunction may influence the rate of HIV disease progression.
HIV infection results in gastrointestinal (GI) tract damage, microbial translocation, and immune activation, which are not completely ameliorated with suppression of viremia by antiretroviral (ARV) therapy. Furthermore, increased morbidity and mortality of ARV-treated HIV-infected individuals is associated with these dysfunctions. Thus, to enhance GI tract physiology, we treated SIV-infected pigtail macaques with ARVs, probiotics, and prebiotics or with ARVs alone. This synbiotic treatment resulted in increased frequency and functionality of GI tract APCs, enhanced reconstitution and functionality of CD4+ T cells, and reduced fibrosis of lymphoid follicles in the colon. Thus, ARV synbiotic supplementation in HIV-infected individuals may improve GI tract immunity and thereby mitigate inflammatory sequelae, ultimately improving prognosis.
Pigtail macaques (PTM) are an excellent model for HIV research; however, the dynamics of simian immunodeficiency virus (SIV) SIVmac239 infection in PTM have not been fully evaluated. We studied nine PTM prior to infection, during acute and chronic SIVmac239 infections, until progression to AIDS. We found PTM manifest clinical AIDS more rapidly than rhesus macaques (RM), as AIDS-defining events occurred at an average of 42.17 weeks after infection in PTM compared to 69.56 weeks in RM (P = 0.0018). However, increased SIV progression was not associated with increased viremia, as both peak and set-point plasma viremias were similar between PTM and RM (P = 0.7953 and P = 0.1006, respectively). Moreover, this increased disease progression was not associated with rapid CD4(+) T cell depletion, as CD4(+) T cell decline resembled other SIV/human immunodeficiency virus (HIV) models. Since immune activation is the best predictor of disease progression during HIV infection, we analyzed immune activation by turnover of T cells by BrdU decay and Ki67 expression. We found increased levels of turnover prior to SIV infection of PTM compared to that observed with RM, which may contribute to their increased disease progression rate. These data evaluate the kinetics of SIVmac239-induced disease progression and highlight PTM as a model for HIV infection and the importance of immune activation in SIV disease progression.
HIV infection is characterized by immune system dysregulation, including depletion of CD4+ T cells, immune activation, and abnormal B- and T-cell responses. However, the immunologic mechanisms underlying lymphocytic dysfunctionality and whether it is restricted to immune responses against neo antigens, recall antigens, or both is unclear. Here, we immunized SIV-infected and uninfected rhesus macaques to induce immune responses against neo and recall antigens using a Leishmania major polyprotein (MML) vaccine given with poly-ICLC adjuvant. We found that vaccinated SIVuninfected animals induced high frequencies of polyfunctional MML-specific CD4+ T cells. However, in SIV-infected animals, CD4+ T-cell functionality decreased after both neo (P = .0025) and recall (P = .0080) MML vaccination. Furthermore, after SIV infection, the frequency of MML-specific antibody-secreting classic memory B cells was decreased compared with vaccinated, SIV-uninfected animals. Specifically, antibody-secreting classic memory B cells that produced IgA in response to either neo (P = .0221) or recall (P = .0356) MML vaccinations were decreased. Furthermore, we found that T-follicular helper cells, which are essential for priming B cells, are preferentially infected with SIV. These data indicate that SIV infection results in dysfunctional T-cell responses to neo and recall vaccinations, and direct SIV infection of T-follicular helper cells, both of which probably contribute to deficient B-cell responses and, presumably, susceptibility to certain opportunistic infections.
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