Lisa La Franco-Scheuch

Bio: Lisa La Franco-Scheuch is an academic researcher from University of California, Davis. The author has contributed to research in topics: Simian immunodeficiency virus & Viral replication. The author has an hindex of 3, co-authored 3 publications receiving 491 citations. Previous affiliations of Lisa La Franco-Scheuch include California National Primate Research Center.

Propagation and Dissemination of Infection after Vaginal Transmission of Simian Immunodeficiency Virus

Abstract: In the current global AIDS pandemic, more than half of new human immunodeficiency virus type 1 (HIV-1) infections are acquired by women through intravaginal HIV exposure. For this study, we explored pathogenesis issues relevant to the development of effective vaccines to prevent infection by this route, using an animal model in which female rhesus macaques were exposed intravaginally to a high dose of simian immunodeficiency virus (SIV). We examined in detail the events that transpire from hours to a few days after intravaginal SIV exposure through week 4 to provide a framework for understanding the propagation, dissemination, and establishment of infection in lymphatic tissues (LTs) during the acute stage of infection. We show that the mucosal barrier greatly limits the infection of cervicovaginal tissues, and thus the initial founder populations of infected cells are small. While there was evidence of rapid dissemination to distal sites, we also show that continuous seeding from an expanding source of production at the portal of entry is likely critical for the later establishment of a productive infection throughout the systemic LTs. The initially small founder populations and dependence on continuous seeding to establish a productive infection in systemic LTs define a small window of maximum vulnerability for the virus in which there is an opportunity for the host, vaccines, or other interventions to prevent or control infection.

Gamma Interferon-Mediated Inflammation Is Associated with Lack of Protection from Intravaginal Simian Immunodeficiency Virus SIVmac239 Challenge in Simian-Human Immunodeficiency Virus 89.6-Immunized Rhesus Macaques

Abstract: Gamma interferon (IFN-γ) plays an important role in effective host immune responses against bacterial and viral infections. IFN-γ is critical for the induction of cell-mediated immunity, especially cytotoxic-T-cell (CTL) responses (8, 28, 53). Furthermore, IFN-γ is one of the main effector molecules released by CTLs after antigenic stimulation (8, 63). IFN-γ knockout mice are highly susceptible to viral infections (20, 58). Direct antiviral effects of IFN-γ, independent of CD8+-T-cell cytotoxicity, have also been demonstrated, but only in hepatitis B virus (31-33) and vaccinia virus (68) infections. CD8-positive T cells are critical in the control of human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) infections. The appearance of HIV- and SIV-specific CD8+ T cells in the acute stage of infection is associated with decreasing plasma viral RNA (vRNA) levels (14, 45, 57). The depletion of CD8+ T cells in the acute stage of SIV infection results in persistently high plasma vRNA levels (39, 72). Furthermore, in HIV-1-infected patients, CTL responses are preserved in asymptomatic HIV-1-infected individuals but not in HIV-1-infected patients who progress to AIDS (54, 59). Consistent with the critical role of CTL responses, HIV-specific IFN-γ T-cell responses are stronger in asymptomatic HIV-1-infected patients than in rapid progressors (44), and the impairment of IFN-γ T-cell responses in HIV and SIV infections is associated with disease progression (26, 79). In addition, in several SIV vaccine studies, protection was correlated with the induction of IFN-γ T-cell responses (4, 10). In fact, it has been proposed that the relative immunogenicities of HIV vaccine candidates can be evaluated by using a HIV peptide-specific IFN-γ enzyme-linked immunospot (ELISPOT) assay to enumerate antigen-specific T cells in peripheral blood mononuclear cells (PBMC) (69). IFN-γ also plays an important role in innate host defenses. It is rapidly induced and secreted by NK cells after pathogen encounter by the host. Furthermore, macrophage and neutrophil activation by IFN-γ results in the secretion of tumor necrosis factor alpha (64) and reactive oxygen intermediates (18, 19, 30). Thus, IFN-γ is a key mediator of inflammatory responses (8, 25). IFN-γ may also play a role in HIV pathogenesis, and increased levels of IFN-γ have been reported in the sera and lymphoid tissues of HIV-1-infected patients (38, 78). IFN-γ expression in lymphoid tissues is associated with the induction of the IFN-γ-inducible chemokines Mig/CXCL9 and IP-10/CXCL10 in SIV-infected rhesus macaques. It has been proposed that the continuous secretion of these chemokines results in increased inflammation in lymphoid tissues that promotes increased viral replication and thus disease progression (66). We have previously shown that the majority of rhesus macaques immunized with nonpathogenic simian-human immunodeficiency virus 89.6 (SHIV89.6) and subsequently challenged with pathogenic SIVmac239 can control challenge virus replication (3, 55). The analysis of immune responses in PBMC during the acute phase postchallenge (p.c.) showed that the relative strengths of SIV-specific CTL, as measured by 51Cr release assays, in the first few weeks p.c. significantly correlated with protection (3, 55). The goal of the present study was to examine the role of IFN-γ immune responses in these same monkeys 6 months p.c. Importantly, because the loss of control of virus replication in the vaccinated-unprotected animals occurred relatively late after SIV challenge, the examination of lymphoid tissues 6 months p.c. is close to the time when challenge virus escape occurred. We found that the relatively high level of virus replication in the lymphoid tissues of vaccinated-unprotected monkeys was associated with increased IFN-γ mRNA levels and inflammation. The patterns of IFN-γ-driven inflammation were similar in all the vaccinated-unprotected animals, even though the time intervals between escape and euthanization were different in individual unprotected monkeys, suggesting that the inflammation developed soon after escape. Importantly, the relationship between virus replication and IFN-γ responses observed in lymphoid tissues during the chronic p.c. phase was not accurately reflected in PBMC. These findings have implications for understanding the nature of protective immunity in attenuated lentiviral vaccine systems.

The immune response during acute HIV-1 infection: clues for vaccine development.

Abstract: The early immune response to HIV-1 infection is likely to be an important factor in determining the clinical course of disease. Recent data indicate that the HIV-1 quasispecies that arise following a mucosal infection are usually derived from a single transmitted virus. Moreover, the finding that the first effective immune responses drive the selection of virus escape mutations provides insight into the earliest immune responses against the transmitted virus and their contributions to the control of acute viraemia. Strong innate and adaptive immune responses occur subsequently but they are too late to eliminate the infection. In this Review, we discuss recent studies on the kinetics and quality of early immune responses to HIV-1 and their implications for developing a successful preventive HIV-1 vaccine.

Targeting early infection to prevent HIV-1 mucosal transmission

Abstract: Measures to prevent sexual mucosal transmission of human immunodeficiency virus (HIV)-1 are urgently needed to curb the growth of the acquired immunodeficiency syndrome (AIDS) pandemic and ultimately bring it to an end. Studies in animal models and acute HIV-1 infection reviewed here reveal potential viral vulnerabilities at the mucosal portal of entry in the earliest stages of infection that might be most effectively targeted by vaccines and microbicides, thereby preventing acquisition and averting systemic infection, CD4 T-cell depletion and pathologies that otherwise rapidly ensue.

Glycerol monolaurate prevents mucosal SIV transmission

Abstract: Clinical trials of microbicides as a means of preventing the transmission of HIV-1 to women have proved disappointing. Now a study in the simian immunodeficiency virus (SIV)–rhesus macaque vaginal transmission model for HIV infection suggests that a prophylactic approach might yet be worth pursuing. The commonly used antimicrobial compound glycerol monolaurate (GML) was found to suppress SIV infection even after repeated virus exposure. But its mechanism of action was surprising. The host's inflammatory response to the virus, rather than helping, was shown to fuel the infection by recruiting the very CD4+ T cells that the virus targets. GML's prophylactic action appeared to result from its ability to block this host response, rather than from a direct effect on the virus. This points to cell signalling and innate host responses in the mucosal cells as potential targets for drugs and vaccines aimed at preventing infection by HIV — and by other pathogens too if they use similar infection strategies. Glycerol monolaurate in a microbicide is shown to protect monkeys from infection after intra-vaginal exposure to high doses of SIV. The suppressive activity may be due to the inhibition of target cell recruitment due to glycerol-monolaurate-mediated inhibition of epithelial cell signalling and inflammatory cytokine expression. Although there has been great progress in treating human immunodeficiency virus 1 (HIV-1) infection1, preventing transmission has thus far proven an elusive goal. Indeed, recent trials of a candidate vaccine and microbicide have been disappointing, both for want of efficacy and concerns about increased rates of transmission2,3,4. Nonetheless, studies of vaginal transmission in the simian immunodeficiency virus (SIV)–rhesus macaque (Macacca mulatta) model point to opportunities at the earliest stages of infection in which a vaccine or microbicide might be protective, by limiting the expansion of infected founder populations at the portal of entry5,6. Here we show in this SIV–macaque model, that an outside-in endocervical mucosal signalling system, involving MIP-3α (also known as CCL20), plasmacytoid dendritic cells and CCR5+cell-attracting chemokines produced by these cells, in combination with the innate immune and inflammatory responses to infection in both cervix and vagina, recruits CD4+ T cells to fuel this obligate expansion. We then show that glycerol monolaurate—a widely used antimicrobial compound7 with inhibitory activity against the production of MIP-3α and other proinflammatory cytokines8—can inhibit mucosal signalling and the innate and inflammatory response to HIV-1 and SIV in vitro, and in vivo it can protect rhesus macaques from acute infection despite repeated intra-vaginal exposure to high doses of SIV. This new approach, plausibly linked to interfering with innate host responses that recruit the target cells necessary to establish systemic infection, opens a promising new avenue for the development of effective interventions to block HIV-1 mucosal transmission.

Mucosal Dendritic Cells

Abstract: The internal surfaces of the human body are covered by distinct types of epithelial cells and mucus-secreting cells. The mucosal surfaces serve many vital functions, such as respiration (nasal passage and lung), absorption (gastrointestinal tract), excretion (lung, urinary tract, large intestine), and reproduction (reproductive tract). In performing these functions, the host is inevitably exposed to environmental antigens, food particles, commensal flora, and pathogens. Mucosal surfaces contain specialized dendritic cells (DCs) capable of sensing these external stimuli and mounting appropriate local responses depending on the nature of the elements they encounter. In the absence of pathogens, mucosal DCs either ignore the antigen or induce regulatory responses. Upon recognition of microorganisms that invade the mucosal barrier, mucosal DCs mount robust protective immunity. This review highlights progress in our understanding of how mucosal DCs process external information and direct appropriate responses by mobilizing various cells of the innate and adaptive immune systems to achieve homeostasis and protection.

Setting the stage: host invasion by HIV.

Abstract: For more than two decades, HIV has infected millions of people worldwide each year through mucosal transmission. Our knowledge of how HIV secures a foothold at both the molecular and cellular levels has been expanded by recent investigations that have applied new technologies and used improved techniques to isolate ex vivo human tissue and generate in vitro cellular models, as well as more relevant in vivo animal challenge systems. Here, we review the current concepts of the immediate events that follow viral exposure at genital mucosal sites where most documented transmissions occur. Furthermore, we discuss the gaps in our knowledge that are relevant to future studies, which will shape strategies for effective HIV prevention.