Lara Compton

Bio: Lara Compton is an academic researcher from University of California, Davis. The author has contributed to research in topics: Simian immunodeficiency virus & Virus. The author has an hindex of 5, co-authored 6 publications receiving 834 citations. Previous affiliations of Lara Compton 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.

CD8+ T-Lymphocyte Response to Major Immunodominant Epitopes after Vaginal Exposure to Simian Immunodeficiency Virus: Too Late and Too Little

Abstract: In the acute stage of infection following sexual transmission of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV), virus-specific CD8+ T-lymphocyte responses partially control but do not eradicate infection from the lymphatic tissues (LTs) or prevent the particularly massive depletion of CD4+ T lymphocytes in gut-associated lymphatic tissue (GALT). We explored hypothetical explanations for this failure to clear infection and prevent CD4+ T-lymphocyte loss in the SIV/rhesus macaque model of intravaginal transmission. We examined the relationship between the timing and magnitude of the CD8+ T-lymphocyte response to immunodominant SIV epitopes and viral replication, and we show first that the failure to contain infection is not because the female reproductive tract is a poor inductive site. We documented robust responses in cervicovaginal tissues and uterus, but only several days after the peak of virus production. Second, while we also documented a modest response in the draining genital and peripheral lymph nodes, the response at these sites also lagged behind peak virus production in these LT compartments. Third, we found that the response in GALT was surprisingly low or undetectable, possibly contributing to the severe and sustained depletion of CD4+ T lymphocytes in the GALT. Thus, the virus-specific CD8+ T-lymphocyte response is “too late and too little” to clear infection and prevent CD4+ T-lymphocyte loss. However, the robust response in female reproductive tissues may be an encouraging sign that vaccines that rapidly induce high-frequency CD8+ T-lymphocyte responses might be able to prevent acquisition of HIV-1 infection by the most common route of transmission.

Simian-Human Immunodeficiency Virus SHIV89.6-Induced Protection against Intravaginal Challenge with Pathogenic SIVmac239 Is Independent of the Route of Immunization and Is Associated with a Combination of Cytotoxic T-Lymphocyte and Alpha Interferon Responses

Abstract: Attenuated primate lentivirus vaccines provide the most consistent protection against challenge with pathogenic simian immunodeficiency virus (SIV). Thus, they provide an excellent model to examine the influence of the route of immunization on challenge outcome and to study vaccine-induced protective anti-SIV immune responses. In the present study, rhesus macaques were immunized with live nonpathogenic simian-human immunodeficiency virus (SHIV) 89.6 either intravenously or mucosally (intranasally or intravaginally) and then challenged intravaginally with pathogenic SIVmac239. The route of immunization did not affect mucosal challenge outcome after a prolonged period of systemic infection with the nonpathogenic vaccine virus. Further, protection from the SIV challenge was associated with the induction of multiple host immune effector mechanisms. A comparison of immune responses in vaccinated-protected and vaccinated-unprotected animals revealed that vaccinated-protected animals had higher frequencies of SIV Gag-specific cytotoxic T lymphocytes and gamma interferon (IFN-gamma)-secreting cells during the acute phase postchallenge. Vaccinated-protected animals also had a more pronounced increase in peripheral blood mononuclear cell IFN-alpha mRNA levels than did the vaccinated-unprotected animals in the first few weeks after challenge. Thus, innate as well as cellular anti-SIV immune responses appeared to contribute to the SHIV89.6-induced protection against intravaginal challenge with pathogenic SIVmac239.

Protection against Simian Immunodeficiency Virus Vaginal Challenge by Using Sabin Poliovirus Vectors

Abstract: Here we provide the first report of protection against a vaginal challenge with a highly virulent simian immunodeficiency virus (SIV) by using a vaccine vector. New poliovirus vectors based on Sabin 1 and 2 vaccine strain viruses were constructed, and these vectors were used to generate a series of new viruses containing SIV gag, pol, env, nef, and tat in overlapping fragments. Two cocktails of 20 transgenic polioviruses (SabRV1-SIV and SabRV2-SIV) were inoculated into seven cynomolgus macaques. All monkeys produced substantial anti-SIV serum and mucosal antibody responses. SIV-specific cytotoxic T-lymphocyte responses were detected in three of seven monkeys after vaccination. All 7 vaccinated macaques, as well as 12 control macaques, were challenged vaginally with pathogenic SIVmac251. Strikingly, four of the seven vaccinated animals exhibited substantial protection against the vaginal SIV challenge. All 12 control monkeys became SIV positive. In two of the seven SabRV-SIV-vaccinated monkeys we found no virological evidence of infection following challenge, indicating that these two monkeys were completely protected. Two additional SabRV-SIV-vaccinated monkeys exhibited a pronounced reduction in postacute viremia to <10(3) copies/ml, suggesting that the vaccine elicited an effective cellular immune response. Three of six control animals developed clinical AIDS by 48 weeks postchallenge. In contrast, all seven vaccinated monkeys remained healthy as judged by all clinical parameters. These results demonstrate the efficacy of SabRV as a potential human vaccine vector, and they show that the use of a vaccine vector cocktail expressing an array of defined antigenic sequences can be an effective vaccination strategy in an outbred population.

Incomplete protection against simian immunodeficiency virus vaginal transmission in rhesus macaques by a topical antiviral agent revealed by repeat challenges.

Abstract: The rising prevalence of human immunodeficiency virus type 1 (HIV-1) infection in women, especially in resource-limited settings, accentuates the need for accessible, inexpensive, and female-controlled preexposure prophylaxis strategies to prevent mucosal transmission of the virus. While many compounds can inactivate HIV-1 in vitro, evaluation in animal models for mucosal transmission of virus may help identify which approaches will be effective in vivo. Macaques challenged intravaginally with pathogenic simian immunodeficiency virus (SIVmac251) provide a model to preclinically evaluate candidate microbicides. 2-Hydroxypropyl-β-cyclodextrin (BCD) prevents HIV-1 and SIV infection of target cells at subtoxic doses in vitro. Consistent with these findings, intravaginal challenge of macaques with SIVmac251 preincubated with BCD prevented mucosal transmission, as measured by plasma viremia and antiviral antibodies, through 10 weeks postchallenge. In an initial challenge, BCD applied topically prior to SIVmac251 prevented intravaginal transmission of virus compared to controls (P < 0.0001). However, upon a second virus challenge following BCD pretreatment, the majority of the previously protected animals became infected. The mechanism through which animals become infected at a frequency similar to that of controls after prior exposure to BCD and SIVmac251 in subsequent intravaginal virus challenges (P = 0.63), despite the potent antiviral properties of BCD, remains to be determined. These results highlight the unpredictability of antiviral compounds as topical microbicides and suggest that repeated exposures to candidate treatments should be considered for in vivo evaluation.

Mucosal vaccines: the promise and the challenge

Abstract: Most infectious agents enter the body at mucosal surfaces and therefore mucosal immune responses function as a first line of defence. Protective mucosal immune responses are most effectively induced by mucosal immunization through oral, nasal, rectal or vaginal routes, but the vast majority of vaccines in use today are administered by injection. As discussed in this Review, current research is providing new insights into the function of mucosal tissues and the interplay of innate and adaptive immune responses that results in immune protection at mucosal surfaces. These advances promise to accelerate the development and testing of new mucosal vaccines against many human diseases including HIV/AIDS.

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.