Last data update: May 06, 2024. (Total: 46732 publications since 2009)
Records 1-13 (of 13 Records) |
Query Trace: Guenthner P[original query] |
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Broadly neutralizing antibody-mediated protection against SHIV infection among macaques with vaginal sexually transmitted infections
Garber DA , Guenthner P , Zhao C , Mitchell J , Ellis S , Jia H , Manganare M , Gazumyan A , Seaman MS , Vishwanathan SA , Heneine W , McNicholl JM . AIDS 2023 37 (5) 723-731 OBJECTIVE: Sexually transmitted infections (STIs) increase mucosal HIV infection risk and have the potential to reduce preexposure prophylaxis efficacy. Clinical trials of a broadly neutralizing antibody (bNAb) provided proof-of-concept that passive immunization against HIV can be efficacious in people. We sought to evaluate preclinically the protective efficacy of passive bNAb immunization against simian-human immunodeficiency virus (SHIV) infection in the context of concurrent vaginal STIs. DESIGN: Using a macaque model of combined ulcerative and nonulcerative vaginal STIs caused by Treponema pallidum, Chlamydia trachomatis, and Trichomonas vaginalis, we determined the protection that passively administered bNAb 10-1074 conferred against repeated vaginal SHIV challenges and compared correlates of protection to contemporaneous and historical controls without STIs. METHODS: Plasma viremia was monitored via RT-qPCR assay. Concentrations of 10-1074 were determined longitudinally in plasma samples via TZM-bl pseudovirus neutralization assay. RESULTS: Among macaques with vaginal STIs, a single subcutaneous injection of 10-1074 durably protected against vaginal SHIV acquisition, as compared with untreated controls. Interestingly, the median plasma concentration of 10-1074 at the time of SHIV breakthrough among macaques with STIs was significantly higher (10-fold) than that previously observed among 10-1074-treated macaques in the absence of STIs. CONCLUSION: Passive immunization with 10-1074 conferred significant protection against repeated vaginal SHIV challenges among macaques harboring vaginal STIs. However, our findings suggest that higher bNAb concentrations may be required for prophylaxis when STIs are present. Our findings potentially impact dose selection for the clinical development of bNAbs and highlight the importance of additional preclinical efficacy testing in STI models. |
Broadly neutralizing antibody-mediated protection of macaques against repeated intravenous exposures to simian-human immunodeficiency virus
Garber DA , Guenthner P , Mitchell J , Ellis S , Gazumyan A , Nason M , Seaman MS , McNicholl JM , Nussenzweig MC , Heneine W . AIDS 2021 35 (10) 1567-1574 OBJECTIVE: The opioid epidemic has increased parentally acquired HIV infection. To inform the development of a long-acting prevention strategy, we evaluated the protective efficacy of broadly neutralizing antibodies (bNAbs) against intravenous SHIV infection in macaques. DESIGN: Five cynomolgus macaques were injected once subcutaneously with 10-1074 and 3BNC117 (10 mg each kg-1) and were repeatedly challenged intravenously once weekly with SHIVAD8-EO (130 TCID50), until infection was confirmed via plasma viral load assay. Two control macaques, which received no antibody, were challenged identically. METHODS: Plasma viremia was monitored via RT-qPCR assay. bNAb concentrations were determined longitudinally in plasma samples via TZM-bl neutralization assays using virions pseudotyped with 10-1074-sensitive (X2088_c9) or 3BNC117-sensitive (Q769.d22) HIV envelope proteins. RESULTS: Passively immunized macaques were protected against a median of five weekly intravenous SHIV challenges, as compared to untreated controls, which were infected following a single challenge. Of the two bNAbs, 10-1074 exhibited relatively longer persistence in vivo. The median plasma level of 10-1074 at SHIV breakthrough was 1.1 μg ml-1 (range: 0.6-1.6 μg ml-1), whereas 3BNC117 was undetectable. Probit modeling estimated that 6.6 μg ml-1 of 10-1074 in plasma corresponded to a 99% reduction in per-challenge infection probability, as compared to controls. CONCLUSIONS: Significant protection against repeated intravenous SHIV challenges was observed following administration of 10-1074 and 3BNC117 and was due primarily to 10-1074. Our findings extend preclinical studies of bNAb-mediated protection against mucosal SHIV acquisition and support the possibility that intermittent subcutaneous injections of 10-1074 could serve as long-acting pre-exposure prophylaxis for persons who inject drugs. |
Durable protection against repeated penile exposures to simian-human immunodeficiency virus by broadly neutralizing antibodies
Garber DA , Adams DR , Guenthner P , Mitchell J , Kelley K , Schoofs T , Gazumyan A , Nason M , Seaman MS , McNicholl J , Nussenzweig MC , Heneine W . Nat Commun 2020 11 (1) 3195 Penile acquisition of HIV accounts for most infections among men globally. Nevertheless, candidate HIV interventions for men advance to clinical trials without preclinical efficacy data, due primarily to a paucity of relevant animal models of penile HIV infection. Using our recently developed macaque model, we show that a single subcutaneous administration of broadly neutralizing antibody (bNAb) 10-1074 conferred durable protection against repeated penile exposures to simian-human immunodeficiency virus (SHIVSF162P3). Macaques co-administered bNAbs 10-1074 and 3BNC117, or 3BNC117 alone, also exhibited significant protection against repeated vaginal SHIVAD8-EO exposures. Regression modeling estimated that individual plasma bNAb concentrations of 5 mug ml(-1) correlated with >/=99.9% relative reduction in SHIV infection probability via penile (10-1074) or vaginal (10-1074 or 3BNC117) challenge routes. These results demonstrate that comparably large reductions in penile and vaginal SHIV infection risk among macaques were achieved at clinically relevant plasma bNAb concentrations and inform dose selection for the development of bNAbs as long-acting pre-exposure prophylaxis candidates for use by men and women. |
Impact of Q-Griffithsin anti-HIV microbicide gel in non-human primates: In situ analyses of epithelial and immune cell markers in rectal mucosa
Gunaydin G , Edfeldt G , Garber DA , Asghar M , Noel-Romas L , Burgener A , Wahlby C , Wang L , Rohan LC , Guenthner P , Mitchell J , Matoba N , McNicholl JM , Palmer KE , Tjernlund A , Broliden K . Sci Rep 2019 9 (1) 18120 Natural-product derived lectins can function as potent viral inhibitors with minimal toxicity as shown in vitro and in small animal models. We here assessed the effect of rectal application of an anti-HIV lectin-based microbicide Q-Griffithsin (Q-GRFT) in rectal tissue samples from rhesus macaques. E-cadherin(+) cells, CD4(+) cells and total mucosal cells were assessed using in situ staining combined with a novel customized digital image analysis platform. Variations in cell numbers between baseline, placebo and Q-GRFT treated samples were analyzed using random intercept linear mixed effect models. The frequencies of rectal E-cadherin(+) cells remained stable despite multiple tissue samplings and Q-GRFT gel (0.1%, 0.3% and 1%, respectively) treatment. Whereas single dose application of Q-GRFT did not affect the frequencies of rectal CD4(+) cells, multi-dose Q-GRFT caused a small, but significant increase of the frequencies of intra-epithelial CD4(+) cells (placebo: median 4%; 1% Q-GRFT: median 7%) and of the CD4(+) lamina propria cells (placebo: median 30%; 0.1-1% Q-GRFT: median 36-39%). The resting time between sampling points were further associated with minor changes in the total and CD4(+) rectal mucosal cell levels. The results add to general knowledge of in vivo evaluation of anti-HIV microbicide application concerning cellular effects in rectal mucosa. |
Impact of the griffithsin anti-HIV microbicide and placebo gels on the rectal mucosal proteome and microbiome in non-human primates.
Girard L , Birse K , Holm JB , Gajer P , Humphrys MS , Garber D , Guenthner P , Noel-Romas L , Abou M , McCorrister S , Westmacott G , Wang L , Rohan LC , Matoba N , McNicholl J , Palmer KE , Ravel J , Burgener AD . Sci Rep 2018 8 (1) 8059 Topical microbicides are being explored as an HIV prevention method for individuals who practice receptive anal intercourse. In vivo studies of these microbicides are critical to confirm safety. Here, we evaluated the impact of a rectal microbicide containing the antiviral lectin, Griffithsin (GRFT), on the rectal mucosal proteome and microbiome. Using a randomized, crossover placebo-controlled design, six rhesus macaques received applications of hydroxyethylcellulose (HEC)- or carbopol-formulated 0.1% GRFT gels. Rectal mucosal samples were then evaluated by label-free tandem MS/MS and 16 S rRNA gene amplicon sequencing, for proteomics and microbiome analyses, respectively. Compared to placebo, GRFT gels were not associated with any significant changes to protein levels at any time point (FDR < 5%), but increased abundances of two common and beneficial microbial taxa after 24 hours were observed in HEC-GRFT gel (p < 2E-09). Compared to baseline, both placebo formulations were associated with alterations to proteins involved in proteolysis, activation of the immune response and inflammation after 2 hours (p < 0.0001), and increases in beneficial Faecalibacterium spp. after 24 hours in HEC placebo gel (p = 4.21E-15). This study supports the safety profile of 0.1% GRFT gel as an anti-HIV microbicide and demonstrates that current placebo formulations may associate with changes to rectal proteome and microbiota. |
Development of a repeat-exposure penile SHIV infection model in macaques to evaluate biomedical preventions against HIV
Garber DA , Mitchell J , Adams D , Guenthner P , Deyounks F , Ellis S , Kelley K , Johnson R , Dobard C , Heneine W , McNicholl J . PLoS One 2018 13 (3) e0194837 Penile acquisition of HIV infection contributes substantially to the global epidemic. Our goal was to establish a preclinical macaque model of penile HIV infection for evaluating the efficacy of new HIV prevention modalities. Rhesus macaques were challenged once or twice weekly with consistent doses of SHIVsf162P3 (a chimeric simian-human immunodeficiency virus containing HIV env) ranging from 4-600 TCID50 (50% tissue culture infective dose), via two penile routes, until systemic SHIV infection was confirmed. One route exposed the inner foreskin, glans and urethral os to virus following deposition into the prepuce (foreskin) pouch. The second route introduced the virus non-traumatically into the distal urethra only. Single-route challenges resulted in dose-dependent rates of SHIV acquisition informing selection of optimal SHIV dosing. Concurrent SHIV challenges via the prepuce pouch (200 TCID50) and urethra (16 TCID50) resulted in infection of 100% (10/10) animals following a median of 2.5 virus exposures (range, 1-12). We describe the first rhesus macaque repeat-exposure SHIV challenge model of penile HIV acquisition. Utilization of the model should further our understanding of penile HIV infection and facilitate the development of new HIV prevention strategies for men. |
Cataloguing of Potential HIV Susceptibility Factors during the Menstrual Cycle of Pig-Tailed Macaques by Using a Systems Biology Approach
Vishwanathan SA , Burgener A , Bosinger SE , Tharp GK , Guenthner PC , Patel NB , Birse K , Hanson DL , Westmacott GR , Henning T , Radzio J , Garcia-Lerma JG , Ball TB , McNicholl JM , Kersh EN . J Virol 2015 89 (18) 9167-77 Our earlier studies in pig-tailed macaques demonstrated varying SHIV susceptibility during the menstrual cycle, likely caused by cyclic variations in immune responses in the female genital tract. There is concern that high-dose, long-lasting, injectable progestin-based contraception could mimic the high-progesterone luteal phase and predispose women to HIV-1 acquisition and transmission. In this study, we adopted a systems biology approach employing proteomics (tandem mass spectrometry), transcriptomics (RNA microarray hybridization), and other specific protein assays (enzyme-linked immunosorbent assays and multiplex chemokine-cytokine measurements) to characterize the effects of hormonal changes on the expression of innate factors and secreted proteins in the macaque vagina. Several antiviral factors and pathways (including acute phase response signaling and complement system) were overexpressed in the follicular phase. Conversely, during the luteal phase there were factors overexpressed (including moesins, syndecans, integrins, among others) that could play direct or indirect roles in enhancing HIV-1 infection. Thus, our study showed that specific pathways and proteins/genes might be working in tandem to regulate innate immunity, thus fostering further investigation and future design of approaches to help counter HIV-1 acquisition in the female genital tract. IMPORTANCE: HIV infection in women is poorly understood. High levels of the hormone progesterone may make women more vulnerable to infection. This could be the case during the menstrual cycle, when using hormone-based birth control, or during pregnancy. The biological basis for increased HIV vulnerability is not known. We used an animal model with high risk for infection during periods of high progesterone. Genital secretions and tissues were studied during the menstrual cycle. Our goal was to identify biological factors upregulated at high progesterone levels, and we indeed show an upregulation of genes and proteins which enhance the ability of HIV to infect when progesterone is high. In contrast, during low progesterone periods, we find more HIV inhibitory factors. This basic research study contributes to our understanding of mechanisms that may regulate HIV infection in females under hormonal influences. Such knowledge is needed for the development of novel prevention strategies. |
SHIV susceptibility changes during the menstrual cycle of pigtail macaques
Kersh EN , Henning T , Vishwanathan SA , Morris M , Butler K , Adams DR , Guenthner P , Srinivasan P , Smith J , Radzio J , Garcia-Lerma JG , Dobard C , Heneine W , McNicholl J . J Med Primatol 2014 43 (5) 310-6 BACKGROUND: Hormonal changes during menstrual cycling may affect susceptibility to HIV. METHODS: We determined the simian human immunodeficiency virus (SHIV) acquisition time point in 43 cycling pigtail macaques infected by repeated vaginal virus exposures initiated randomly in the cycle. RESULTS: SHIV infection was first detected in the follicular phase in 38 macaques (88%), and in the luteal phase in five macaques (12%), indicating a statistically significant timing difference. Assuming a 7-day eclipse phase, most infections occurred during or following a high-progesterone period associated with menstruation, vaginal epithelium thinning, and suppressed mucosal immunity. CONCLUSIONS: This raises questions whether other high-progesterone conditions (pregnancy, hormonal contraception) similarly affect HIV risk. |
Longitudinal assessment of pigtailed macaque lower genital tract microbiota by pyrosequencing reveals dissimilarity to the genital microbiota of healthy humans
Spear GT , Kersh E , Guenthner P , Vishwanathan SA , Gilbert D , Zariffard MR , Mirmonsef P , Landay A , Zheng L , Gillevet P . AIDS Res Hum Retroviruses 2012 28 (10) 1244-9 Vaginal bacterial communities play an important role in human health and have been shown to influence HIV infection. Pigtailed macaques (Macaca nemestrina) are used as an animal model of HIV vaginal infection of women. Since the bacterial microbiota could influence retrovirus infection of pigtailed macaques, the genital microbiota in 10 cycling macaques was determined by pyrosequencing. The microbiota of all macaques was polymicrobial with a median of 13 distinct genera. Strikingly, the genera Sneathia and Fusobacterium, both in the phylum Fusobacteria, accounted for 18.9% and 13.3% of sequences while the next most frequent were Prevotella (5.6%), Porphyromonas (4.1%), Atopobium (3.6%), and Parvimonas (2.6%). Sequences corresponding to Lactobacillus comprised only 2.2% of sequences on average and were essentially all L. amylovorus. Longitudinal sampling of the 10 macaques over an 8-week period, which spanned at least one full ovulatory cycle, showed a generally stable presence of the major types of bacteria with some exceptions. These studies show that the microbiota of the pigtailed macaques is substantially dissimilar to that found in most healthy humans, where the genital microbiota is usually dominated by Lactobacillus sp. The polymicrobial makeup of the macaque bacterial populations, the paucity of lactobacilli, and the specific types of bacteria present suggest that the pigtailed macaque microbiota could influence vaginal retrovirus infection. |
High susceptibility to repeated, low-dose, vaginal SHIV exposure late in the luteal phase of the menstrual cycle of pigtail macaques
Vishwanathan SA , Guenthner PC , Lin CY , Dobard C , Sharma S , Adams DR , Otten RA , Heneine W , Hendry RM , McNicholl JM , Kersh EN . J Acquir Immune Defic Syndr 2011 57 (4) 261-4 Fluctuations in susceptibility to HIV or SHIV during the menstrual cycle are currently not fully documented. To address this, time point of infection was determined in 19 adult female pigtail macaques vaginally challenged during their undisturbed menstrual cycles with repeated, low-dose SHIVSF162P3 exposures. Eighteen macaques (95%) first displayed viremia in the follicular phase, as compared to 1 macaque (5%) in the luteal phase (p<0.0001). Due to a viral eclipse phase, we estimated a window of most frequent virus transmission between days 24-31 of the menstrual cycle, in the late luteal phase. Thus, susceptibility to vaginal SHIV infection is significantly elevated in the second half of the menstrual cycle when progesterone levels are high, and when local immunity may be low. Such susceptibility windows have been postulated before but not definitively documented. Our data support findings of higher susceptibility to HIV in women during progesterone-dominated periods including pregnancy and contraceptive use. |
Resistance to simian HIV infection is associated with high plasma interleukin-8, RANTES and Eotaxin in a macaque model of repeated virus challenges
Promadej-Lanier N , Hanson DL , Srinivasan P , Luo W , Adams DR , Guenthner PC , Butera S , Otten RA , Kersh EN . J Acquir Immune Defic Syndr 2010 53 (5) 574-81 Animal models for research on susceptibility to HIV are currently not available. Here we explore whether a macaque model of repeated low-dose rectal or vaginal virus challenges could be employed. We tested the hypothesis that susceptibility to Simian HIV is not merely stochastic in this model but rather is associated with identifiable host factors. Forty macaques required a median of 3.5 SHIVSF162P3 challenges for infection. We studied the association of their susceptibility with 13 predisposing plasma cytokines/chemokines (RANTES, Eotaxin, monocyte chemoattractant protein (MCP)-1, IL-7, MIP-1beta, TNF-alpha, MIP-1alpha, granulocyte colony-stimulating factor, IL-8, interferon-gamma, IL-17, IL-1beta, IL-6). Higher plasma RANTES, IL-8, and Eotaxin were associated with lower susceptibility, that is, higher resistance to infection. In a group of macaques with low IL-8 and RANTES, a median 3 exposures were required to infect; whereas, when either IL-8 or RANTES were high, a median 12 exposures were required. Thus, susceptibility was associated with identifiable discrete host factors and was not stochastic. In addition, the macaque model identified key human resistance factors (RANTES, Eotaxin), but also revealed a novel association with resistance (IL-8). Future direct evaluation of these or other factors in the animal model may be beneficial for developing new immunomodulation strategies for HIV prevention. |
Multi-site comparison of anti-HIV microbicide activity in explant assays using a novel endpoint analysis
Richardson-Harman N , Lackman-Smith C , Fletcher PS , Anton PA , Bremer JW , Dezzutti CS , Elliott J , Grivel JC , Guenthner P , Gupta P , Jones M , Lurain NS , Margolis LB , Mohan S , Ratner D , Reichelderfer P , Roberts P , Shattock RJ , Cummins JE Jr . J Clin Microbiol 2009 47 (11) 3530-9 Microbicide candidates with promising in vitro activity are often advanced for evaluations using human primary tissue explants relevant to the in vivo mucosal transmission of HIV-1, such as tonsil, cervical or rectal tissue. To compare virus growth or the anti-HIV-1 efficacy of candidate microbicides in tissue explants, a novel 'soft endpoint' method, was evaluated to provide a single, objective measurement of virus growth. The applicability of the soft endpoint is shown across several different ex vivo tissue types, performed in different laboratories, and for a candidate microbicide (PRO 2000). The soft endpoint was compared to several other endpoint methods including: 1) the growth of virus on specific days after infection; 2) the area under the virus growth curve; and 3) the slope of the virus growth curve. Virus growth at the assay soft endpoint was compared between laboratories, methods and experimental conditions using non-parametric statistical analyses. Intra-assay variability determinations using the coefficient of variation demonstrated higher variability for virus growth in rectal explants. Significant virus inhibition by PRO 2000 and significant differences in the growth of certain primary HIV-1 isolates were observed by the majority of laboratories. These studies indicate that different laboratories can provide consistent measurements of anti-HIV-1 microbicide efficacy when: (i) the soft endpoint or other standardized endpoint is used; (ii) drugs and/or virus reagents are centrally sourced and; (iii) the same explant tissue type and method are used. Application of the soft endpoint reduces the inherent variability in comparisons of pre-clinical assays used for microbicide development. |
Complete protection from repeated vaginal simian-human immunodeficiency virus exposures in macaques by a topical gel containing tenofovir alone or with emtricitabine
Parikh UM , Dobard C , Sharma S , Cong ME , Jia H , Martin A , Pau CP , Hanson DL , Guenthner P , Smith J , Kersh E , Garcia-Lerma JG , Novembre FJ , Otten R , Folks T , Heneine W . J Virol 2009 83 (20) 10358-65 New-generation gels that deliver potent antiretroviral drugs against HIV-1 have renewed hopes in topical prophylaxis as a prevention strategy. Previous preclinical research in monkey models suggested that high concentrations and drug combinations are needed for high efficacy. We evaluated two long-acting reverse transcriptase inhibitors, tenofovir and emtricitabine (FTC), using a twice-weekly repeat-challenge macaque model and showed that a pre-exposure vaginal application of gel with 1% tenofovir alone or in combination with 5% FTC both fully protected macaques from a total of 20 exposures to SHIVSF162p3. FTC and TFV were detected in plasma 30 minutes after vaginal application suggesting rapid absorption. FTC was more frequently detected than TFV and showed higher levels reflecting the 5-fold higher concentration of this drug relative to TFV. Two of 12 repeatedly exposed but protected macaques showed limited T-cell priming which did not induce resistance to infection when macaques were re-challenged. Thus, single drugs with durable antiviral activity can provide highly effective topical prophylaxis and overcome the need for non-coital use or for drug combinations which are more complex and costly to formulate and approve. |
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