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Current approaches do not eliminate all HIV-1 maternal-to-infant transmissions (MTIT); new prevention paradigms might help avert new infections. We administered Maraviroc (MVC) to rhesus macaques (RMs) to block CCR5-mediated entry, followed by repeated oral exposure of a CCR5-dependent clone of simian immunodeficiency virus (SIV)mac251 (SIVmac766). MVC significantly blocked the CCR5 coreceptor in peripheral blood mononuclear cells and tissue cells. All control animals and 60% of MVC-treated infant RMs became infected by the 6th challenge, with no significant difference between the number of exposures (p=0.15). At the time of viral exposures, MVC plasma and tissue (including tonsil) concentrations were within the range seen in humans receiving MVC as a therapeutic. Both treated and control RMs were infected with only a single transmitted/founder variant, consistent with the dose of virus typical of HIV-1 infection. The uninfected RMs expressed the lowest levels of CCR5 on the CD4+ T cells. Ramp-up viremia was significantly delayed (p=0.05) in the MVC-treated RMs, yet peak and postpeak viral loads were similar in treated and control RMs. In conclusion, in spite of apparent effective CCR5 blockade in infant RMs, MVC had marginal impact on acquisition and only a minimal impact on post infection delay of viremia following oral SIV infection. Newly developed, more effective CCR5 blockers may have a more dramatic impact on oral SIV transmission than MVC.ImportanceWe have previously suggested that the very low levels of simian immunodeficiency virus (SIV) maternal-to-infant transmissions (MTIT) in African nonhuman primates that are natural hosts of SIVs are due to a low availability of target cells (CCR5+ CD4+ T cells) in the oral mucosa of the infants, rather than maternal and milk factors. To confirm this new MTIT paradigm, we performed a proof of concept study, in which we therapeutically blocked CCR5 with maraviroc (MVC) and orally exposed MVC treated and naïve infant rhesus macaques to SIV. MVC had only a marginal effect on oral SIV transmission. However, the observation that the infant RMs that remained uninfected at the completion of the study, after 6 repeated viral challenges, had the lowest CCR5 expression on the CD4+ T cells prior to the MVC treatment, appear to confirm our hypothesis, also suggesting that the partial effect of MVC is due to a limited efficacy of the drug. Newly, more effective CCR5 inhibitors may have a better effect in preventing SIV and HIV transmission.

Copyright: © 2019. American Society for Clinical Investigation., Consuming a high-fat diet (HFD) is a risk factor for obesity and diabetes; both of these diseases are also associated with systemic inflammation, similar to HIV infection. A HFD induces intestinal dysbiosis and impairs liver function and coagulation, with a potential negative impact on HIV/SIV pathogenesis. We administered a HFD rich in saturated fats and cholesterol to nonpathogenic (African green monkeys) and pathogenic (pigtailed macaques) SIV hosts. The HFD had a negative impact on SIV disease progression in both species. Thus, increased cell-associated SIV DNA and RNA occurred in the HFD-receiving nonhuman primates, indicating a potential reservoir expansion. The HFD induced prominent immune cell infiltration in the adipose tissue, an important SIV reservoir, and heightened systemic immune activation and inflammation, altering the intestinal immune environment and triggering gut damage and microbial translocation. Furthermore, HFD altered lipid metabolism and HDL oxidation and also induced liver steatosis and fibrosis. These metabolic disturbances triggered incipient atherosclerosis and heightened cardiovascular risk in the SIV-infected HFD-receiving nonhuman primates. Our study demonstrates that dietary intake has a discernable impact on the natural history of HIV/SIV infections and suggests that dietary changes can be used as adjuvant approaches for HIV-infected subjects, to reduce inflammation and the risk of non-AIDS comorbidities and possibly other infectious diseases., This study was funded through NIH/NHLBI/NIAID/NIDDK/ NCRR R01 grants HL117715 (to IP), HL123096 (to IP), AI119346 (to CA), DK113919 (to IP and CA), DK119936 (to CA), RR025781 (to CA and IP), and AI104373 (to RMR). RMR was funded by grant PTDC/ MAT-APL/31602/2017 from the Fundação para a Ciência e Tecnologia (Portugal). DNF and CCW were supported by the University of Colorado GI and Liver Innate Immunity Program. KDR and BBP were partly supported by the NIH Training Grant T32AI065380. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright © 2018 American Society for Microbiology. All Rights Reserved, CD8+ cells play a key role in human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) infection, but their specific mechanism(s) of action in controlling the virus is unclear. Two-long-terminal-repeat (2-LTR) circles are extrachromosomal products generated upon failed integration of HIV/SIV. To understand the specific effects of CD8+ cells on infected cells, we analyzed the dynamics of 2-LTR circles in SIVmac251-infected rhesus macaques (RMs) treated with an integrase inhibitor (INT). Twenty RMs underwent CD8+ cell depletion and received raltegravir (RAL) monotherapy or a combination of both. Blood, lymph nodes (LNs), and gut biopsy specimens were routinely sampled. Plasma viral loads (pVLs) and 2-LTR circles from peripheral blood mononuclear cells (PBMCs) and LN lymphocytes were measured with quantitative reverse transcription-PCR (qRT-PCR). In the CD8 depletion group, an ∼1-log increase in pVLs and a slow increase in PBMC 2-LTRs occurred following depletion. In the INT group, a strong decline in pVLs upon treatment initiation and no change in 2-LTR levels were observed. In the INT and CD8+ cell depletion group, an increase in pVLs following CD8 depletion similar to that in the CD8 depletion group was observed, with a modest decline following INT initiation, and 2-LTR circles significantly increased in PBMCs and LNs. Analyzing the 2-LTR data across all treatment groups with a mathematical model indicates that the data best support an effect of CD8+ cells in killing cells prior to viral integration. Sensitivity analyses of these results confirm that effect but also allow for additional effects, which the data do not discriminate well. Overall, we show that INT does not significantly increase the levels of 2-LTR circles. However, CD8+ cell depletion increases the 2-LTR levels, which are enhanced in the presence of an INT.IMPORTANCE CD8+ T cells play an essential role in controlling HIV and SIV infection, but the specific mechanisms involved remain poorly understood. Due to failed viral infection, HIV and SIV can form 2-LTR extrachromosomal circles that can be quantified. We present novel data on the dynamics of these 2-LTR forms in a SIV-infected macaque model under three different treatment conditions: depletion of CD8+ cells, administration of the integrase inhibitor in a monotherapy, which favors the formation of 2-LTR circles, and a combination of the two treatments. We used a new mathematical model to help interpret the data, and the results suggest that CD8+ cells exert a killing effect on infected cells prior to virus integration. These results provide new insights into the mechanisms of action of CD8+ cells in SIV infection. Confirmation of our results would be an important step in understanding immune control of HIV., This work was supported by the National Institutes of Health/National Center for Research Resources/National Institute of Allergy and Infectious Diseases/National Heart, Lung and Blood Institute grants AI104373 (R.M.R.), R01 HL117715 (I.P.), R01 AI119346 (C.A.), and R01 HL123096 (I.P.). B.B.P. was supported in part by the NIH training grant T32 AI065380.

Viruses that persist despite seemingly effective antiretroviral treatment (ART) and can reinitiate infection if treatment is stopped preclude definitive treatment of HIV-1 infected individuals, requiring lifelong ART. Among strategies proposed for targeting these viral reservoirs, the premise of the “shock and kill” strategy is to induce expression of latent proviruses [for example with histone deacetylase inhibitors (HDACis)] resulting in elimination of the affected cells through viral cytolysis or immune clearance mechanisms. Yet, ex vivo studies reported that HDACis have variable efficacy for reactivating latent proviruses, and hinder immune functions. We developed a nonhuman primate model of post-treatment control of SIV through early and prolonged administration of ART and performed in vivo reactivation experiments in controller RMs, evaluating the ability of the HDACi romidepsin (RMD) to reactivate SIV and the impact of RMD treatment on SIV-specific T cell responses. Ten RMs were IV-infected with a SIVsmmFTq transmitted-founder infectious molecular clone. Four RMs received conventional ART for >9 months, starting from 65 days post-infection. SIVsmmFTq plasma viremia was robustly controlled to, Author Summary Antiretroviral therapy (ART) does not eradicate HIV-1 in infected individuals due to virus persistence in latently infected reservoir cells, despite apparently effective ART. The persistent virus and can rekindle infection when ART is interrupted. The goal of the “shock and kill” viral clearance strategy is to induce expression of latent proviruses and eliminate the infected cells through viral cytolysis or immune clearance mechanisms. Latency reversing agents (LRAs) tested to date have been reported to have variable effects, both on virus reactivation and on immune functions. We performed in vivo reactivation experiments in SIV-infected RMs that controlled viral replication after a period of ART to evaluate the ability of the histone deacetylase inhibitor romidepsin (RMD) to reactivate SIV and its impact on SIV-specific immune responses. Our results suggest that RMD treatment can increase virus expression in this setting, and that it does not markedly or durably impair the ability of SIV-specific T cells to control viral replication.

In 2009, the emergence of pandemic A influenza virus (pH1N1) demonstrated greater severity in pregnant women as recognized previously in other influenza pandemics. The Centers for Disease Control and Prevention reported a death rate of 20% in pregnant women in the United States who were hospitalized with influenza-like symptoms. To understand the immunological basis for the enhanced influenza-associated morbidity and mortality observed in pregnant women, pregnant and nonpregnant ferrets were challenged with aerosolized pH1N1 strain A/California/04/09. The pregnant ferrets had poorer gestational outcomes and presented a more rapid and severe clinical disease when compared to the nonpregnant ferret group. Viral load and tissue tropism were similar for both groups as determined by quantitative RT-PCR. Influenza virus was detected in the brains of both groups. Gross pathological analysis and H&E stains identified interstitial pneumonia in the lungs, with no significant pathology in any other tissues. Virus was also detected in placental tissue and kits of the pregnant ferrets suggesting transmission across the placental barrier. This model will be useful in discerning the differences in the host response to infection that results in greater morbidity and mortality during pregnancy.