Hydrogen sulfide blocks HIV rebound by maintaining mitochondrial bioenergetics and redox homeostasis.

A fundamental challenge in human immunodeficiency virus (HIV) eradication is to understand how the virus establishes latency, maintains stable cellular reservoirs, and promotes rebound upon interruption of antiretroviral therapy (ART). Here, we discovered an unexpected role of the ubiquitous gasotransmitter hydrogen sulfide (H2S) in HIV latency and reactivation. We show that reactivation of HIV is associated with downregulation of the key H2S producing enzyme cystathionine-γ-lyase (CTH) and reduction in endogenous H2S. Genetic silencing of CTH disrupts redox homeostasis, impairs mitochondrial function, and remodels the transcriptome of latent cells to trigger HIV reactivation. Chemical complementation of CTH activity using a slow-releasing H2S donor, GYY4137, suppressed HIV reactivation and diminished virus replication. Mechanistically, GYY4137 blocked HIV reactivation by inducing the Keap1-Nrf2 pathway, inhibiting NF-κB, and recruiting the epigenetic silencer, YY1, to the HIV promoter. In latently infected CD4+ T cells from ART-suppressed human subjects, GYY4137 in combination with ART prevented viral rebound and improved mitochondrial bioenergetics. Moreover, prolonged exposure to GYY4137 exhibited no adverse influence on proviral content or CD4+ T cell subsets, indicating that diminished viral rebound is due to a loss of transcription rather than a selective loss of infected cells. In summary, this work provides mechanistic insight into H2S-mediated suppression of viral rebound and suggests exploration of H2S donors to maintain HIV in a latent form.

Biogenesis of P-TEFb in CD4+ T cells to reverse HIV latency is mediated by protein kinase C (PKC)-independent signaling pathways.

The switch between HIV latency and productive transcription is regulated by an auto-feedback mechanism initiated by the viral trans-activator Tat, which functions to recruit the host transcription elongation factor P-TEFb to proviral HIV. A heterodimeric complex of CDK9 and one of three cyclin T subunits, P-TEFb is expressed at vanishingly low levels in resting memory CD4+ T cells and cellular mechanisms controlling its availability are central to regulation of the emergence of HIV from latency. Using a well-characterized primary T-cell model of HIV latency alongside healthy donor memory CD4+ T cells, we characterized specific T-cell receptor (TCR) signaling pathways that regulate the generation of transcriptionally active P-TEFb, defined as the coordinate expression of cyclin T1 and phospho-Ser175 CDK9. Protein kinase C (PKC) agonists, such as ingenol and prostratin, stimulated active P-TEFb expression and reactivated latent HIV with minimal cytotoxicity, even in the absence of intracellular calcium mobilization with an ionophore. Unexpectedly, inhibition-based experiments demonstrated that PKC agonists and TCR-mobilized diacylglycerol signal through MAP kinases ERK1/2 rather than through PKC to effect the reactivation of both P-TEFb and latent HIV. Single-cell and bulk RNA-seq analyses revealed that of the four known isoforms of the Ras guanine nucleotide exchange factor RasGRP, RasGRP1 is by far the predominantly expressed diacylglycerol-dependent isoform in CD4+ T cells. RasGRP1 should therefore mediate the activation of ERK1/2 via Ras-Raf signaling upon TCR co-stimulation or PKC agonist challenge. Combined inhibition of the PI3K-mTORC2-AKT-mTORC1 pathway and the ERK1/2 activator MEK prior to TCR co-stimulation abrogated active P-TEFb expression and substantially suppressed latent HIV reactivation. Therefore, contrary to prevailing models, the coordinate reactivation of P-TEFb and latent HIV in primary T cells following either TCR co-stimulation or PKC agonist challenge is independent of PKC but rather involves two complementary signaling arms of the TCR cascade, namely, RasGRP1-Ras-Raf-MEK-ERK1/2 and PI3K-mTORC2-AKT-mTORC1.

Time to first viral load testing among pregnant women living with HIV initiated on option B+ at 5 government clinics in Kampala city, Uganda: Retrospective cohort study.

BACKGROUND: Timely viral load (VL) testing is critical in the care of pregnant women living with HIV and receiving anti-retroviral therapy (ART). There is paucity of data regarding the Time to First Viral Load (TFVL) testing in resource-limited settings. METHODS: We extracted clinical and VL test data from records of a cohort of ART-naïve pregnant women living with HIV who initiated Option B + and were retained in care between 01 Jan 2015 and 31 Dec 2015. The data were verified against laboratory VL registers. TFVL (in months) was calculated based on the time difference between the date of ART initiation and FVL test. Descriptive and Cox regression analyses of data up to 30 Sep 2017 (33 months later) were done. RESULTS: Of the 622 records retrieved, 424 women were retained in care. Of 424 women retained in care, 182/424 (43%) had at least one VL result post ART initiation while 242/424 (57%) had no VL performed. Only 30/182 (16.5%) had a second VL. At six, nine, and twelve months, only 8/424 (1.9%), 47/424 (11.1%), and 94/424 (22.2%) had VL testing performed respectively post ART initiation. The median TFVL testing was 12.7 months (95 CI 11.6-13.7) post ART initiation. Across the five clinics, patient factors (age, gravidity, gestational age, marital status, and adherence at 12 months) were not significant predictors. CONCLUSION: A dismal 1.9% rate of achieving WHO-recommended TFVL testing and a median TFVL testing of twelve months post ART initiation were observed. The non-association of patient factors to these observations may suggest a serious need to review health system factors likely associated with these observations and their effective interventions.

Bioactive Natural Antivirals: An Updated Review of the Available Plants and Isolated Molecules.

Viral infections and associated diseases are responsible for a substantial number of mortality and public health problems around the world. Each year, infectious diseases kill 3.5 million people worldwide. The current pandemic caused by COVID-19 has become the greatest health hazard to people in their lifetime. There are many antiviral drugs and vaccines available against viruses, but they have many disadvantages, too. There are numerous side effects for conventional drugs, and active mutation also creates drug resistance against various viruses. This has led scientists to search herbs as a source for the discovery of more efficient new antivirals. According to the World Health Organization (WHO), 65% of the world population is in the practice of using plants and herbs as part of treatment modality. Additionally, plants have an advantage in drug discovery based on their long-term use by humans, and a reduced toxicity and abundance of bioactive compounds can be expected as a result. In this review, we have highlighted the important viruses, their drug targets, and their replication cycle. We provide in-depth and insightful information about the most favorable plant extracts and their derived phytochemicals against viral targets. Our major conclusion is that plant extracts and their isolated pure compounds are essential sources for the current viral infections and useful for future challenges.

Ending the epidemic of HIV/AIDS by 2030: Will there be an endgame to HIV, or an endemic HIV requiring an integrated health systems response in many countries?

The third Sustainable Development Goal (SDG-3) has a target to end the epidemic of HIV/AIDS by 2030 (Project 2030). This will be achieved when the number of new HIV infections and 'AIDS-related deaths' decline by 90% between 2010 and 2030. So far, the rate of drop in AIDS-related deaths is on track, whereas the rate of drop in new HIV infections is off track to achieve Project 2030. Even if Project 2030 was achieved, HIV would be an endemic health problem. Hence, HIV prevention and control programmes cannot close down for the foreseeable future. This rather demands a paradigm shift from a fully vertical to an integrated health systems response that provides services according to disease burden towards universal health coverage. This will ensure the sustainability of HIV services in the post-2030 era. These all entail unrelenting political commitment, and increased and sustainable funding from both national and global sources.

The role of iron in viral infections.

Crucial cellular processes such as DNA synthesis and the generation of ATP require iron. Viruses depend on iron in order to efficiently replicate within living host cells. Some viruses selectively infect iron - acquiring cells or influence the cellular iron metabolism via Human hemochromatosis protein (HFE) or hepcidin. During infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV) iron overload is associated with poor prognosis for the patient and enhanced progression of the disease. Recent findings still lack to fully describe the viral interaction with the host iron metabolism during infection. This review summarizes the current knowledge of the viral regulation on the host cell iron metabolism in order to discuss the therapeutic option of iron chelation as a potential and beneficial adjuvant in antiviral therapy.

Challenges of reaching 90-90-90 in the Southern United States.

PURPOSE OF REVIEW: More than half of new HIV diagnoses occur in the Southern United States where the epidemic disproportionately affects persons of color. Although other areas of the country are seeing dramatic declines in the number of new cases, the progress in the South lags behind. This review will examine the reasons for that disparity. Many are unique to the South. RECENT FINDINGS: Despite advances in antiretroviral therapy for HIV, many in the South are not benefiting from these medications, at either a personal or public health level. The reasons are complex and include lack of access to healthcare, lower levels of funding than other areas of the country, stigma, structural racism, increased barriers due to social determinants of health, coexisting mental health disorders, substance use disorders and sexually transmitted diseases and insufficient workforce capacity to meet the needs of those living with HIV. SUMMARY: These findings should underline the need for investment in the South for a holistic healthcare approach to persons living with HIV including supporting basic needs such as access to food, transportation and housing. Prioritization among politicians for policy and systems changes and approaches to decrease stigma and enhance education about HIV will be key.

The Impact of Anti-Retroviral Therapy on Tuberculosis Detection at the National Level in South Africa.

Human immunodeficiency virus/tuberculosis (HIV/TB) coinfection is particularly prevalent in South Africa, where TB has been the leading cause of death for more than a decade. The 2004-2008 national rollout of antiretroviral therapy (ART) provides a unique opportunity to examine the population-level impact of ART on the TB epidemic. We performed longitudinal regression analysis to follow the evolution of TB outcomes before and after the introduction of ART using a large data set from the National Health Laboratory Service. This is the first study to produce estimates of the impact of the ART rollout by exploiting staggered timing and geographic variation in the rollout. After ART became available in a health facility, 3.7% (P < 0.0001) more patients were tested for TB and 3.2% (P < 0.0001) more received repeat testing; however, there was a steep rise in testing before the introduction of ART. Although the number of TB-positive patients increased by 4.3% (P = 0.0002) in the first year post-ART, the TB rate among tested patients fell by 2 percentage points (8%, P = 0.001) after 2 years. Sputum smear testing declined relative to more technologically advanced diagnostics post-ART. Antiretroviral therapy availability increased the attention to TB screening and drew new patients into the health-care system. Small increases in the numbers of repeat patients are indicative of retention in care. The decline in TB rates post-ART suggests that the reduction in TB risk due to improved immune functioning and health-care contact likely outweighed the increased TB risk because of the longer lifespan of ART initiators.

Vitamin D in Human Immunodeficiency Virus Infection: Influence on Immunity and Disease.

People living with human immunodeficiency virus (HIV) infection typically have hypovitaminosis D, which is linked to a large number of pathologies, including immune disorders and infectious diseases. Vitamin D (VitD) is a key regulator of host defense against infections by activating genes and pathways that enhance innate and adaptive immunity. VitD mediates its biological effects by binding to the Vitamin D receptor (VDR), and activating and regulating multiple cellular pathways. Single nucleotide polymorphisms in genes from those pathways have been associated with protection from HIV-1 infection. High levels of VitD and VDR expression are also associated with natural resistance to HIV-1 infection. Conversely, VitD deficiency is linked to more inflammation and immune activation, low peripheral blood CD4+ T-cells, faster progression of HIV disease, and shorter survival time in HIV-infected patients. VitD supplementation and restoration to normal values in HIV-infected patients may improve immunologic recovery during combination antiretroviral therapy, reduce levels of inflammation and immune activation, and increase immunity against pathogens. Additionally, VitD may protect against the development of immune reconstitution inflammatory syndrome events, pulmonary tuberculosis, and mortality among HIV-infected patients. In summary, this review suggests that VitD deficiency may contribute to the pathogenesis of HIV infection. Also, VitD supplementation seems to reverse some alterations of the immune system, supporting the use of VitD supplementation as prophylaxis, especially in individuals with more severe VitD deficiency.

Towards novel therapeutics for HIV through fragment-based screening and drug design.

Fragment-based drug discovery has been applied with varying levels of success to a number of proteins involved in the HIV (Human Immunodeficiency Virus) life cycle. Fragment-based approaches have led to the discovery of novel binding sites within protease, reverse transcriptase, integrase, and gp41. Novel compounds that bind to known pockets within CCR5 have also been identified via fragment screening, and a fragment-based approach to target the TAR-Tat interaction was explored. In the context of HIV-1 reverse transcriptase (RT), fragment-based approaches have yielded fragment hits with mid-µM activity in an in vitro activity assay, as well as fragment hits that are active against drug-resistant variants of RT. Fragment-based drug discovery is a powerful method to elucidate novel binding sites within proteins, and the method has had significant success in the context of HIV proteins.

Screening for noise in gene expression identifies drug synergies.

Stochastic fluctuations are inherent to gene expression and can drive cell-fate specification. We used such fluctuations to modulate reactivation of HIV from latency-a quiescent state that is a major barrier to an HIV cure. By screening a diverse library of bioactive small molecules, we identified more than 80 compounds that modulated HIV gene-expression fluctuations (i.e., "noise"), without changing mean expression. These noise-modulating compounds would be neglected in conventional screens, and yet, they synergized with conventional transcriptional activators. Noise enhancers reactivated latent cells significantly better than existing best-in-class reactivation drug combinations (and with reduced off-target cytotoxicity), whereas noise suppressors stabilized latency. Noise-modulating chemicals may provide novel probes for the physiological consequences of noise and an unexplored axis for drug discovery, allowing enhanced control over diverse cell-fate decisions.

[Correlation study of HIV/AIDS abnormal immune activation and disease progression].

OBJECTIVE: To learn the levels of immune function and immune activation of HIV/AIDS patients in China and find the correlation between the immune activation and CD4+ T lymphocyte and disease progression. And discuss the relevance of immune activation with HIV/AIDS pathogenesis. METHOD: Two hundred and eighty seven cases of HIV/AIDS patients in different disease stages who never accept HAART before and 40 healthy HIV negative donors have been involved in the research. Their immune function and abnormal immune activation markers are detected by flow cytometry counts, and the immune activation markers include CD8 CD38+ T cells and CD8+ HLA-DR+ T cell. Compare the difference of abnormal immune activation between patients of various disease stages. And by Pearson correlation test analysis, the correlation between the immune activation levels and abnormal CD4+ T lymphocyte count and disease progression will be found. RESULT: The immune abnormal activation levels were significantly different between patients of different disease stages (P < 0.001). Correlation analysis showed that there was a significant negative correlation between peripheral blood CD4+ T cell counts and immune activation markers. CONCLUSION: Immune activation induced by HIV infection may lead to decreased CD4+ T cell count and disease progression.

[Discussion on AIDS etiology, pathogenesis and treatment of traditional Chinese medicine].

In recent years, Chinese medicine have gotten certain experience and made progress on the treatment of AIDS. Focus on AIDS main pathogenic factors of epidemic toxin and key pathogenesis of "epidemic toxin invasion, vital-Qi deficiency", this paper discuss on Chinese medicine theory of AIDS etiology and pathogenesis, and put forward the theory of "preventive treatment of disease" and enhanced the importance of "strengthening body resistance and eliminating evil" in the treatment of AIDS.

Nerium oleander derived cardiac glycoside oleandrin is a novel inhibitor of HIV infectivity.

We evaluated the effectiveness of Anvirzel™, an aqueous extract of Nerium oleander on HIV infection of human peripheral blood mononuclear cells. Oleandrin, the principle cardiac glycoside (CG) in Anvirzel™ has been shown to exhibit anti-cancer properties but its efficacy against HIV is unknown. Treatment with Anvirzel™ significantly reduced the infectivity of virus produced from infected cells without any change in the total amount of virus produced. This is in contrast to treatment with AZT, a potent inhibitor of HIV replication that has been shown to significantly reduce virus production. Relative to untreated cultures, virus in cultures treated with oleandrin had significantly reduced expression of the envelope protein gp120, the sole determinant of virus infectivity, suggesting a novel mechanism underlying the impaired infectivity. These results support the potential utility of the Nerium oleander aqueous extract, containing the CG oleandrin as a novel candidate anti-HIV therapeutic.

Systematic identification of synergistic drug pairs targeting HIV.

The systematic identification of effective drug combinations has been hindered by the unavailability of methods that can explore the large combinatorial search space of drug interactions. Here we present multiplex screening for interacting compounds (MuSIC), which expedites the comprehensive assessment of pairwise compound interactions. We examined ∼500,000 drug pairs from 1,000 US Food and Drug Administration (FDA)-approved or clinically tested drugs and identified drugs that synergize to inhibit HIV replication. Our analysis reveals an enrichment of anti-inflammatory drugs in drug combinations that synergize against HIV. As inflammation accompanies HIV infection, these findings indicate that inhibiting inflammation could curb HIV propagation. Multiple drug pairs identified in this study, including various glucocorticoids and nitazoxanide (NTZ), synergize by targeting different steps in the HIV life cycle. MuSIC can be applied to a wide variety of disease-relevant screens to facilitate efficient identification of compound combinations.

Zinc acetate/carrageenan gels exhibit potent activity in vivo against high-dose herpes simplex virus 2 vaginal and rectal challenge.

Topical microbicides that block the sexual transmission of HIV and herpes simplex virus 2 (HSV-2) are desperately needed to reduce the incidence of HIV infections worldwide. Previously we completed phase 3 testing of the carrageenan-based gel Carraguard. Although the trial did not show that Carraguard is effective in preventing HIV transmission during vaginal sex, it did show that Carraguard is safe when used weekly for up to 2 years. Moreover, Carraguard has in vitro activity against human papillomavirus (HPV) and HSV-2 and favorable physical and rheological properties, which makes it a useful vehicle to deliver antiviral agents such as zinc acetate. To that end, we previously reported that a prototype zinc acetate carrageenan gel protects macaques against vaginal challenge with combined simian-human immunodeficiency virus reverse transcriptase (SHIV-RT). Herein, we report the safety and efficacy of a series of zinc acetate and/or carrageenan gels. The gels protected mice (75 to 85% survival; P < 0.001) against high-dose (10(6)-PFU) HSV-2 vaginal or rectal challenge. In contrast, zinc acetate formulated in HEC (hydroxyethylcellulose; or the Universal Placebo) failed to protect mice against the high-dose vaginal HSV-2 challenge (similar to aqueous zinc acetate solution and the placebo controls). The gels were found to be effective spreading gels, exhibited limited toxicity in vitro, caused minimal damage to the architecture of the cervicovaginal and rectal mucosae in vivo, and induced no increased susceptibility to HSV-2 infection in a mouse model. Our results provide a strong rationale to further optimize and evaluate the zinc acetate/carrageenan gels for their ability to block the sexual transmission of HIV and HSV-2.

Vitamin D supplementation does not increase immunogenicity of seasonal influenza vaccine in HIV-infected adults.

The influence of vitamin D on influenza vaccine immunogenicity in HIV was assessed using data from a phase 3, randomized trial conducted during the 2008-2009 influ-enza season. Thirty-three percent of participants were on supplemental vitamin D at baseline. Neither seroconversion nor seroprotection were predicted by vitamin D use for any of the 3 vaccine strains. There is no evidence of improved influenza vaccine immunogenicity with vitamin D supplementation in this HIV-positive population.

Bitter gourd (Momordica charantia) is a cornucopia of health: a review of its credited antidiabetic, anti-HIV, and antitumor properties.

Bitter gourd (Momordica charantia, BG) is both a nutritious and healthy food with a distinctive bitter flavor, and it is also widely exploited in folklore medicine. This review focuses on the efficacies and molecular mechanisms of BG-induced anti-diabetic, anti-HIV, and antitumor activities contributed by over twenty active components. The intent of this review is to provide comprehensive and valuable information for medicinal researchers, drug investigators, clinicians, and even patients with an interest in BG. In conclusion, BG is a cornucopia of health and it deserves in-depth investigations for clinical application in the future.

Alterations in brain metabolism during the first year of HIV infection.

Migration of both uninfected and infected monocytes into the brain during acute HIV infection likely initiates metabolic changes that can be observed with magnetic resonance spectroscopy (MRS). Herein, we measured changes in brain metabolism during the first year of HIV infection and examined the relationship of these metabolite levels to CD16+ monocyte populations measured in the blood. MRS was performed on nine HIV+ subjects identified during acute HIV infection and nine seronegative control subjects. HIV+ subjects were examined within 90 days of an indeterminate Western blot, then again 2 and 6 months later, during early infection. Blood samples were collected for plasma viral RNA and monocyte subset quantification. HIV+ subjects were identified with acute viral ailment and did not display severe cognitive deficits such as dementia or minor cognitive motor disorder. Changes in lipid membrane metabolism (choline levels) in the frontal cortex and white matter were observed during the initial year of HIV infection. Greater numbers of CD16+ monocytes were associated with lower N-acetylaspartate levels and higher choline levels in the brain. These results suggest that HIV infection induces metabolic changes in the brain early during infection and that these changes may be related to monocyte dynamics in the periphery.