pH-sensitive dual-preventive siRNA-based nanomicrobicide reactivates autophagy and inhibits HIV infection in vaginal CD4+ cells.

Women are more susceptible to HIV transmission through unprotected heterosexual intercourse due to biological and social vulnerabilities. Intravaginal delivery of siRNAs targeting viral genes, host genes, or in combination has shown promising outcomes against HSV, HPV and HIV. Therefore, in this study, we designed, developed and evaluated a pH-sensitive RNAi-based combination nanomicrobide for the prevention/reduction of vaginal transmission of HIV. The nanomicrobide was composed of siRNA-PEI encapsulated PLGA-PEG nanoparticles (siRNA NP) loaded in a HEC gel dosage form with siRNA targeting host gene CCR5 and the viral gene Nef as a dual preventive strategy. Knocking down CCR5, a co-receptor for HIV could prevent HIV from attaching to and entering host cells and knocking down Nef could reactivate autophagy that was inhibited by Nef to improve the elimination of intracellular virus that escaped the first line of defense. The siRNA NP showed a desirable particle size and zeta potential for intravaginal delivery and a pH-dependent release profile whereby low amounts of siRNA was released under acidic vaginal conditions (vaginal fluid simulant; VFS, pH 4.2) (6.0 ± 0.4% released over 15 days) but significantly higher amounts of siRNA was released under neutral pH conditions (phosphate buffered saline; PBS, pH 7.4) (22.9 ± 0.4% released over 15 days). The CCR5-Nef-specific siRNA NP efficiently knocked down CCR5 and Nef protein expression by 43% and 63%, respectively, reactivated Nef-blocked autophagy and inhibited the replication of HIV in vitro (71.8% reduction in p24 expression). After being formulated into a gel dosage form, siRNA NP could be readily released from the gel, penetrate the vaginal epithelial layer, get taken up into the target cells and knockdown Nef and CCR5 without causing cytotoxicity in a vaginal mucosal co-culture model. Functionalization of siRNA NP with anti-CD4 antibody and loaded into a 0.5% HEC gel improved vaginal distribution and uptake of siRNA in a mouse model with distribution of siRNA restricted to the reproductive tract without any unwanted systemic uptake. The 0.5% HEC gel loaded with siRNA NP-(m)CD4 significantly downregulated approximately 40% of CCR5 protein in the lower vagina and 36% of CCR5 protein in the upper vaginal and cervical region. In contrast, 0.5% HEC gel loaded with siRNA NP-IgG did not result in significant gene knockdown.

AKT signaling modulates latent viral reservoir viability in HIV-1-infected blood-brain barrier pericytes.

Despite antiretroviral therapy (ART), chronic forms of HIV-associated neurocognitive disorders (HAND) affect an estimated 50% of individuals living with HIV, greatly impacting their quality of life. The prevailing theory of HAND progression posits that chronic inflammation arising from the activation of latent viral reservoirs leads to progressive damage in the central nervous system (CNS). Recent evidence indicates that blood-brain barrier (BBB) pericytes are capable of active HIV-1 infection; however, their latent infection has not been defined. Given their location and function, BBB pericytes are poised to be a key viral reservoir in the development of HAND. We present the first transcriptional analysis of uninfected, active, and latent human BBB pericytes, revealing distinct transcriptional phenotypes. In addition, we demonstrate that latent infection of BBB pericytes relies on AKT signaling for reservoir survival. These findings provide insight into the state of reservoir maintenance in the CNS during HIV-1 infection and provide novel targets for reservoir clearance.

A Three-Year Follow-Up of Bone Density Among Thai Adolescents With Perinatally Acquired HIV After Completion of Vitamin D and Calcium Supplementation.

PURPOSE: To determine changes in bone mineral density (BMD) and bone metabolism-related biomarkers among Thai adolescents with perinatally acquired HIV infection (PHIVA) at 3 years following completion of vitamin D and calcium (VitD/Cal) supplementation. METHODS: An observational follow-up study was conducted among PHIVA who received 48-week VitD/Cal supplementation (either high-dose [3,200 IU/1,200 mg daily] or standard-dose [400 IU/1,200 mg daily]). Lumbar spine BMD (LSBMD) was assessed by dual-energy x-ray absorptiometry. Serum 25-hydroxyvitamin D, intact parathyroid hormone, and bone turnover markers were measured. Changes in LSBMD z-scores and other bone parameters at 3 years after stopping VitD/Cal supplementation compared with baseline or week 48 of supplementation were assessed among participants previously receiving high-dose and standard-dose VitD/Cal supplementation. RESULTS: Of 114 enrolled PHIVA, 46% and 54% had previously received high-dose and standard-dose VitD/Cal supplementation, respectively. The median age was 20 years; 53% were male. At 3 years after completion of VitD/Cal supplementation, we observed a significant decline in 25-hydroxyvitamin D and increase in intact parathyroid hormone but no significant rebounds of C-terminal telopeptides of collagen type I and procollagen type I amino-terminal propeptides and no significant changes in LSBMD z-scores among PHIVA in both treatment groups, compared with the measurements at week 48 of supplementation. Notably, LSBMD z-scores at 3 years after stopping VitD/Cal supplements were not significantly altered from baseline evaluations in both PHIVA groups. DISCUSSION: Three years after completion of high-dose or standard-dose VitD/Cal supplementation, LSBMD z-scores of our Thai PHIVA were not significantly changed from baseline and week 48 of supplementation. VitD/Cal supplementation of PHIVA during periods of peak bone mass accrual may have sustained and long-term skeletal benefits.

Highlights From CROI, the Conference on Retroviruses and Opportunistic Infections-Postexposure Prophylaxis for Sexually Transmitted Infections, a New Protease Inhibitor for COVID-19, Goals for Preventing HIV Transmission, and More.

This Medical News Q&A discusses research highlights from the recent Conference on Retroviruses and Opportunistic Infections.

Vulnerability of the young university population to HIV/AIDS and other sexually transmitted infections

Introduction: Brazilian universities receive annually thousands of young people who experience situations of vulnerability to the human immunodeficiency virus, sexually transmitted infections, and viral hepatitis. Objective: The aim of the present study was to analyze the secondary data obtained from the attendance record of the rapid testing campaign for these health problems at a federal university in the state of Minas Gerais, Brazil, in 2019. Methods: A cross-sectional study was conducted with secondary data of students (n=1,113) obtained from the standard attendance form by the Ministry of Health during the campaigns Fique Sabendo (Be Aware) in the period between November 25 and 29, 2019. Analyses were performed with the support of the Statistical Package for Social Sciences program, with the calculation of absolute and relative frequencies. Pearson's chi-square test (5%) was used for comparison. Results: The results revealed a young, heterosexual, white profile. More than half reported having consumed alcohol and drugs in their lives. Other findings were the non-use of condoms with steady partners (18.1%) and occasional partners (21.3%), oral sex (86.8%), and unprotected sex in the last intercourse (45.6%). Most declared never being tested for human immunodeficiency virus (74.5%), syphilis (67.4%), hepatitis B (76.1%), or hepatitis C (77.0%). Conclusion: The university population is vulnerable to human immunodeficiency virus and other sexually transmitted infections due to the number of sexual partners and discontinued use of condoms with occasional partners. Such vulnerability is increased by the use of alcohol and other drugs

Using phylogenetics to infer HIV-1 transmission direction between known transmission pairs.

Inferring the transmission direction between linked individuals living with HIV provides unparalleled power to understand the epidemiology that determines transmission. Phylogenetic ancestral-state reconstruction approaches infer the transmission direction by identifying the individual in whom the most recent common ancestor of the virus populations originated. While these methods vary in accuracy, it is unclear why. To evaluate the performance of phylogenetic ancestral-state reconstruction to determine the transmission direction of HIV-1 infection, we inferred the transmission direction for 112 transmission pairs where transmission direction and detailed additional information were available. We then fit a statistical model to evaluate the extent to which epidemiological, sampling, genetic, and phylogenetic factors influenced the outcome of the inference. Finally, we repeated the analysis under real-life conditions with only routinely available data. We found that whether ancestral-state reconstruction correctly infers the transmission direction depends principally on the phylogeny's topology. For example, under real-life conditions, the probability of identifying the correct transmission direction increases from 32%-when a monophyletic-monophyletic or paraphyletic-polyphyletic tree topology is observed and when the tip closest to the root does not agree with the state at the root-to 93% when a paraphyletic-monophyletic topology is observed and when the tip closest to the root agrees with the root state. Our results suggest that documenting larger differences in relative intrahost diversity increases our confidence in the transmission direction inference of linked pairs for population-level studies of HIV. These findings provide a practical starting point to determine our confidence in transmission direction inference from ancestral-state reconstruction.

Impact of Caveolin-Mediated Endocytosis on the Trafficking of HIV within the Colonic Barrier.

In the United States, most new cases of human immunodeficiency virus (HIV) belong to the at-risk group of gay and bisexual men. Developing therapies to reverse viral latency and prevent spread is paramount for the HIV cure agenda. In gay and bisexual men, a major, yet poorly characterized, route of HIV entry is via transport across the colonic epithelial barrier. While colonic tears and paracellular transport contribute to infection, we hypothesize that HIV entry through the colonic mucosa proceeds via a process known as transcytosis, involving (i) virion binding to the apical surface of the colonic epithelium, (ii) viral endocytosis, (iii) transport of virions across the cell, and (iv) HIV release from the basolateral membrane. Using Caco-2 colonic epithelial cells plated as a polarized monolayer in transwells, we characterized the mechanism of HIV transport. After exposing the monolayer to HIV apically, reverse transcription quantitative PCR (RT-qPCR) of the viral genome present in the basolateral chamber revealed that transport is dose dependent, cooperative, and inefficient, with released virus first detectable at 12 h. Inefficiency may be associated with >50% decline in detectable intracellular virus that correlates temporally with increased association of the virion with lysosomal-associated membrane protein 1 (LAMP-1+) endosomes. Microscopy revealed green fluorescent protein (GFP)-labeled HIV within the confines of the epithelial monolayer, with no virus detectable between cells, suggesting that viral transport is transcellular. Treatment of the monolayer with endocytosis inhibitors, cholesterol reducing agents, and small interfering RNA (siRNA) to caveolin showed that viral endocytosis is mediated by caveolin-coated endosomes contained in lipid rafts. These results indicate that HIV transport across the intestinal epithelial barrier via transcytosis is a viable mechanism for viral spread and a potential therapeutic target. IMPORTANCE Despite the success of combination antiretroviral therapy in suppressing HIV replication and the emergence and effectiveness of PrEP-based prevention strategies, in 2018, 37,968 people in the United States received a new HIV diagnosis, accompanied by 15,820 deaths. While the annual number of new diagnoses decreased 7% from 2014 to 2018, 14% of people with HIV did not know they were infected. Gay and bisexual men accounted for 69% of all HIV diagnoses and 83% of diagnoses among males. Due to the scope of the HIV epidemic, determining and understanding precise routes of infection and the mechanisms of viral spread are paramount to ending the epidemic. Since transcellular transport of HIV across an intact colonic epithelial barrier is poorly understood, our overall goal is to characterize the molecular events involved in HIV transcytosis across the intestinal epithelial cell.

HIV-1 and HTLV-1 Transmission Modes: Mechanisms and Importance for Virus Spread.

So far, only two retroviruses, human immunodeficiency virus (HIV) (type 1 and 2) and human T-cell lymphotropic virus type 1 (HTLV-1), have been recognized as pathogenic for humans. Both viruses mainly infect CD4+ T lymphocytes. HIV replication induces the apoptosis of CD4 lymphocytes, leading to the development of acquired immunodeficiency syndrome (AIDS). After a long clinical latency period, HTLV-1 can transform lymphocytes, with subsequent uncontrolled proliferation and the manifestation of a disease called adult T-cell leukemia (ATLL). Certain infected patients develop neurological autoimmune disorder called HTLV-1-associated myelopathy, also known as tropical spastic paraparesis (HAM/TSP). Both viruses are transmitted between individuals via blood transfusion, tissue/organ transplantation, breastfeeding, and sexual intercourse. Within the host, these viruses can spread utilizing either cell-free or cell-to-cell modes of transmission. In this review, we discuss the mechanisms and importance of each mode of transmission for the biology of HIV-1 and HTLV-1.

An analysis of the HIV testing cascade of a group of HIV-exposed infants from birth to 18 months in peri-urban Khayelitsha, South Africa.

BACKGROUND: Despite the reduction of HIV mother-to-child transmission, there are concerns regarding transmission rate in the breastfeeding period. We describe the routine uptake of 6 or 10 (6/10) weeks, 9 months and 18 months testing, with and without tracing, in a cohort of infants who received HIV PCR testing at birth (birth PCR) (with and without point of care (POC) testing) in a peri-urban primary health care setting in Khayelitsha, South Africa. METHODS: In this cohort study conducted between November 2014 and February 2018, HIV-positive mothers and their HIV-exposed babies were recruited at birth and all babies were tested with birth PCR. Results of routine 6/10 weeks PCR, 9 months and 18 months testing were followed up by a patient tracer. We compared testing at 6/10 weeks with a subgroup from historical cohort who was not tested with birth PCR. RESULTS: We found that the uptake of 6/10 weeks testing was 77%, compared to 82% with tracing. When including all infants in the cascade and comparing to a historical cohort without birth testing, we found that infants who tested a birth were 22% more likely to have a 6/10 weeks test compared to those not tested at birth. There was no significant difference between the uptake of 6/10 weeks testing after birth PCR POC versus birth PCR testing without POC. Uptake of 9 months and 18 months testing was 39% and 24% respectively. With intense tracing efforts, uptake increased to 45% and 34% respectively. CONCLUSION: Uptake of HIV testing for HIV-exposed uninfected infants in the first 18 months of life shows good completion of the 6/10 weeks PCR but suboptimal uptake of HIV testing at 9 months and 18 months, despite tracing efforts. Birth PCR testing did not negatively affect uptake of the 6/10 weeks HIV test compared to no birth PCR testing.

Diagnosis and Treatment of Sexually Transmitted Infections: A Review.

Importance: Approximately 1 in 5 adults in the US had a sexually transmitted infection (STI) in 2018. This review provides an update on the epidemiology, diagnosis, and treatment of gonorrhea, chlamydia, syphilis, Mycoplasma genitalium, trichomoniasis, and genital herpes. Observations: From 2015 to 2019, the rates of gonorrhea, chlamydia, and syphilis increased in the US; from 1999 to 2016, while the rates of herpes simplex virus type 1 (HSV-1) and HSV-2 declined. Populations with higher rates of STIs include people younger than 25 years, sexual and gender minorities such as men and transgender women who have sex with men, and racial and ethnic minorities such as Black and Latinx people. Approximately 70% of infections with HSV and trichomoniasis and 53% to 100% of extragenital gonorrhea and chlamydia infections are asymptomatic or associated with few symptoms. STIs are associated with HIV acquisition and transmission and are the leading cause of tubal factor infertility in women. Nucleic acid amplification tests have high sensitivities (86.1%-100%) and specificities (97.1%-100%) for the diagnosis of gonorrhea, chlamydia, M genitalium, trichomoniasis, and symptomatic HSV-1 and HSV-2. Serology remains the recommended method to diagnose syphilis, typically using sequential testing to detect treponemal and nontreponemal (antiphospholipid) antibodies. Ceftriaxone, doxycycline, penicillin, moxifloxacin, and the nitroimidazoles, such as metronidazole, are effective treatments for gonorrhea, chlamydia, syphilis, M genitalium, and trichomoniasis, respectively, but antimicrobial resistance limits oral treatment options for gonorrhea and M genitalium. No cure is available for genital herpes. Effective STI prevention interventions include screening, contact tracing of sexual partners, and promoting effective barrier contraception. Conclusions and Relevance: Approximately 1 in 5 adults in the US had an STI in 2018. Rates of gonorrhea, chlamydia, and syphilis in the US have increased, while rates of HSV-1 and HSV-2 have declined. Ceftriaxone, doxycycline, penicillin, moxifloxacin, and the nitroimidazoles are effective treatments for gonorrhea, chlamydia, syphilis, Mycoplasma genitalium, and trichomoniasis, respectively, but antimicrobial resistance limits oral therapies for gonorrhea and Mycoplasma genitalium, and no cure is available for genital herpes.

Prevention of Mother-to-Child Human Immunodeficiency Virus Transmission in Resource-Limited Countries.

The first pediatric AIDS cases were reported in 1982. A decade later, the World Health Organization estimated there were more than 500,000 pediatric AIDS cases resulting from mother-to-child transmission, 90% of which were in sub-Saharan Africa. Although the rate of new infections globally has been cut in half since the peak of the pandemic, human immunodeficiency virus (HIV) remains a public health threat, and rates of new infections continue to increase in some regions. Mother-to-child transmission of HIV has now been virtually eliminated in many parts of the world but remains an issue in resource-limited countries.

Representações sociais de adolescentes sobre a transmissão do HIV/AIDS nas relações sexuais: vulnerabilidades e riscos / Representaciones sociales de adolescentes sobre la transmisión del VIH/AIDS en relaciones sexuales: vulnerabilidades y riesgos / Social representations of adolescents about HIV/AIDS transmission in sexual relations: vulnerabilities and risks

RESUMO Objetivo compreender as representações sociais de adolescentes sobre vulnerabilidades e riscos para contrair o HIV/Aids nas relações sexuais. Método estudo de representações sociais, realizado a partir de entrevistas individuais com 15 adolescentes e grupo focal com oito adolescentes de uma escola pública do Recife, Pernambuco, Brasil. Os dados foram coletados no período de maio a outubro de 2016. Para tratamento dos dados, empregou-se a técnica de análise de conteúdo temática-categorial com o auxílio do Software QSR Nvivo11. Resultados as categorias: riscos de contrair HIV/Aids nas relações sexuais; e dos riscos de contrair HIV/Aids nas relações sexuais às vulnerabilidades abrigam os temas não usar preservativo, ter usado álcool e/ou drogas, ter vários parceiros, ter dificuldades de acesso aos serviços de saúde e de educação sexual nas escolas; e não ter conversas com os pais ou familiares. Conclusão e implicações para a prática compreendeu-se que as representações sociais circulam no imaginário e no ambiente escolar, interferindo na realidade dos adolescentes. Propõe-se priorizar políticas públicas focadas nas dimensões emocionais, afetivas e sociais.

RESUMEN Objetivo comprender las representaciones sociales de adolescentes acerca de las vulnerabilidades y riesgos de contraer el VIH/SIDA en relaciones sexuales. Método estudio de representaciones sociales realizado a partir de entrevistas individuales con 15 adolescentes y un grupo focal con ocho adolescentes de una escuela pública en Recife, Pernambuco, Brasil. Los datos se recolectaron entre mayo y octubre de 2016. Para el tratamiento de los datos, se utilizó la técnica de análisis de contenido temático-categórico, con la ayuda del software QSR Nvivo11. Resultados las categorías riesgos de contraer el VIH/SIDA en las relaciones sexuales; y de los riesgos de contraer el VIH/SIDA en las relaciones sexuales a las vulnerabilidades que cubren los temas de no usar condón, haber consumido alcohol y/o drogas, tener varios pares, tener dificultades para acceder a los servicios de salud y de educación sexual en las escuelas; y no tener conversaciones con los padres o miembros de la familia. Conclusión e implicaciones para la práctica se entendió que las representaciones sociales circulan en el imaginario y en el ámbito escolar, interfiriendo en la realidad de los adolescentes. Se propone priorizar políticas públicas enfocadas en las dimensiones emocionales, afectivas y sociales.

ABSTRACT Objective To understand social representations of adolescents about vulnerabilities and risks of contracting HIV/AIDS in sexual relations. Method Study of social representations, based on individual interviews with 15 adolescents and a focus group with eight adolescents from a public school in Recife, Pernambuco, Brazil. Data were collected from May to October 2016. For the processing of data, the thematic-categorial content analysis technique was used with the aid of the QSR Nvivo11 Software. Results The categories: risks of contracting HIV/AIDS in sexual relations; and from the risks of contracting HIV/AIDS in sexual relations to the vulnerabilities cover the themes of not using condoms, having used alcohol and/or drugs, having several partners, having difficulties in accessing health and sex education services in schools; and not having conversations with parents or family members. Conclusion and implications for practice it was understood that social representations circulate in the imaginary and in the school environment, interfering in the reality of adolescents. It is proposed to prioritize public policies focused on the emotional, affective and social dimensions.

Tendência temporal e distribuição espacial dos casos de transmissão vertical do HIV em Santa Catarina, 2007-2017: um estudo ecológico / Tendencia temporal y distribución espacial de los casos de transmisión vertical del VIH en el estado de Santa Catarina, Brasil, 2007-2017: un estudio ecológico / Temporal trend and spatial distribution of cases of mother-to-child transmission of HIV in the state of Santa Catarina, Brazil, 2007-2017: an ecological study

Objetivo: Analisar a tendência temporal e a distribuição espacial dos casos de transmissão vertical do HIV, Santa Catarina, 2007-2017. Métodos: Estudo ecológico misto, com dados do Sistema de Informação de Agravos de Notificação. Realizou-se regressão linear para análise de série temporal; calcularam-se as taxas médias no período e variações percentuais médias anuais das taxas de gestantes infectadas pelo HIV, de crianças expostas ao HIV na gestação e de soroconversão das crianças expostas ao HIV/aids na gestação, além do geoprocessamento dos dados. Resultados: Foram registradas 5.554 gestantes infectadas pelo HIV, com taxa de 5,6 gestantes/1 mil nascidos vivos. A taxa média de soroconversão foi de 13,5/100 mil nascidos vivos (IC95% 6,8;20,1) e apresentou tendência decrescente (APC = -99,4%; IC95% -99,9;-93,1). A taxa de soroconversão foi mais elevada em municípios de pequeno porte. Conclusão: A taxa de gestantes infectadas pelo HIV foi estável; houve diminuição de crianças infectadas com HIV por via vertical.

Objetivo: Estimar la tendencia temporal y la distribución de casos de VIH por transmisión vertical en Santa Catarina, 2007-2017. Métodos: Estudio ecológico mixto con datos del Sistema de Información de Enfermedades de Declaración Obligatoria. Se utilizó la regresión lineal para análisis de series temporales y se calcularon las tasas medias en el período y los cambios porcentuales medios anuales en las tasas de mujeres embarazadas infectadas por el VIH; de niños expuestos al VIH; y seroconversión de niños expuestos al VIH/SIDA durante el embarazo, además del geoprocesamiento de datos Resultados: Había 5.554 gestantes infectadas por el VIH, con tasa de 5,6 gestantes/1.000 nacidos vivos. La tasa media de seroconversión fue 13,5/100.000 de nacidos vivos (IC95% 6,8;20,1) y mostró tendencia decreciente (APC = -99,4%; IC95%-99,9;-93,1). La tasa de seroconversión fue más expresiva en los municipios pequeños. Conclusão: Hubo una tasa estable de mujeres embarazadas infectadas por el VIH, mientras que el número de niños infectados por el VIH disminuyó.

Objective: To analyze the temporal trend and spatial distribution of mother-to-child HIV transmission in Santa Catarina between 2007 and 2017. Methods: This was a mixed ecological study with data from the Notifiable Health Conditions Information System. Linear regression was performed for time series analysis and the mean rates in the period and mean annual percentage changes in the rates of HIV-infected pregnant women were calculated, children exposed to HIV during pregnancy, and seroconversion of children exposed to HIV/AIDS during pregnancy, in addition to data geoprocessing. Results: There were 5,554 records of HIV-infected pregnant women, with a rate of 5.6 pregnant women per 1,000 live births. The mean seroconversion rate was 13.5/100,000 live births (95%CI 6.8;20.1) and it showed a falling trend (APC = -99.4%; 95%CI -99.9;-93.1). The seroconversion rate was more expressive in small towns. Conclusion: The rate of HIV-infected pregnant women was stable in the period, whereas the number of children infected with HIV through mother-to-child transmission decreased.

HIV knowledge and its correlation with the Undetectable = Untransmittable slogan in Brazil

ABSTRACT Knowledge about HIV transmission and prevention is a necessary step for adopting preventive behaviors. We assessed HIV knowledge and its correlation with the perceived accuracy of the "Undetectable = Untransmittable" (U=U) slogan in an online sample with 401 adult Brazilians. Overall, 28% of participants showed high HIV knowledge level. The perceived accuracy of the U=U slogan significantly correlated with HIV knowledge. Younger participants, those reporting lower income or lower education, or who had never tested for HIV showed poorer HIV knowledge. Filling gaps of knowledge among specific populations is urgent in order to increase preventive behaviors and decrease HIV stigma.

Intestinal microbial communities and Holdemanella isolated from HIV+/- men who have sex with men increase frequencies of lamina propria CCR5+ CD4+ T cells.

Men who have sex with men (MSM), regardless of HIV infection status, have an intestinal microbiome that is compositionally distinct from men who have sex with women (MSW) and women. We recently showed HIV-negative MSM have elevated levels of intestinal CD4+ T cells expressing CCR5, a critical co-receptor for HIV. Whether elevated expression of CCR5 is driven by the altered gut microbiome composition in MSM has not been explored. Here we used in vitro stimulation of gut Lamina Propria Mononuclear Cells (LPMCs) with whole intact microbial cells isolated from stool to demonstrate that fecal bacterial communities (FBCs) from HIV-positive/negative MSM induced higher frequencies of CCR5+ CD4+ T cells compared to FBCs from HIV-negative MSW and women. To identify potential microbial drivers, we related the frequency of CCR5+ CD4+ T cells to the abundance of individual microbial taxa in rectal biopsy of HIV-positive/negative MSM and controls, and Holdemanella biformis was strongly associated with increased frequency of CCR5+ CD4+ T cells. We used in vitro stimulation of gut LPMCs with the type strain of H. biformis, a second strain of H.biformis and an isolate of the closely related Holdemanella porci , cultured from either a HIV-positive or a HIV-negative MSM stool. H. porci elevated the frequency of both CCR5+ CD4+ T cells and the ratio of TNF-α/IL-10 Genomic comparisons of the 3 Holdemanella isolates revealed unique cell wall and capsular components, which may be responsible for their differences in immunogenicity. These findings describe a novel mechanism potentially linking intestinal dysbiosis in MSM to HIV transmission and mucosal pathogenesis.

Cultural and religious determinants of HIV transmission: A qualitative study with people living with HIV in Belu and Yogyakarta, Indonesia.

As a part of a larger qualitative study to understand HIV-risk factors and impacts on people living with HIV (PLHIV) (52 women and 40 men) in Belu and Yogyakarta, Indonesia, this paper reports the influences of cultural practices and religious beliefs on sexual relationships and behaviours of participants as contributors for HIV transmission. This study was conducted from June to December 2020. Data collection was conducted using one-one-one in-depth interviews. Participants were recruited using the snowball sampling technique. Data analysis was guided by a qualitative data analysis framework. The findings showed that cultural practices in Belu related to the use of bride wealth, managing spousal disputes, marriage, and condom use, influenced spousal relationships and sexual behaviours or practices which contributed to HIV transmission. Javanese cultural practices and expectation of an 'ideal wife', Islamic religious beliefs about expected husband-wife relationships, forbidden premarital sex, and the participants' individual interpretation of their religious beliefs about condom use spousal sexual relations, also influenced spousal sexual relations and behaviours, which supported HIV transmission among the participants. The findings indicate the need for HIV education programs that address cultural practices and religious beliefs for community members and population groups to enhance their understanding about HIV, condom use, and how cultural practices and religious beliefs play a role in HIV transmission. The findings also indicate the need for involvement of religious leaders in HIV education programs to bring insights to people and help them interpret their religious beliefs in health promoting ways. Future studies that explore different aspects of culture and religion which may contribute to HIV transmission are recommended.

Cathepsins and Their Endogenous Inhibitors in Host Defense During Mycobacterium tuberculosis and HIV Infection.

The moment a very old bacterial pathogen met a young virus from the 80's defined the beginning of a tragic syndemic for humanity. Such is the case for the causative agent of tuberculosis and the human immunodeficiency virus (HIV). Syndemic is by definition a convergence of more than one disease resulting in magnification of their burden. Both pathogens work synergistically contributing to speed up the replication of each other. Mycobacterium tuberculosis (Mtb) and HIV infections are in the 21st century among the leaders of morbidity and mortality of humankind. There is an urgent need for development of new approaches for prevention, better diagnosis, and new therapies for both infections. Moreover, these approaches should consider Mtb and HIV as a co-infection, rather than just as separate problems, to prevent further aggravation of the HIV-TB syndemic. Both pathogens manipulate the host immune responses to establish chronic infections in intracellular niches of their host cells. This includes manipulation of host relevant antimicrobial proteases such as cathepsins or their endogenous inhibitors. Here we discuss recent understanding on how Mtb and HIV interact with cathepsins and their inhibitors in their multifactorial functions during the pathogenesis of both infections. Particularly we will address the role on pathogen transmission, during establishment of intracellular chronic niches and in granuloma clinical outcome and tuberculosis diagnosis. This area of research will open new avenues for the design of innovative therapies and diagnostic interventions so urgently needed to fight this threat to humanity.

Role of direct and indirect social and spatial ties in the diffusion of HIV and HCV among people who inject drugs: a cross-sectional community-based network analysis in New Delhi, India.

Background: People who inject drugs (PWID) account for some of the most explosive human immunodeficiency virus (HIV) and hepatitis C virus (HCV) epidemics globally. While individual drivers of infection are well understood, less is known about network factors, with minimal data beyond direct ties. Methods: 2512 PWID in New Delhi, India were recruited in 2017-19 using a sociometric network design. Sampling was initiated with 10 indexes who recruited named injection partners (people who they injected with in the prior month). Each recruit then recruited their named injection partners following the same process with cross-network linkages established by biometric data. Participants responded to a survey, including information on injection venues, and provided a blood sample. Factors associated with HIV/HCV infection were identified using logistic regression. Results: The median age was 26; 99% were male. Baseline HIV prevalence was 37.0% and 46.8% were actively infected with HCV (HCV RNA positive). The odds of prevalent HIV and active HCV infection decreased with each additional degree of separation from an infected alter (HIV AOR: 0.87; HCV AOR: 0.90) and increased among those who injected at a specific venue (HIV AOR: 1.50; HCV AOR: 1.69) independent of individual-level factors (p<0.001). In addition, sociometric factors, for example, network distance to an infected alter, were statistically significant predictors even when considering immediate egocentric ties. Conclusions: These data demonstrate an extremely high burden of HIV and HCV infection and a highly interconnected injection and spatial network structure. Incorporating network and spatial data into the design/implementation of interventions may help interrupt transmission while improving efficiency. Funding: National Institute on Drug Abuse and the Johns Hopkins University Center for AIDS Research.

Understanding the social and spatial relationships that connect people is a key element to stop the spread of infectious diseases. These networks are particularly relevant to combat epidemics among populations that are hard to reach with public health interventions. Network-based approaches, for example, can help to stop HIV or hepatitis C from spreading amongst populations that use injectable drugs. Yet how social and geographic connections such as acquaintances, injection partners, or preferred drug use places impact the risk of infection is still poorly mapped out. To address this question, Clipman et al. focused on people who inject drugs in New Delhi, India, a population heavily impacted by HIV and hepatitis C. Over 2500 people were recruited, each participant inviting their injection partners to also take part. The volunteers answered survey questions, including where they used drugs, and provided a blood sample to be tested. The results showed that, even after adjusting for individual risk factors, where people used drugs and with whom affected their risk of becoming infected with HIV and hepatitis C. In terms of social ties, the likelihood of HIV and hepatitis C infection decreased by about 13% for each person separating a given individual from an infected person. However, geographical networks also had a major impact. Injecting at a popular location respectively increased the odds of HIV and hepatitis C infection by 50% and 69%. In fact, even if the participant was not using drugs at these specific places, having an injection partner who did was enough to increase the risk for disease: for each person separating an individual from the location, the likelihood of being infected with HIV and hepatitis C decreased by respectively 14% and 10%. The results by Clipman et al. highlight how the relationships between physical spaces and social networks contribute to the spread of dangerous diseases amongst people who inject drugs. Ultimately, this knowledge may help to shape better public health interventions that would take into account the importance of geographical locations.