The Importance of Tissue Sanctuaries and Cellular Reservoirs of HIV-1

Current HIV Research ◽

10.2174/1570162x20666211227161237 ◽

2021 ◽

Vol 20 ◽

Author(s):

William Kalada ◽

Theodore James Cory

Keyword(s):

Lymphoid Tissue ◽

People Living With Hiv ◽

Viral Reservoirs ◽

New Methods ◽

Antiretroviral Therapies ◽

Current Therapies ◽

Living With Hiv ◽

Specific Barriers ◽

Hiv 1 ◽

Transporter Expression

Purpose of Review: There have been significant developments in the treatment of people living with HIV-1/AIDS with current antiretroviral therapies; however, these developments have not been able to achieve a functional or sterilizing cure for HIV-1. While there are multiple barriers, one such barrier is the existence of pharmacological sanctuaries and viral reservoirs where the concentration of antiretrovirals is suboptimal, which includes the gut-associated lymphoid tissue, central nervous system, lymph nodes, and myeloid cells. This review will focus on illustrating the significance of these sanctuaries, specific barriers to optimal antiretroviral concentrations in each of these sites, and potential strategies to overcome these barriers. Recent Findings: Research and studies have shown that a uniform antiretroviral distribution is not achieved with current therapies. This may allow for low-level replication associated with low antiretroviral concentrations in these sanctuaries/reservoirs. Many methods are being investigated to increase antiretroviral concentrations in these sites, such as blocking transporting enzymes functions, modulating transporter expression and nanoformulations of current antiretrovirals. While these methods have been shown to increase antiretroviral concentrations in the sanctuaries/reservoirs, no functional or sterilizing cure has been achieved due to these approaches. Summary: New methods of increasing antiretroviral concentrations at the specific sites of HIV-1 replication has the potential to target cellular reservoirs. In order to optimize antiretroviral distribution into viral sanctuaries/reservoirs, additional research is needed.

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Crucial Role of Central Nervous System as a Viral Anatomical Compartment for HIV-1 Infection

Microorganisms ◽

10.3390/microorganisms9122537 ◽

2021 ◽

Vol 9 (12) ◽

pp. 2537

Author(s):

Ana Borrajo ◽

Valentina Svicher ◽

Romina Salpini ◽

Michele Pellegrino ◽

Stefano Aquaro

Keyword(s):

Central Nervous System ◽

Nervous System ◽

People Living With Hiv ◽

Viral Reservoirs ◽

Virus Eradication ◽

The Central Nervous System ◽

Neurological Research ◽

Living With Hiv ◽

Hiv 1

The chronic infection established by the human immunodeficiency virus 1 (HIV-1) produces serious CD4+ T cell immunodeficiency despite the decrease in HIV-1 ribonucleic acid (RNA) levels and the raised life expectancy of people living with HIV-1 (PLWH) through treatment with combined antiretroviral therapies (cART). HIV-1 enters the central nervous system (CNS), where perivascular macrophages and microglia are infected. Serious neurodegenerative symptoms related to HIV-associated neurocognitive disorders (HAND) are produced by infection of the CNS. Despite advances in the treatment of this infection, HAND significantly contribute to morbidity and mortality globally. The pathogenesis and the role of inflammation in HAND are still incompletely understood. Principally, growing evidence shows that the CNS is an anatomical reservoir for viral infection and replication, and that its compartmentalization can trigger the evolution of neurological damage and thus make virus eradication more difficult. In this review, important concepts for understanding HAND and neuropathogenesis as well as the viral proteins involved in the CNS as an anatomical reservoir for HIV infection are discussed. In addition, an overview of the recent advancements towards therapeutic strategies for the treatment of HAND is presented. Further neurological research is needed to address neurodegenerative difficulties in people living with HIV, specifically regarding CNS viral reservoirs and their effects on eradication.

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HIV-1 subverts the complement system in semen to enhance viral transmission

Mucosal Immunology ◽

10.1038/s41385-021-00376-9 ◽

2021 ◽

Author(s):

Bernadien M. Nijmeijer ◽

Marta Bermejo-Jambrina ◽

Tanja M. Kaptein ◽

Carla M. S. Ribeiro ◽

Doris Wilflingseder ◽

...

Keyword(s):

Ex Vivo ◽

Virus Transmission ◽

Sexual Contact ◽

Target Cells ◽

People Living With Hiv ◽

Lectin Receptor ◽

Pre Treatment ◽

Living With Hiv ◽

Hiv 1

AbstractSemen is important in determining HIV-1 susceptibility but it is unclear how it affects virus transmission during sexual contact. Mucosal Langerhans cells (LCs) are the first immune cells to encounter HIV-1 during sexual contact and have a barrier function as LCs are restrictive to HIV-1. As semen from people living with HIV-1 contains complement-opsonized HIV-1, we investigated the effect of complement on HIV-1 dissemination by human LCs in vitro and ex vivo. Notably, pre-treatment of HIV-1 with semen enhanced LC infection compared to untreated HIV-1 in the ex vivo explant model. Infection of LCs and transmission to target cells by opsonized HIV-1 was efficiently inhibited by blocking complement receptors CR3 and CR4. Complement opsonization of HIV-1 enhanced uptake, fusion, and integration by LCs leading to an increased transmission of HIV-1 to target cells. However, in the absence of both CR3 and CR4, C-type lectin receptor langerin was able to restrict infection of complement-opsonized HIV-1. These data suggest that complement enhances HIV-1 infection of LCs by binding CR3 and CR4, thereby bypassing langerin and changing the restrictive nature of LCs into virus-disseminating cells. Targeting complement factors might be effective in preventing HIV-1 transmission.

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Nationwide Study of Drug Resistance Mutations in HIV-1 Infected Individuals under Antiretroviral Therapy in Brazil

International Journal of Molecular Sciences ◽

10.3390/ijms22105304 ◽

2021 ◽

Vol 22 (10) ◽

pp. 5304

Author(s):

Ana Santos-Pereira ◽

Vera Triunfante ◽

Pedro M. M. Araújo ◽

Joana Martins ◽

Helena Soares ◽

...

Keyword(s):

Drug Resistance ◽

People Living With Hiv ◽

Resistance Mutations ◽

Subtype C ◽

Viral Loads ◽

Drug Resistance Mutations ◽

Subtype B ◽

Low Prevalence ◽

Living With Hiv ◽

Hiv 1

The success of antiretroviral treatment (ART) is threatened by the emergence of drug resistance mutations (DRM). Since Brazil presents the largest number of people living with HIV (PLWH) in South America we aimed at understanding the dynamics of DRM in this country. We analyzed a total of 20,226 HIV-1 sequences collected from PLWH undergoing ART between 2008–2017. Results show a mild decline of DRM over the years but an increase of the K65R reverse transcriptase mutation from 2.23% to 12.11%. This increase gradually occurred following alterations in the ART regimens replacing zidovudine (AZT) with tenofovir (TDF). PLWH harboring the K65R had significantly higher viral loads than those without this mutation (p < 0.001). Among the two most prevalent HIV-1 subtypes (B and C) there was a significant (p < 0.001) association of K65R with subtype C (11.26%) when compared with subtype B (9.27%). Nonetheless, evidence for K65R transmission in Brazil was found both for C and B subtypes. Additionally, artificial neural network-based immunoinformatic predictions suggest that K65R could enhance viral recognition by HLA-B27 that has relatively low prevalence in the Brazilian population. Overall, the results suggest that tenofovir-based regimens need to be carefully monitored particularly in settings with subtype C and specific HLA profiles.

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Lower SARS-CoV-2-Specific Humoral Immunity in People Living With HIV-1 Recovered From Symptomatic Non-Hospitalized COVID-19

SSRN Electronic Journal ◽

10.2139/ssrn.4000542 ◽

2022 ◽

Author(s):

Daniel J. Schuster ◽

Shelly T. Karuna ◽

Caroline Brackett ◽

Martina Wesley ◽

Shuying S. Li ◽

...

Keyword(s):

Humoral Immunity ◽

People Living With Hiv ◽

Living With Hiv ◽

Hiv 1

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834. Characterization of Heavily Treatment Experienced HIV-1 Infected Clinical Trial Participants Infected with SARS-CoV-2 COVID 19: Fostemsavir BRIGHTE Phase 3 Clinical Trial

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.1030 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S509-S509

Author(s):

Shiven Chabria ◽

Stephane De Wit ◽

Amy Pierce ◽

Bronagh M Shepherd ◽

Michael Warwick-Sanders ◽

...

Keyword(s):

Clinical Trial ◽

Supplemental Oxygen ◽

Multidrug Resistant ◽

Cd4 Count ◽

People Living With Hiv ◽

Research Support ◽

Increased Risk ◽

Living With Hiv ◽

Hiv 1

Abstract Background BRIGHTE is an ongoing global study evaluating the gp120 attachment inhibitor fostemsavir (FTR) in heavily treatment-experienced (HTE) adults with multidrug resistant (MDR) HIV-1 unable to form a viable antiretroviral (ARV) regimen. An estimated 2 million people living with HIV-1 have been infected with SARS-CoV-2. Those with HIV viremia and/or low CD4+ counts are at increased risk of serious adverse outcome. We describe the reported COVID cases in a clinical trial population of people living with MDR HIV and immune suppression. Methods At the start of the COVID pandemic, all ongoing BRIGHTE subjects had achieved ≥ 192 weeks on FTR and optimized background ARVs; results through Week 96 were presented previously. Investigators used WHO guidelines for COVID diagnosis and reported exposure, testing results and symptom presence. Figure 1. BRIGHTE Study Design Results 371 subjects [272 Randomized Cohort (RC), 99 Non-Randomized Cohort (NC)] were enrolled; 44% were ≥ 50 years of age and 86% had an AIDS history. Median CD4+ count at study start of was 80 cells/mm3 (IQR 11–202); 30% with ≤ 20 cells/mm3. 250 subjects remained in BRIGHTE at pandemic start. By April 2021, 17 subjects (14 RC, 3 NC) had confirmed COVID infection (positive PCR test). Severity was Grade 1-3, all cases resolved with no deaths. Six subjects were hospitalized (Table 1); most recent CD4+ count prior to COVID were 293-1641 cells/mm3 and 5/6 subjects were virologically suppressed. Treatments often included prophylactic anticoagulants and supplemental oxygen; no cART changes were made. The remaining 11/17 confirmed cases were managed outpatient. Five more subjects had suspect COVID not confirmed by PCR and 2 subjects had negative PCR tests. Table 1. Characterization of Participants with Serious AEs of Confirmed COVID-19 Infections – All Hospitalizations Conclusion A total of 22/250 COVID-19 cases (17 confirmed, 5 unconfirmed) have been reported in BRIGHTE. Outcomes were reassuring with no deaths or known persistent sequelae, despite having advanced HIV and comorbid diseases at baseline associated with poorer COVID outcomes. Outcomes may have benefitted from immunologic improvement during the trial. Disclosures Shiven Chabria, MD, Viiv Healthcare (Employee) Stephane De Wit, MD, Gilead (Grant/Research Support)Janssen (Grant/Research Support)Merck Sharpe & Dohme (Grant/Research Support)ViiV Healthcare (Grant/Research Support) Amy Pierce, BS, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Bronagh M. Shepherd, PhD, GlaxoSmithKline (Employee, Shareholder) Michael Warwick-Sanders, BM BSc DPM MFPM, GSK (Employee) Marcia Wang, PhD, GlaxoSmithKline (Employee, Shareholder) Andrew Clark, MD, GlaxoSmithKline (Shareholder)ViiV Healthcare (Employee) Peter Ackerman, MD, GSK/ViiV Healthcare (Employee, Shareholder)

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Comorbidities associated with HPV and HSV infections among people living with HIV-1 in the Southeastern US: a retrospective clinical cohort study

10.21203/rs.2.13654/v1 ◽

2019 ◽

Author(s):

Yuanfan Ye ◽

Greer A. Burkholder ◽

Howard W. Wiener ◽

Russell Griffin ◽

Stella Aslibekyan ◽

...

Keyword(s):

Large Scale ◽

White Women ◽

Incidence Rates ◽

People Living With Hiv ◽

Anogenital Warts ◽

Gender And Race ◽

Clinical Cohort ◽

Southeastern Us ◽

Living With Hiv ◽

Hiv 1

Abstract Background The southeastern US is a domestic epicenter for incident HIV with high prevalence of human papillomavirus (HPV) and herpes simplex virus (HSV) co-infections. However, epidemics of HPV and HSV- associated clinical conditions (CC) among people living with HIV-1 infection (PLWH) are not fully known. Methods Electronic medical records (EMR) of PLWH attending one of the leading HIV clinics in the southeastern US between 2006 and 2018 were reviewed and analyzed. The retrospective study was nested within the University of Alabama at Birmingham HIV clinical cohort, which has electronically collected over 7000 PLWH’s clinical and sociobehavioral data since 1999. Incidence rates of HPV-related CC including anogenital warts, penile, anal, cervical, and vaginal/vulvar low- and high-grade squamous intraepithelial lesions (LSIL and HSIL) and HSV- related CC including anogenital herpetic ulcers were estimated in per 10000 person years. Joinpoint regressions were performed to examine temporal changes in the trends of incident CC. All rates and trends were stratified by gender and race. Results Of the 4,484 PLWH eligible individuals (3,429 men, 1,031 women, and 24 transgender), we observed 1,038 and 425 patients with HPV-and HSV-related CC respectively, and 163 patients with both conditions. The mean log10 viral load (VL) was higher in all of the case groups than the non-cases with neither conditions (5.0) (whereas the median nadir CD4 counts (cells/uL) was higher in the non-cases than in any of the case groups (P<0.05). Anogenital warts, anal LSIL, HSIL, and cancer were more likely to be diagnosed among HIV-infected men than women. White men presented more frequently with anal LSIL and anal and penile cancers than black men (P<0.03). White women were also more likely to be diagnosed with cervical HSIL (P=0.023) and cancer (P=0.037) than black women By contrast, herpetic ulcers were more frequent in women than men. Conclusions There were significant differences between gender and race with incidence of HPV- and HSV-related CC among HIV patients. EMR-based studies provide insights on understudied epidemics; however, large-scale studies in other regions are needed to generalize current findings and draw public health attention to co-infection induced non-AIDS defining comorbidities among PLWH.

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EBV AND HHV-6 CIRCULATING SUBTYPES IN PEOPLE LIVING WITH HIV IN BURKINA FASO, IMPACT ON CD4 T CELL COUNT AND HIV VIRAL LOAD

Mediterranean Journal of Hematology and Infectious Diseases ◽

10.4084/mjhid.2017.049 ◽

2017 ◽

Vol 9 (1) ◽

pp. 2017049 ◽

Cited By ~ 2

Author(s):

Lassina TRAORE ◽

Ouéogo NIKIEMA ◽

Abdoul Karim OUATTARA ◽

Tegwindé Rébéca COMPAORE ◽

Serge Théophile SOUBEIGA ◽

...

Keyword(s):

Viral Load ◽

T Cell ◽

Cell Count ◽

Cd4 Count ◽

Cd4 T Cell ◽

People Living With Hiv ◽

Study Population ◽

Living With Hiv ◽

Hiv 1 ◽

Cd4 T Cell Count

Epstein Barr Virus (EBV) and Human Herpes Virus 6 (HHV-6) are responsible for severe diseases, particularly in immunocompromised persons. There are poor data on the infection with these opportunistic viruses in Burkina Faso.The purpose of this study is to characterize EBV and HHV-6 subtypes and to assess their impact on CD4 T cell count, HIV-1 viral load and antiretroviral treatment in people living with HIV-1.The study population consisted of 238 HIV-positive patients with information on CD4 count, HIV-1 viral load and HAART. Venous blood samples collected on EDTA tubes were used for EBV and HHV-6 Real Time PCR subtyping.An infection rate of 6.7% (16/238) and 7.1% (17/238) were found respectively for EBV and HHV-6 in the present study. Among EBV infections, similar prevalences were noted for both subtypes (3.9% [9/238] for EBV-1 vs 4.6% [11/238] for EBV-2) with 2.1% (5/238) of co-infection. HHV-6A infection represented 6.3% (15/238) of the study population against 5.0% (12/238) for HHV-6B. . EBV-2 infection was significantly higher in patients with CD4 count ≥ 500 compared to those with CD4 count less than 500 cells (1.65% vs 8.56%, p = 0,011). The prevalence of EBV and HHV-6 infections were almost similar in HAART-naive and HAART-experienced patients.The present study provides information on the prevalence of EBV and HHV-6 subtypes in people living with HIV-1 in Burkina Faso. The study also suggests that HAART treatment has no effect on infection with these opportunistic viruses in people living with HIV-1.

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The lncRNA LOC102549805 (U1) modulates neurotoxicity of HIV-1 Tat protein

Cell Death and Disease ◽

10.1038/s41419-020-03033-4 ◽

2020 ◽

Vol 11 (10) ◽

Author(s):

Bahareh Torkzaban ◽

Kalimuthusamy Natarajaseenivasan ◽

Taha Mohseni Ahooyi ◽

Masoud Shekarabi ◽

Shohreh Amini ◽

...

Keyword(s):

People Living With Hiv ◽

Tat Protein ◽

Atp Production ◽

Neuronal Homeostasis ◽

Molecular Events ◽

Non Coding Rna ◽

Apoptosis Pathways ◽

Infected Cells ◽

Living With Hiv ◽

Hiv 1

Abstract HIV-1 Tat is a potent neurotoxic protein that is released by HIV-1 infected cells in the brain and perturbs neuronal homeostasis, causing a broad range of neurological disorders in people living with HIV-1. Furthermore, the effects of Tat have been addressed in numerous studies to investigate the molecular events associated with neuronal cells survival and death. Here, we discovered that exposure of rat primary neurons to Tat resulted in the up-regulation of an uncharacterized long non-coding RNA (lncRNA), LOC102549805 (lncRNA-U1). Our observations showed that increased expression of lncRNA-U1 in neurons disrupts bioenergetic pathways by dysregulating homeostasis of Ca2+, mitigating mitochondrial oxygen reduction, and decreasing ATP production, all of which point mitochondrial impairment in neurons via the Tat-mediated lncRNA-U1 induction. These changes were associated with imbalances in autophagy and apoptosis pathways. Additionally, this study showed the ability of Tat to modulate expression of the neuropeptide B/W receptor 1 (NPBWR1) gene via up-regulation of lncRNA-U1. Collectively, our results identified Tat-mediated lncRNA-U1 upregulation resulting in disruption of neuronal homeostasis.

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