scholarly journals Proviral Turnover During Untreated HIV Infection Is Dynamic and Variable Between Hosts, Impacting Reservoir Composition on ART

2021 ◽  
Vol 12 ◽  
Author(s):  
Kelsie Brooks ◽  
F. Harrison Omondi ◽  
Richard H. Liang ◽  
Hanwei Sudderuddin ◽  
Bradley R. Jones ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Subtype C ◽  
Proviral Dna ◽  
Art Initiation ◽  
Cell Decline ◽  
Active Viral Replication ◽  
Rate Of Decay ◽  
Infected Cells ◽  
Using Data ◽  
Main Barrier

Human immunodeficiency virus (HIV) can persist as an integrated provirus, in a transcriptionally repressed state, within infected cells. This small yet enduring pool of cellular reservoirs that harbor replication-competent HIV is the main barrier to cure. Entry of viral sequences into cellular reservoirs begins shortly after infection, and cells containing integrated proviral DNA are extremely stable once suppressive antiretroviral therapy (ART) is initiated. During untreated HIV infection however, reservoir turnover is likely to be more dynamic. Understanding these dynamics is important because the longevity of the persisting proviral pool during untreated infection dictates reservoir composition at ART initiation. If the persisting proviral pool turns over slowly pre-ART, then HIV sequences seeded into it during early infection would have a high likelihood of persisting for long periods. However, if pre-ART turnover was rapid, the persisting proviral pool would rapidly shift toward recently circulating HIV sequences. One-way to estimate this turnover rate is from the age distributions of proviruses sampled shortly after therapy initiation: this is because, at the time of sampling, the majority of proviral turnover would have already occurred prior to ART. Recently, methods to estimate a provirus’ age from its sequence have made this possible. Using data from 12 individuals with HIV subtype C for whom proviral ages had been determined phylogenetically, we estimated that the average proviral half-life during untreated infection was 0.78 (range 0.45–2.38) years, which is >15 times faster than that of proviral DNA during suppressive ART. We further show that proviral turnover during untreated infection correlates with both viral setpoint and rate of CD4+ T-cell decline during this period. Overall, our results support dynamic proviral turnover pre-ART in most individuals, which helps explain why many individuals’ reservoirs are skewed toward younger HIV sequences. Broadly, our findings are consistent with the notion that active viral replication creates an environment less favorable to proviral persistence, while viral suppression creates conditions more favorable to persistence, where ART stabilizes the proviral pool by dramatically slowing its rate of decay. Strategies to inhibit this stabilizing effect and/or to enhance reservoir turnover during ART could represent additional strategies to reduce the HIV reservoir.

scholarly journals Abundant HIV-infected cells in blood and tissues are rapidly cleared upon ART initiation during acute HIV infection

2020 ◽  
Vol 12 (533) ◽  
pp. eaav3491 ◽  
Author(s):  
Louise Leyre ◽  
Eugène Kroon ◽  
Claire Vandergeeten ◽  
Carlo Sacdalan ◽  
Donn J. Colby ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Stage Iv ◽  
T Cell Subsets ◽  
Viral Reservoir ◽  
Lymphoid Tissues ◽  
Acute Hiv Infection ◽  
Tissue Samples ◽  
Art Initiation ◽  
Acute Hiv ◽  
Infected Cells

The timing and location of the establishment of the viral reservoir during acute HIV infection remain unclear. Using longitudinal blood and tissue samples obtained from HIV-infected individuals at the earliest stage of infection, we demonstrate that frequencies of infected cells reach maximal values in gut-associated lymphoid tissue and lymph nodes as early as Fiebig stage II, before seroconversion. Both tissues displayed higher frequencies of infected cells than blood until Fiebig stage III, after which infected cells were equally distributed in all compartments examined. Initiation of antiretroviral therapy (ART) at Fiebig stages I to III led to a profound decrease in the frequency of infected cells to nearly undetectable level in all compartments. The rare infected cells that persisted were preferentially found in the lymphoid tissues. Initiation of ART at later stages (Fiebig stages IV/V and chronic infection) induced only a modest reduction in the frequency of infected cells. Quantification of HIV DNA in memory CD4+ T cell subsets confirmed the unstable nature of most of the infected cells at Fiebig stages I to III and the emergence of persistently infected cells during the transition to Fiebig stage IV. Our results indicate that although a large pool of cells is infected during acute HIV infection, most of these early targets are rapidly cleared upon ART initiation. Therefore, infected cells present after peak viremia have a greater ability to persist.

scholarly journals Shared Mechanisms Govern HIV Transcriptional Suppression in Circulating CD103+ and Gut CD4+ T Cells

2020 ◽  
Vol 95 (2) ◽  
pp. e01331-20
Author(s):  
Steven A. Yukl ◽  
Shahzada Khan ◽  
Tsui-Hua Chen ◽  
Martin Trapecar ◽  
Frank Wu ◽  
...  
Keyword(s):  
T Cells ◽  
Hiv Infection ◽  
Cd4 T Cells ◽  
Molecular Mechanisms ◽  
Hiv Latency ◽  
Expression Levels ◽  
Hiv Rna ◽  
Infected Cells ◽  
Latent Hiv ◽  
Main Barrier

ABSTRACTLatent HIV infection is the main barrier to cure, and most HIV-infected cells reside in the gut, where distinct but unknown mechanisms may promote viral latency. Transforming growth factor β (TGF-β), which induces the expression of CD103 on tissue-resident memory T cells, has been implicated in HIV latency. Using CD103 as a surrogate marker to identify cells that have undergone TGF-β signaling, we compared the HIV RNA/DNA contents and cellular transcriptomes of CD103+ and CD103− CD4 T cells from the blood and rectum of HIV-negative (HIV−) and antiretroviral therapy (ART)-suppressed HIV-positive (HIV+) individuals. Like gut CD4+ T cells, circulating CD103+ cells harbored more HIV DNA than did CD103− cells but transcribed less HIV RNA per provirus. Circulating CD103+ cells also shared a gene expression profile that is closer to that of gut CD4 T cells than to that of circulating CD103− cells, with significantly lower expression levels of ribosomal proteins and transcriptional and translational pathways associated with HIV expression but higher expression levels of a subset of genes implicated in suppressing HIV transcription. These findings suggest that blood CD103+ CD4 T cells can serve as a model to study the molecular mechanisms of HIV latency in the gut and reveal new cellular factors that may contribute to HIV latency.IMPORTANCE The ability of HIV to establish a reversibly silent, “latent” infection is widely regarded as the main barrier to curing HIV. Most HIV-infected cells reside in tissues such as the gut, but it is unclear what mechanisms maintain HIV latency in the blood or gut. We found that circulating CD103+ CD4+ T cells are enriched for HIV-infected cells in a latent-like state. Using RNA sequencing (RNA-seq), we found that CD103+ T cells share a cellular transcriptome that more closely resembles that of CD4+ T cells from the gut, suggesting that they are homing to or from the gut. We also identified the cellular genes whose expression distinguishes gut CD4+ or circulating CD103+ T cells from circulating CD103− T cells, including some genes that have been implicated in HIV expression. These genes may contribute to latent HIV infection in the gut and may serve as new targets for therapies aimed at curing HIV.

Evolution of antibodies to native trimeric envelope and their Fc dependent functions in untreated and treated primary HIV infection

2021 ◽  
Author(s):  
Lauren Nagel ◽  
Sanket Kant ◽  
Christopher Leeks ◽  
Jean-Pierre Routy ◽  
Cécile Tremblay ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Specific Antibody ◽  
People Living With Hiv ◽  
Specific Antibodies ◽  
Closed Conformation ◽  
Art Initiation ◽  
Infected Cells ◽  
Bystander Cells ◽  
Living With Hiv ◽  
Antibody Levels

People living with HIV (PLWH) develop both anti-Envelope-specific antibodies, which bind the closed trimeric HIV Envelope present on infected cells and anti-gp120-specific antibodies, which bind gp120 monomers shed by infected cells and taken up by CD4 on uninfected bystander cells. Both antibodies have an Fc portion that binds to Fc Receptors on several types of innate immune cells and stimulates them to develop anti-viral functions. Among these Fc dependent functions (FcDFs) are antibody dependent (AD) cellular cytotoxicity (ADCC), AD cellular trogocytosis (ADCT) and AD phagocytosis (ADCP). Here, we assessed the evolution of total immunoglobulin G (IgG), anti-gp120 and anti-Envelope IgG antibodies and their FcDFs in plasma samples from anti-retroviral therapy (ART) naïve subjects during early HIV infection (28-194 days post infection [DPI]). We found that both the concentrations and FcDFs of anti-gp120 and anti-Envelope antibodies increased with time in ART-naïve PLWH. Although generated concurrently, anti-gp120-specific antibodies were 20.7-fold more abundant than anti-Envelpe-specific antibodies, both specificities being strongly correlated with each other and FcDFs. Among the FcDFs, only ADCP activity was inversely correlated with concurrent viral load. PLWH who started ART >90 DPI showed higher anti-Envelope-specific antibody levels, ADCT and ADCP activities than those starting ART <90 DPI. However, in longitudinally collected samples, ART initiation at >90 DPI was accompanied by a faster decline in anti-Envelope-specific antibody levels, which did not translate to a faster decline in FcDFs compared to those starting ART <90 DPI. IMPORTANCE Closed conformation Envelope is expressed on the surface of HIV-infected cells. Antibodies targeting this conformation and that support FcDFs have the potential to control HIV. This study tracks the timing of the appearance and evolution of antibodies to closed conformation Envelope, whose concentration increases over the first 6 mos of infection. Antiretroviral therapy (ART) initiation blunts further increases in the concentration of these antibodies and their and FcDFs. However, antibodies to open conformation Envelope also increase with DPI until ART initiation. These antibodies target uninfected bystander cells, which may contribute to loss of uninfected CD4 cells and pathogenicity. This manuscript presents, for the first time, the evolution of antibodies to closed conformation Envelope and their fate on-ART. This information may be useful in making decisions on the timing of ART initiation in early HIV infection.

scholarly journals Refractory pharyngeal ulceration due to cytomegalovirus in a patient with HIV infection: a case report and literature review

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Morichika Osa ◽  
Akihiro Sato ◽  
Maki Sakagami ◽  
Masaki Machida ◽  
Takao Sato ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Pathological Examination ◽  
Cmv Infection ◽  
Case Presentation ◽  
Immunodeficiency Virus ◽  
Before And After ◽  
Infected Cells ◽  
Immunocompromised Hosts ◽  
Inflammatory Syndrome ◽  
Nonspecific Inflammation

Abstract Background Cytomegalovirus (CMV) is an important pathogen among immunocompromised hosts. Typically, CMV in human immunodeficiency virus (HIV) infection causes diseases of the retina, digestive tract, lungs and liver, but there are few cases of CMV infection of the pharynx and larynx. Case presentation A 57-year-old man with HIV infection was admitted because of pharyngeal pain. Before and after admission, pharyngeal biopsies guided by laryngeal endoscopy were performed four times, but pathological examination showed nonspecific inflammation, and the cause of pharyngeal ulceration was unclear. Additionally, the ulceration deteriorated after initiation of retroviral therapy. Laryngomicrosurgery was conducted under general anesthesia to remove tissue, and pathological diagnosis confirmed CMV infection. Pathological features included enlargement of the cytoplasm and nucleus in infected cells, and intranuclear bodies called owl’s eye inclusions. Ganciclovir dramatically improved the symptoms and laryngoscopic findings. Conclusions This case was diagnosed as pharyngitis and pharyngeal ulceration caused by CMV infection, related to immune reconstitution inflammatory syndrome. In previous reports of CMV-induced pharyngeal or laryngeal ulceration in HIV infection, we found six cases similar to our present case. All cases were diagnosed by biopsy. The present case indicates the importance of biopsy for definitive diagnosis. CMV infection should be considered as a differential diagnosis of pharyngeal ulceration in patients with HIV infection.

scholarly journals Genotypical diversity of HIV clades and central nervous system impairment

2011 ◽  
Vol 69 (6) ◽  
pp. 964-972 ◽  
Author(s):  
Indianara Rotta ◽  
Sérgio Monteiro de Almeida
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Hiv Infection ◽  
Opportunistic Infections ◽  
Regulatory Protein ◽  
Viral Meningitis ◽  
Neurological Involvement ◽  
Subtype C ◽  
Vacuolar Myelopathy ◽  
The Central Nervous System

The central nervous system (CNS) and the immune system are considered major target organs for HIV infection. The neurological manifestations directly related to HIV are acute viral meningitis, chronic meningitis, HIV associated dementia, vacuolar myelopathy and involvement of the peripheral nervous system. Changes in diagnosis and clinical management have changed the aspect of HIV infection so that it is no longer a fatal disease, and has become a chronic disease requiring sustained medical management. After HAART the incidence of most opportunistic infections, including those affecting the CNS, has dropped markedly. Some studies suggest that neurological involvement of infected patient occur with different frequency, depending on HIV subtype involved in the infection. Subtype C may have reduced neuroinvasive capacity, possibly due to its different primary conformation of HIV transactivating regulatory protein (Tat), involved in monocyte chemotaxis. This review focus on physiopathologic aspects of HIV infection in CNS and its correlation with HIV clades.

scholarly journals Longitudinal analysis of sociodemographic, clinical and therapeutic factors of HIV-infected individuals in Kinshasa at antiretroviral therapy initiation during 2006-2017

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0259073
Author(s):  
Nadine Mayasi Ngongo ◽  
Gilles Darcis ◽  
Hippolyte Situakibanza Nanituna ◽  
Marcel Mbula Mambimbi ◽  
Nathalie Maes ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Early Detection ◽  
Hiv Infection ◽  
Median Time ◽  
Clinical Stage ◽  
Hiv Care ◽  
Hiv Disease ◽  
Art Initiation ◽  
Time To Initiation ◽  
Advanced Hiv Disease

Background The benefits of antiretroviral therapy (ART) underpin the recommendations for the early detection of HIV infection and ART initiation. Late initiation (LI) of antiretroviral therapy compromises the benefits of ART both individually and in the community. Indeed, it promotes the transmission of infection and higher HIV-related morbidity and mortality with complicated and costly clinical management. This study aims to analyze the evolutionary trends in the median CD4 count, the median time to initiation of ART, the proportion of patients with advanced HIV disease at the initiation of ART between 2006 and 2017 and their factors. Methods and findings HIV-positive adults (≥ 16 years old) who initiated ART between January 1, 2006 and December 31, 2017 in 25 HIV care facilities in Kinshasa, the capital of DRC, were eligible. The data were processed anonymously. LI is defined as CD4≤350 cells/μl and/or WHO clinical stage III or IV and advanced HIV disease (AHD), as CD4≤200 cells/μl and/or stage WHO clinic IV. Factors associated with advanced HIV disease at ART initiation were analyzed, irrespective of year of enrollment in HIV care, using logistic regression models. A total of 7278 patients (55% admitted after 2013) with an average age of 40.9 years were included. The majority were composed of women (71%), highly educated women (68%) and married or widowed women (61%). The median CD4 was 213 cells/μl, 76.7% of patients had CD4≤350 cells/μl, 46.1% had CD4≤200 cells/μl, and 59% of patients were at WHO clinical stages 3 or 4. Men had a more advanced clinical stage (p <0.046) and immunosuppression (p<0.0007) than women. Overall, 70% of patients started ART late, and 25% had AHD. Between 2006 and 2017, the median CD4 count increased from 190 cells/μl to 331 cells/μl (p<0.0001), and the proportions of patients with LI and AHD decreased from 76% to 47% (p< 0.0001) and from 18.7% to 8.9% (p<0.0001), respectively. The median time to initiation of ART after screening for HIV infection decreased from 40 to zero months (p<0.0001), and the proportion of time to initiation of ART in the month increased from 39 to 93.3% (p<0.0001) in the same period. The probability of LI of ART was higher in married couples (OR: 1.7; 95% CI: 1.3–2.3) (p<0.0007) and lower in patients with higher education (OR: 0.74; 95% CI: 0.64–0.86) (p<0.0001). Conclusion Despite increasingly rapid treatment, the proportions of LI and AHD remain high. New approaches to early detection, the first condition for early ART and a key to ending the HIV epidemic, such as home and work HIV testing, HIV self-testing and screening at the point of service, must be implemented.

scholarly journals Temporal proteomic analysis of HIV infection reveals remodelling of the host phosphoproteome by lentiviral Vif variants

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Edward JD Greenwood ◽  
Nicholas J Matheson ◽  
Kim Wals ◽  
Dick JH van den Boomen ◽  
Robin Antrobus ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Time Course ◽  
Cellular Proteins ◽  
Temporal Expression ◽  
Aurora Kinases ◽  
Regulatory Subunits ◽  
Tandem Mass Tag ◽  
Infected Cells ◽  
Necessary And Sufficient ◽  
Viral Accessory Protein

Viruses manipulate host factors to enhance their replication and evade cellular restriction. We used multiplex tandem mass tag (TMT)-based whole cell proteomics to perform a comprehensive time course analysis of >6500 viral and cellular proteins during HIV infection. To enable specific functional predictions, we categorized cellular proteins regulated by HIV according to their patterns of temporal expression. We focussed on proteins depleted with similar kinetics to APOBEC3C, and found the viral accessory protein Vif to be necessary and sufficient for CUL5-dependent proteasomal degradation of all members of the B56 family of regulatory subunits of the key cellular phosphatase PP2A (PPP2R5A-E). Quantitative phosphoproteomic analysis of HIV-infected cells confirmed Vif-dependent hyperphosphorylation of >200 cellular proteins, particularly substrates of the aurora kinases. The ability of Vif to target PPP2R5 subunits is found in primate and non-primate lentiviral lineages, and remodeling of the cellular phosphoproteome is therefore a second ancient and conserved Vif function.

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