ABSTRACT
Background/Aims: The clinical course of hepatitis B virus (HBV) infection in individuals with HIV-1 coinfection is marked by accelerated disease progression. A tenofovir-containing antiretroviral regimen is recommended in most people with HIV-1/HBV-coinfection, but there have not been randomized studies of tenofovir disoproxil fumarate (TDF) vs tenofovir alafenamide (TAF) in treatment- naive HIV-1/HBV-coinfected individuals. We report primary endpoint results from a Phase 3 study comparing bictegravir/emtricitabine/ TAF (B/F/TAF) vs dolutegravir + emtricitabine/TDF (DTG + F/TDF) at Week (W)48 in participants initiating treatment for both viruses. Method(s): Adults with HIV-1/HBV coinfection were randomized 1:1 to initiate blinded treatment with B/F/TAF or DTG + F/TDF (with placebo). Primary endpoints were the proportion of participants with HIV-1 RNA<50 copies/mL (FDA Snapshot) and plasma HBV DNA<29 IU/mL (missing = failure) at W48. Noninferiority was assessed with 95% CI (12% margin). Secondary and other endpoints included change from baseline cluster of differentiation 4 (CD4) count, proportion with hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) loss/seroconversion, and alanine transaminase (ALT) normalization (AASLD criteria). Result(s): Participants (N = 243) were randomized and treated (B/F/ TAF [n = 121], DTG + F/TDF [n = 122]) from 11 countries in Asia, Europe, North, and Latin America. Baseline characteristics were median age of 32 years, 4.5% female, 88% Asian, 30% HIV-1 RNA>100,000 c/mL, 40% CD4<200 cells/lL, median HBV DNA 8.1 log10 IU/mL, 78% HBeAg+. At W48, B/F/TAF was noninferior to DTG + F/TDF at achieving HIV-1 RNA<50 copies/mL (95% vs 91%, difference 4.1%;95% CI -2.5%-10.8%;P = 0.21), with mean CD4 gains of + 200 and + 175 cells/lL, respectively. B/F/TAF was superior to DTG + F/TDF at achieving HBV DNA<29 IU/mL (63% vs 43%, difference 16.6%;95% CI 5.9%-27.3%;P = 0.0023). Participants treated with B/F/TAF vs DTG + F/TDF had numerically higher HBsAg loss (13% vs 6%;P = 0.059), HBeAg loss (26% vs 14%;P = 0.055), HBeAg seroconversion (23% vs 11%;P = 0.031), and ALT normalization (73% vs 55%;P = 0.066). The most frequent adverse events among participants treated with B/F/TAF vs DTG + F/TDF were upper respiratory tract infection (17% vs 11%), COVID- 19 (13% vs 11%), pyrexia (9% vs 12%), ALT increase (7% vs 11%), and nasopharyngitis (11% vs 4%). ALT flares (elevations at >= 2 consecutive postbaseline visits) occurred in 11 participants (7 B/F/ TAF, 4 DTG + F/TDF), and all resolved. Conclusion(s): Among adults with HIV-1/HBV-coinfection starting antiviral therapy, both B/F/TAF and DTG + F/TDF had high HIV-1 suppression at year 1, with B/F/TAF resulting in superior HBV DNA suppression and significantly more HBeAg seroconversion. Safety findings were similar between groups.
ABSTRACT
Dr. Worobey will discuss the scientific evidence for when, where and how both the HIV/AIDS pandemic and the COVID-19 pandemic originated, and what we can learn from this knowledge to prevent or mitigate future pandemics?. In both cases, cross-species transmission into humans via wildlife consumption, versus via laboratory accident, were plausible hypotheses of origin. And in both cases, there is now overwhelming evidence in favor of the natural zoonosis route. Indeed, in the case of COVID-19, we have insights into the genesis of the pandemic that are in many ways unparalleled in the history of investigating pandemic origins.
ABSTRACT
Background: In 2018 we reported the emergence of the new HIV-1 recombinant CRF94-02BF2 involved in a large transmission cluster of 49 French MSM mostly infected in 2016-2017. This CRF94 raised concerns of enhanced virulence. Prevention actions were undertaken in the area and population affected. This study reported the molecular and epidemiological evolution of this CRF94 until June 2022. Method(s): In 2021-2022, French sequence databases were screened for patients infected with HIV-1 subtype CRF94 or similar strain. HIV subtyping was confirmed by phylogenetic analysis of genes encoding both protease and reverse transcriptase (1070bps), and integrase (696bps) using IQ-Tree. Five whole genomes, related but distinct from CRF94, were obtained with the DeepChek assay Whole Genome kits. Recombination breakpoints were estimated using RDP4 and SimPlot. Mann-Whitney and LogRank tests were used for statistical analyses to compare patients' characteristics. Result(s): In June 2022, 49 new HIV-1 sequences were collected: 14 clustered with the 49 previous CRF94, 32 formed a new cluster next to but distinct from CRF94, and 3 strains could not be classified. Analysis of 5 whole genomes from the new cluster revealed a new recombinant, the CRF132-94B, mainly consisting of CRF94 which recombined with subtype B in the POL and accessory genes. Vif gene changed from the F2 to the B subtype. Both CRF94 and 132 clusters involved >95% of MSM, mostly infected < 1 year before diagnosis. However, there were differences: 97% were diagnosed in 2013-2019 for CRF94 vs 90% in 2020-2022 for CRF132. At time of diagnosis, 33% of patients infected with CRF94 knew the Prep vs 95% for CRF132. In the cluster CRF94, patients were older (34 vs 30 years, p=0.02), had higher viral loads (5.42 vs 4.42 log10 copies/Ml;p< 0.001), a lower CD4 cell counts (358 vs 508 /mm3, p=0.002). On treatment, the patients with the CRF94 reached viremia < 50 copies/Ml significantly later than those infected with CRF132 (p=0.0002). The prevention activities targeting the CRF94 cluster could explained the few patients infected with this strain after 2018. The CRF132 is mainly located in another Paris region area, but no specific transmission place has been identified. Conclusion(s): After 2019, the CRF94 spread seems greatly slowed down but the very close CRF132-94B has given birth to a new highly active cluster in 2020- 2022, despite the COVID social-distancing and a strong knowledge of the Prep. CRF132 appears to be less virulent perhaps due to the Vif gene change. Identified breakpoints positions of the new HIV-1 CRF132-94B. GenBank accession numbers of the five references : ON901787 to ON901791.
ABSTRACT
Many studies have dealt with the medicinal properties of Jatropha curcas;however, there are limited studies on the scope of its antiviral potential. This is a fact associated with the current challenges posed by HIV-AIDS and COVID-19, which has reinforced the need to expand the knowledge about its antiviral resource. Based on the search for natural products with anti-HIV-1 and anti-SARS-CoV-2 activities, this work analyzed the extract of J. curcas seed, the structure of the plant whose antiviral references were not found in the literature, and the compounds that can potentiate it as a candidate for herbal medicine. GC-MS analysis was used to screen for the active substances of the J. curcas seeds, and the literature was searched to find those with anti-HIV-1 and anti-SARS-CoV-2 indication. The results showed they have 27 compounds, of which glycerol 1-palmitate, stigmasterol and gamma-sitosterol were shown to have antiviral action in the literature. Regarding glycerol 1-palmitate, no detailed description of its antiviral action was found. Stigmasterol and gamma-sitosterol act as anti-HIV-1 and anti-SARS-CoV-2, respectively, inhibiting the reverse transcriptase of HIV-1, the proteases 3CLpro, PLpro and the spike proteins of SARS-CoV-2. However, despite the fact that the extract of J. curcas seeds consist of antiviral compounds that fight against the etiological agents of HIV-AIDS and COVID-19, it is concluded that there is a need to deepen this evidence, by in vitro and in vivo assays.
ABSTRACT
Background: Tenofovir-lamivudine-dolutegravir (TLD) is the WHO-preferred first-line regimen for people with HIV, but drug-drug interactions between dolutegravir (DTG) and rifampin (RIF) require an additional 50mg DTG (TLD+50) in people receiving tuberculosis (TB)/HIV co-treatment. RIF is a key drug in TB treatment, but is a potent inducer of metabolizing enzymes and efflux transporters, which can markedly lower drug concentrations. There are limited data on the effectiveness of TLD+50 in people with TB/HIV from program settings. Method(s): We conducted a prospective, observational study at 12 sites in 6 countries (Haiti, Kenya, Malawi, South Africa, Uganda, Zimbabwe). Participants received concomitant TLD+50 and RIF-based TB treatment provided as standard of care by HIV and TB treatment programs. Primary outcome was HIV-1 RNA <1000 copies/mL (cpm) at end of TB treatment. New DTG resistance mutations were defined as those present at end of TB treatment but not present at start. Result(s): From 11/2019-6/2021, we enrolled 91 participants with TB/HIV, including 75 ART-naive participants (82%) starting TLD+50 after a median of 15 days on TB treatment, 10 ART-naive participants (11%) starting TLD+50 and RIF together, 5 (5%) starting TB treatment and changing to TLD+50 after a median of 3.3y on TLD, and 1 (1%) starting RIF and TLD+50 after changing from EFV/3TC/TDF. Median age was 37y (IQR 32-43), 35% were female, 100% cis-gender, median CD4 count was 120 cells/mm3 (IQR 50-295), 87% had HIV-1 RNA >1000 copies/mL. Two participants died during TB treatment (week 4 disseminated TB, week 12 suspected COVID-19), 1 interrupted TLD+50 due to jaundice;and 1 discontinued TB treatment due to drug-induced liver injury. Among 89 surviving participants, 6 were lost to follow-up and a further 10 had no HIV-1 RNA result due to missed or remote visits. Primary virologic outcome was therefore assessed in 73 (80%), of whom 69 (95%, Wald 95% CI 89-100%) had HIV-1 RNA <=1000 cpm;68 (93%) had HIV-1 RNA <200 cpm. No sex specific differences in viral suppression were observed. No DTG resistance mutations were detected among 4 participants with HIV-1 RNA >1000 cpm. Conclusion(s): Concomitant RIF-containing TB treatment and TLD+50 was welltolerated and achieved excellent viral suppression in a cohort of predominantly ART-naive people with TB/HIV. These multi-country data from program settings support feasibility and effectiveness of current treatment approaches for TB/ HIV co-infection.
ABSTRACT
RNA viruses are diverse and abundant pathogens responsible for numerous human ailments, from common colds to AIDS, SARS, Ebola, and other dangerous diseases. RNA viruses possess relatively compact genomes and have therefore evolved multiple mechanisms to maximize their coding capacities, often using overlapping reading frames. In this way, one RNA sequence can encode multiple proteins via mechanisms including alternative splicing and ribosomal frameshifting. Many such processes in gene expression involve the RNA folding into three-dimensional structures that can recruit ribosomes without initiation factors, hijack host proteins, cause ribosomes to frameshift, and expose or occlude regulatory protein binding motifs to ultimately control each key process in the viral life cycle. I will discuss the RNA structure of HIV-1 and SARS-CoV-2 and the importance of alternative conformations assumed by the same RNA sequence in controlling gene expression of viruses and bacteria.Copyright © 2023 The American Society for Biochemistry and Molecular Biology, Inc.
ABSTRACT
Background: Different viruses employ similar pathways for replication, revealing key intracellular hotspots to target with host-directed therapies and achieve a broad-spectrum antiviral activity. Plitidepsin is a clinically approved antitumoral agent that blocks the elongation factor eEF1A required for protein translation. This drug counteracts SARS-CoV-2 replication and shows a favorable safety profile in COVID-19 patients. Yet, the precise antiviral mechanism of action of plitidepsin remains unknown. Method(s): Here we used a deep quantitative proteomic analysis to measure the impact of plitidepsin on the proteome of SARS-CoV-2-infected Vero E6 cells. This was complemented with transmission electron microscopy assays, which unraveled the subcellular and morphological changes associated to plitidepsin treatment. In addition, we performed functional in vitro assays to dissect the antiviral activity of plitidepsin against SARS-CoV-2 and other viruses. Result(s): We found that this drug inhibited the synthesis of all SARS-CoV-2 proteins in a dose-dependent manner. These included the R1AB polyproteins, which facilitate the synthesis of non-structural proteins involved in the formation of double membrane vesicles (DMV) required for viral replication. Plitidepsin reduced DMV formation and the morphogenesis of new viruses, having a greater impact on viral than on host proteins. Less than 14% of the cellular proteome was significantly affected by plitidepsin, inducing the up-regulation of key molecules associated with protein biosynthesis, such as the translation initiation factors eIF4A2 and eIF2S3. Therefore, plitidepsin induced a compensatory state that rescued protein translation. This proteostatic response explains how cells preserve the cellular proteome after treatment with a translation inhibitor such as plitidepsin. In addition, it suggests that plitidepsin could inhibit other RNA-dependent and non-integrated DNA viruses, as we confirmed in vitro using Zika virus, Hepatitis C virus replicon and Herpes simplex virus. However, the compensatory proteostasis induced by plitidespin also explains why this drug failed to inhibit the replication of integrated DNA proviruses such as HIV-1. Conclusion(s): Unraveling the mechanism of action of host-directed therapies like plitidepsin is imperative to define the indications and antiviral profile of these compounds. This knowledge will be key to develop broad-spectrum treatments and have them ready to deploy when future pandemic viruses break through.
ABSTRACT
Background: Achieving UNAIDS global 95 targets among people living with HIV (PLHIV) is key to HIV epidemic control. Eswatini, a country with one of the severest HIV epidemics, has implemented an aggressive national HIV response with comprehensive HIV prevention and treatment services. We assessed progress towards these targets in the high HIV disease burden setting of Eswatini. Method(s): We compared 95-95-95 indicators and HIV incidence from two sequential Population-based HIV Impact Assessment (PHIA) surveys conducted in Eswatini in 2016 and 2021. These PHIAs were similarly designed as nationally representative household surveys among individuals 15 years and older. Respondents completed interviews and provided blood samples for HIV rapid testing (Determine and Unigold), antiretrovirals (ARV) testing, and viral load (VL) measurement. The first 95 (diagnosed PLHIV) was assessed by self-report or detectable ARVs;second 95 (on treatment) by self-report or detectable ARVs among diagnosed PLHIV, and third 95 (VL suppression, VLS) as VL < 1,000 copies/mL among PLHIV on treatment. Annual HIV incidence was estimated from recent infections (classified by HIV-1 LAg avidity assay, VL and ARV detection) using the formula recommended by the World Health Organization Incidence Working Group. Survey weights accounting for sample selection probabilities and adjusted for nonresponse and noncoverage were applied. Result(s): The 11,199 adults in the 2021 PHIA were at 94-97-96, while the 10,934 adults in the 2016 PHIA were at 87-89-91, a statistically significant increase of 5-10% in all 95 indicators (see Table). Target achievement varied by sex, but all 95 indicators improved among men (92-96-97 in 2021 vs 80-90-91 in 2016) and women (95-98-96 in 2021 vs 91-88-91 in 2016). Overall annual HIV incidence declined by 45% from 1.13% in 2016 to 0.62% in 2021 (p = 0.055). Annual HIV incidence in 2021 was nearly seven times higher among women (1.11%) than among men (0.17%). Conclusion(s): These findings reflect substantial progress toward HIV epidemic control, a remarkable achievement in the context of health, social and economic disruptions and challenges associated with the COVID-19 era. The 2021 data highlight remaining gaps in knowledge of HIV status, particularly among men, and HIV incidence reduction, particularly among women.
ABSTRACT
Background: Adults living with HIV may have higher risk of SARS-CoV- 2 infection than HIV negative adults. There are no published data on seroprevalence of SARS-CoV-2 in children and adolescents living with HIV (CALWHIV). Method(s): We did a repeat SARS-CoV-2 seroprevalence study in 7 paediatric HIV observational cohorts in 5 countries in the European Pregnancy & Paediatric Infections Cohort Collaboration (EPPICC;Belgium, Greece, Spain, Ukraine, United Kingdom (UK)) and also the Cape Town Adolescent Antiretroviral Cohort (CTAAC), South Africa (SA) (CALWHIV and HIV negative adolescents). Participants gave 2 blood samples for SARS-CoV-2 antibody testing ~6 months apart during routine visits between May 2020 and July 2022, and completed questionnaires on SARS-CoV-2 exposure/infection and vaccine status. Clinical and demographic data were extracted from clinic records. Result(s): Of 906 participants, 53%(477) were female, 89%(803) CALWHIV, median [IQR] age at first visit 17[15-19] years. Most were enrolled in SA (45%, 410/906), UK (23%, 205/906) or Ukraine (18%, 160/906). 85%(767/906) had 2 blood samples and the rest a single sample. For CALWHIV, at time of first sample, 99%(761/765) were on antiretroviral therapy, median CD4 count was 666[478-858] cells/mL, 70%(535/764) had HIV-1 viral load < 50c/mL. Of those with known SARS-CoV-2 vaccine status, 23%(181/773) CALWHIV and 22% (22/100) HIV negative participants received >=1 vaccine dose. 6%(43/762) of CALWHIV had a documented prior SARS-CoV-2 positive PCR (including 2 hospitalised for COVID, neither severe), and 16%(124/762) self-reported previous positive test and/or COVID-19 symptoms, giving a total of 17%(128/762) with any previous infection. Based on serum testing, 63%(562/898) of participants overall were seropositive on at least one sample (55% (269/488) Europe, 67% (205/307) SA CALWHIV, 85% (88/103) SA HIV negative group), and among the unvaccinated subgroup, 53%(408/765) were seropositive (41% (167/412) Europe, 64% (168/263) SA CALWHIV, 81% (73/90) SA HIV negative). Among samples taken prior to or in absence of vaccination, the proportion testing antibody positive increased over time (Figure). Of unvaccinated CALWHIV with >=1 positive result, 17%(52/299) reported any previous SARS-CoV-2 infection. Conclusion(s): Most CALWHIV were SARS-CoV-2 seropositive by mid-2022 despite low vaccine coverage. Fewer had documented or self-reported COVID-19 infection or disease, suggesting most infections were mild or asymptomatic. Seroprevalence of SARS-CoV-2 antibodies in Europe and South Africa, by HIV status and calendar quarter of sampling. Colours indicate dominant variant based on GISAID data for adults and children.
ABSTRACT
The advent of cheaper viral sequencing and opportunity to offer customized treatment through identification of resistance mutations in patients with HIV-1, also offered the first large-scale opportunity to use sequencing to generate insights into a global infectious disease pandemic. Using HIV-1 sequences, scientists were able to track mutations globally and within countries and use them to gain groundbreaking understanding of virus transmission and the evolution of resistance. Though invaluable in contributing to our knowledge of virus dynamics, much of what was feasible with HIV-1 was difficult to extend to other viruses due to the challenges and expense of full-genome sequences and the difficulty of obtaining samples from acute infections. More recent advances have made next-generation sequencing (NGS) possible and affordable, and growing realization of the insights sequencing can contribute has increased interest in generating sequences for an increasing variety of viruses. Against this backdrop of an advent of a new age of genomics in viral research, the SARSCoV- 2 pandemic has thrown sequencing and phylogenetics into the limelight, allowing the collection and sequencing of more samples than could even be conceived prior to 2020. It's a opportune time to consider not only where we've come from, but how the promise of 14 million sequences has been realized, and what the future holds for sequence-enabled pathogen research.
ABSTRACT
Background: Long-acting cabotegravir (CAB-LA) is highly effective as HIV PrEP and superior to daily oral F/TDF in sexually active adults. We report a 28-yearold gender diverse patient assigned male at birth who acquired HIV-1 91 days after transitioning from F/TAF to CAB-LA despite on-time dosing. Method(s): Electronic medical records were reviewed to assess patient history and CAB-LA administration details. Plasma 4th generation HIV-1/2 Ag/Ab combination immunoassay and HIV-1 RNA quantitative PCR were performed at each injection visit. Result(s): Patient was on daily F/TAF for ten months prior to CAB-LA with acceptable adherence, missing 1 dose per week. Their medical history included hypothyroidism on levothyroxine and unconfirmed hypogonadism with illicit use of IM testosterone cypionate complicated by significantly elevated total testosterone levels. They were sexually active with cisgender men, endorsing condomless oral and anal sex with one primary partner and 20-30 unique partners per month. In the past 6 months, patient was diagnosed with syphilis and mpox. Patient was given 600mg of CAB-LA into their left gluteal medius on Day 0, 27, and 91. Day 0 and 27, plasma HIV 1/2 Ag/Ab was non-reactive and HIV-1 RNA PCR was not detected. Patient reported flu-like illness on Day 76 with positive SARS-COV-2 PCR;they completed a five-day course of nirmatrelvirritonavir with rapid resolution of symptoms. At the third injection of 600mg CAB-LA on Day 91, their plasma HIV 1/2 Ag/Ab was non-reactive but the HIV-1 RNA PCR test was detected at 1.48log c/mL. On repeat testing on Day 100, plasma HIV 1/2 Ag/Ab was reactive with HIV-1 Ab detected on differentiation assay and HIV-1 RNA PCR was detected at 1.30 log c/mL. Patient's primary partner was living with HIV resistant to NRTIs (65R, 118I) and INSTIs (92G) with undetectable plasma HIV-1 RNA for the past 24 months. Patient's viremia was below the threshold to perform standard HIV-1 sequencing;HIV-1 DNA qualitative PCR and HIV-1 proviral DNA resistance testing are currently pending. Patient ultimately started on F/TAF/DRV/COBI and DTG on Day 112. Conclusion(s): This patient's history suggests HIV-1 infection despite on-time and appropriate CAB-LA injections. To our knowledge, this is the first case of CAB-LA PrEP failure outside the setting of a clinical trial and highlights the diagnostic and management challenges that may arise with such breakthrough infections in the real world.
ABSTRACT
Background: Antigen-driven CD4+ T cell proliferation is a proposed mechanism of HIV-1 reservoir persistence. We previously reported that SARSCoV- 2 infection leads to increased detectable low-level HIV-1 plasm RNA blips months after COVID-19, but the impact of SARS-CoV-2-mediated T cell activation on expansion of HIV-1 reservoirs is not known. We sought to identify if SARSCoV- 2 infection leads to expansion of preferentially HIV-infected CD4+ T cells in people with HIV (PWH) on ART. Method(s): Five PWH with samples collected prior to and approximately two months after SARS-CoV-2 infection were identified. We performed a surface activation induced marker (AIM) assay using a CD4-optimized overlapping SARS-CoV-2 peptide pool to measure OX40/CD137 expression following peptide stimulation and sorted CD4+ T cells based on surface marker expression. ddPCR quantification of genomic HIV-1 DNA was performed on sorted subsets. Result(s): We observed an increase in the frequency of SARS-CoV-2 AIM+ non-naive CD4+ T cells following COVID-19 in samples from 4 of 5 participants (mean AIM+ % 0.13 pre- vs 0.31 post). A large percentage of non-naive AIM+ CD4+ T cells expressed PD1 compared with total non-naive cells before (76% vs 36%) and after (65% vs 19%) COVID-19;PD1 expression was lower following SARS-CoV-2 in both AIM+ and AIM- CD4+ T cell subsets (although very few cells were AIM+ prior to COVID-19). HIV-1 DNA levels in non-naive AIM- CD4+ T cells prior to COVID-19 unexpectedly decreased following infection (mean 3,522 to 766 copies/106 cells). The numbers of AIM+ cells obtained by cell sorting were overall low ( 3,863 mean) and only one participant had detectable DNA in post-COVID AIM+ CD4+ T cells. However, a large majority of this participant's post-COVID AIM+ cells harbored HIV-1 DNA (0.89 copies per cell) whereas HIV DNA in their AIM- cells decreased from 8,387 to not detected following SARSCoV- 2 infection. No HIV-1 DNA was detected in the small number of AIM+ cells obtained prior to COVID-19 in this participant. Conclusion(s): COVID-19 in PWH led to a modest SARS-CoV-2-specific CD4+ cell response approximately two months following acute presentation. One participant may have preferentially expanded HIV-1-infected, SARS-CoV-2- specific CD4+ T cells following COVID-19 but studies involving larger numbers of participants and larger numbers of cells will be needed to fully understand the impact of SARS-CoV-2 on clonal expansion and HIV persistence.
ABSTRACT
Four broad themes run through this year's N'Galy-Mann lecture: clinical medicine, HIV, health security, and global health. Three patterns of disease characterized medicine in East Africa at the time that AIDS was first described in the United States: diseases of poverty, mainly infectious;non-communicable diseases with differing international epidemiology;and classic tropical diseases restricted in distribution by ecologic needs of parasites and vectors. Limited resources did not prevent the practice of good medicine under adverse circumstances, nor application of basic principles of research. The recognition of a second AIDS virus (HIV-2) in West Africa in the mid-late 1980s required applied research to assess implications and potential global impact of this novel infection. CDC established a second collaborative research site in sub-Saharan Africa, Projet RETRO-CI, in Abidjan, Cote d'Ivoire (the first was Projet SIDA in the Democratic Republic of Congo, where N'Galy and Mann made seminal contributions). Controversy around HIV-2 diagnosis, transmission, and pathogenicity was slowly resolved through West African research showing HIV-2 was an AIDS-causing pathogen, slower than HIV-1 in its progression, and less transmissible until late in the course of infection. Mother-to-child transmission was exceptionally rare. Claims that HIV-2 protected against HIV-1 were not substantiated. Projet RETRO-CI clarified the spectrum of HIVassociated disease and the dominant role of tuberculosis. Placebo-controlled trials demonstrated efficacy of short-course zidovudine for prevention of perinatal transmission of HIV-1, and of cotrimoxazole prophylaxis in reducing hospitalization and mortality in persons with HIV. Global health today is dominated by discourse around health security. The West African and Congolese Ebola epidemics since 2014 aroused strong declarations, yet the world was poorly prepared to address the pandemic of COVID-19. Health in the world has changed substantially since AIDS emerged. As 2030, the year for delivery on the Sustainable Development Goals, approaches, development assistance for health remains essential to address traditional, unfinished commitments yet does not match today's global burden of disease. CROI attendees are encouraged to remember colleagues lost to COVID-19 and other challenges;to assess priorities in today's global health, including relating to HIV;and to reflect on what issues? N'Galy and Mann would focus on today.
ABSTRACT
Over the past four decades, remarkable progress has been made in understanding HIV epidemiology, pathogenesis, treatment, and prevention from the combined efforts of community members, clinicians, investigators, and funding agencies worldwide. Yet more work and new approaches are needed to achieve the ambitious goal of ending the epidemic and ensuring optimal quality of life for those living with HIV. To encourage and stimulate the next generation of investigators, the CROI Program Committee organizes an annual Workshop for New Investigators and Trainees comprised of expert and comprehensible talks to cover current knowledge and controversies in basic, clinical, and public health investigation into HIV and related infections, and to highlight relevant work to be presented over the ensuing days at CROI. This year, the program will begin with a presentation by Dr Stuart Neil on novel aspects of the molecular virology of HIV-1 and SARS-CoV-2. Following this, Dr Guido Silvestri will cover the immune responses against HIV and SARS-CoV-2. Ms Dawn Averitt, an HIV treatment policy advocate and activist will provide a community perspective on the power of community engagement in research. In the following presentation, Dr Monica Gandhi will review novel therapeutic strategies for HIV. Dr Raphael Landovitz will address advances in different strategies for preventing HIV transmission. Dr John Mellors will review advances in preclinical and clinical approaches for functional or sterilizing HIV-1 cure. The workshop will end with an intervention by Dr Rochelle Walensky, who will discuss career opportunities in research and public health. By completing the workshop, attendees will have achieved a head start toward maximizing the knowledge gained and research ideas arising from CROI 2022.
ABSTRACT
Background: COVID-19 vaccination is effective at preventing symptomatic infection, hospitalization, and death from COVID-19, but many people have experienced barriers to receiving this life preserving intervention. A study examining COVID-19 vaccination in New York state found that persons with HIV (PWH) were less likely to be vaccinated than the general population. We examined whether PWH are less likely to be vaccinated than persons without HIV (PWoH) in the Veterans Affairs (VA) Healthcare System. Method(s): We examined COVID-19 vaccination receipt by HIV status in the Veterans Aging Cohort Study (VACS), an open cohort of PWH and 1:2 age-, race/ethnicity-, sex-, and site-matched PWoH. Among participants with a VA encounter from 10 December 2020 to 12 September 2022, we calculated the proportion of individuals who were fully vaccinated and boosted. Fully vaccinated was defined as: 14 days after second dose of mRNA vaccine (either Pfizer BNT162b2 or Moderna mRNA-1273) or single dose of a viral vector vaccine (Janssen Ad26.COV2.S). Boosted was defined as an additional vaccination at least 180 days after full vaccination. We assessed differences using chi-square tests. Result(s): Among 109,421 participants, PWH (n=31,337) were more likely than PWoH (n=78,084) to be fully vaccinated (77.6% vs 68.7%, p< 0.001) and boosted (71.1% vs 63.0%, p< 0.001) (Table). Most people received an mRNA vaccine with 6.9% of fully vaccinated PWH and 7.5% of fully vaccinated PWoH receiving the Janssen vaccine. Among PWH, having an undetectable HIV viral load was more common in those fully vaccinated than those not fully vaccinated (79.4% vs 72.0%, p< 0.001). Conclusion(s): In a matched cohort of veterans with and without HIV in VA care, we found that PWH were more likely than PWoH to be fully vaccinated and boosted. These findings contrast with a New York state study which found lower COVID-19 vaccination rates in PWH, possibly due to differential healthcare access;all patients in our cohort have access to VA care. Further studies are needed to understand differences in vaccine acceptance and receipt to prevent COVID-19 hospitalizations and deaths. COVID-19 Vaccination in People with HIV (PWH) and People without HIV (PWoH) - Veterans Aging Cohort Study, as of 12 September 2022.
ABSTRACT
In this presentation, Dr Paul Bieniasz will discuss antibody-driven evolution of HIV-1 and SARS-CoV-2.
ABSTRACT
Some of the first immunological experiments of the 20th century-on antibody feedback inhibition-demonstrated that past exposure does not merely expedite the humoral response to secondary challenges but, rather, alters the nature of that response. Despite this history, the mechanisms underpinning these classic observations and their relationship to modern vaccine design remain obscure. Circulating antibodies produced during a primary challenge can have enhancing or, conversely, inhibitory effects on later humoral responses. Using preclinical vaccine models, we dissected this apparent contradiction to find that the interaction between serum antibodies and the entry of cognate naive B cell lineages to germinal centers was determined by the interplay of breadth, affinity, and titer. Epitope-focused vaccine designs for HIV-1 elicit circulating antibodies capable of entirely obstructing their cognate naive B cells, with important implications for the ongoing design of boostphase immunogens. Conversely, SARS-CoV receptor binding domain (RBD) immunization elicits a polyclonal serum response that enhances the proportion of high-affinity cognate B cells in germinal centers, providing a partial explanation for the effectiveness of current boost protocols but also presaging diminishing returns unless new epitopes are introduced. The resolution of these surface-level contradictions points toward a unified interactive model and emphasizes that, to move vaccinology forward, the basic biology of the humoral immune system cannot remain a black box.
ABSTRACT
Background: COVID-19, the disease caused by SARS-CoV-2, has resulted in devastating morbidity and mortality worldwide. Alarming evidence indicates that long-term adverse outcomes of COVID-19 can affect all major systems of the body, including the immune, respiratory, cardiovascular, and neurological systems. While acute COVID-19 pathology does not appear to be markedly different by HIV status, long-term outcomes of COVID-19 in People with HIV (PWH) are unknown and require further investigation. This study evaluates the inflammatory profile longitudinally up to three months after COVID-19. In addition, markers of the blood-brain barrier (BBB) integrity and vascular dysfunction were also evaluated. Method(s): Plasma samples were collected from 15 males and 6 females with COVID-19 and HIV infection (COVID+/HIV+) and 9 males and 14 females with COVID-19 without HIV infection (COVID+/HIV-) between March 2020 and March 2021. Baseline samples were obtained approx. 10 days after COVID-19 diagnosis (T=0) and three months after (T=3). Mean age group for COVID+/HIV-was 45.4+/-17.8 years for males and 39.7+/-15.3 for females and for COVID+/HIV+ was 52.1+/-12.3 for males and 48.7+/-1 for females (N=15 and 6, respectively). 27 inflammatory molecules were measured by Bio-Plex Multiplex Immunoassay (Bio-Rad) and two markers of BBB and vascular dysfunction (soluble ICAM1 and S100beta) by ELISA. Result(s): Out of 27 inflammatory analytes, 20 had detectable signals. Eotaxin (CCL11) and G-CSF levels were differentially upregulated in the COVID+/HIV+ group as compared to the COVID+/HIV-group in both time point studied (Table 1). IFN-g showed sustained increased levels at T=3 in the COVID+/HIV+ group, whereas there was a significant reduction over time in the COVID+/HIV-group. At T3, inflammatory markers (IL-4, IL-8, IL-13, basic FGF, TNF-alpha, MIP-1alpha, and CCL2) either decreased or remained unchanged in both groups. In contrast, the markers of the BBB disruption and vascular dysfunction, such as S100beta and soluble ICAM-1 increased in the COVID+/HIV+ group, suggesting long-term progressive BBB and vascular alterations. Conclusion(s): HIV-1 may potentiate long COVID-19-induced neuropathology, with progressive BBB breakdown and sustained increase in eotaxin-1 and G-CSF. Plasma inflammatory markers in COVID-19 patients with or without HIV-1 co-infection.
ABSTRACT
A substantial number of individuals who experience COVID-19 infection experience prolonged physical and mental symptoms after resolution of their initial infection, and among them, many individuals experience cognitive difficulties including memory lapses and executive function difficulties, often referred to as "brain fog." The possible impact of COVID-19 infection on cognition in persons with HIV-related cognitive disorders is unknown. In this report, we describe post-COVID-19 cognitive and driving function in a 62-year-old man with HIV infection since the early 1990s.
ABSTRACT
The proceedings contain 115 papers. The topics discussed include: prevention and health promotion regarding sexual transmitted infections among university students in Germany;sexual risk behavior and condom use among Arab men tourists in Pattaya, Thailand;prevalence of individuals with risk for severe COVID-19 in whom ritonavir-containing therapies are contraindicated or may lead to interactions with concomitant medications;therapy adjustment using proviral DNA information among multi-class resistant HIV-1 infected and ART-experienced patients;are we on track to reach the WHO elimination goals for viral hepatitis among HIV+-individuals? updates on HBV prevalence and incidence, 1996-2019;telehealth or in-person HIV care? care continuity drove the decision process during the COVID-19 pandemic. results from a qualitative study in South Carolina;high burden of human papilloma virus infection in people living with HIV;and safety and effectiveness outcomes from the CARISEL study: Phase 3b hybrid-3 implementation study integrating CAB+RPV LA Into European clinical settings.