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Viruses Jun 2024Although antiretroviral therapy (ART) effectively halts disease progression in HIV infection, the complete eradication of the virus remains elusive. Additionally,... (Review)
Review
BACKGROUND
Although antiretroviral therapy (ART) effectively halts disease progression in HIV infection, the complete eradication of the virus remains elusive. Additionally, challenges such as long-term ART toxicity, drug resistance, and the demanding regimen of daily and lifelong adherence required by ART highlight the imperative need for alternative therapeutic and preventative approaches. In recent years, broadly neutralizing antibodies (bNAbs) have emerged as promising candidates, offering potential for therapeutic, preventative, and possibly curative interventions against HIV infection.
OBJECTIVE
This review aims to provide a comprehensive overview of the current state of knowledge regarding the passive immunization of bNAbs in HIV-1-infected individuals.
MAIN FINDINGS
Recent findings from clinical trials have highlighted the potential of bNAbs in the treatment, prevention, and quest for an HIV-1 cure. While monotherapy with a single bNAb is insufficient in maintaining viral suppression and preventing viral escape, ultimately leading to viral rebound, combination therapy with potent, non-overlapping epitope-targeting bNAbs have demonstrated prolonged viral suppression and delayed time to rebound by effectively restricting the emergence of escape mutations, albeit largely in individuals with bNAb-sensitive strains. Additionally, passive immunization with bNAb has provided a "proof of concept" for antibody-mediated prevention against HIV-1 acquisition, although complete prevention has not been obtained. Therefore, further research on the use of bNAbs in HIV-1 treatment and prevention remains imperative.
Topics: Humans; HIV Infections; HIV-1; HIV Antibodies; Antibodies, Neutralizing; Immunization, Passive; Broadly Neutralizing Antibodies; Anti-HIV Agents; Animals
PubMed: 38932203
DOI: 10.3390/v16060911 -
Microorganisms Jun 2024Developing new anti-human immunodeficiency virus (HIV) drug candidates that target different sites in HIV-1 replication, with better resistance profiles and lower drug...
Developing new anti-human immunodeficiency virus (HIV) drug candidates that target different sites in HIV-1 replication, with better resistance profiles and lower drug toxicity, is essential to eradicating HIV. This study investigated the potential of fractionated crude extracts of as immunomodulatory or anti-HIV drug candidates. Solid-phase extraction (SPE) was used to fractionate PO4PR2 using three different columns: MAX (Mixed-mode, strong Anion-eXchange), MCX (Mixed-mode, strong Cation-eXchange), and HLB (Hydrophilic-Lipophilic Balance) with methanol gradient methods (5%, 45%, and 95%). An MTT (3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay was used to assess the cell viability and cytotoxicity of the fractionated crude extract PO4PR2 in the TZM-bl cell lines. This was followed by a luciferase-based antiviral assay to assess the antiviral activity of PO4PR2. A time of addition (TOA) assay was performed to ascertain the mechanism of inhibition employed by the fractionated crude extract of PO4PR2 in the HIV life cycle. The p24 titer was determined using an ELISA, while a luciferase-based antiviral assay was used to evaluate the HIV percentage inhibition for different HIV-1 replication cycles. The TOA assay was established using antiviral drugs that target different sites in the HIV replication cycle. These included maraviroc, azidothymidine, raltegravir, and amprenavir. The immunomodulatory effect of the fractionated crude extracts on CD4+ T cells was measured by a flow cytometric analysis, for which fluorochrome-labelled monoclonal antibodies were used as markers for activation (CD38 and HLA-DR) and exhaustion (PD-1). The MCX fraction demonstrated a more significant anti-HIV inhibition than that of the fractions generated in other columns, with an IC of 0.3619 µg/mL, an HIV inhibition of 77%, 5% HLB (IC: 0.7232 µg/mL; HIV inhibition of 64%), and 5% MAX (IC: 5.240 µg/mL; HIV inhibition of 67%). It was evident from the time of addition data that the crude extract and the 5% MCX fraction inhibited viral binding (68%), reverse transcription (75%), integration (98%), and proteolysis (77%). It was shown that (the MCX fraction) have a significant inhibitory effect on reverse transcription (75% HIV inhibition) and integration (100% HIV inhibition). The 5% MCX ( = 0.0062), 5% HLB ( = 0.0269), and 5% MAX ( = 0.0117) fractionated crude extracts had low levels of CD4+ T cell (CD38 + HLA-DR+) activation compared to those of the AZT treatment, while CD4+ T cell activation was insignificant. The 5% MAX and HLB fractions may possess immunomodulatory compounds with less anti-HIV-1 activity. could be a key source of innovative anti-HIV drugs with immunomodulatory characteristics.
PubMed: 38930532
DOI: 10.3390/microorganisms12061150 -
The Lancet. HIV Jul 2024Rates of new HIV acquisition remain unacceptably high in most populations in low-income, middle-income, and high-income settings despite advances in treatment and... (Review)
Review
Rates of new HIV acquisition remain unacceptably high in most populations in low-income, middle-income, and high-income settings despite advances in treatment and prevention strategies. Although biomedical advances in primary prevention of new infections exist, systematic scale-up of these interventions has not occurred at the pace required to end AIDS by 2030. Low population coverage, adherence to oral pre-exposure prophylaxis in settings with high rates of HIV acquisition, and the fact that a significant proportion of new HIV infections occurs in populations not identified as high risk and are hence not targeted for prevention approaches impedes current prevention strategies. Although long-acting injectables and monoclonal antibodies are promising approaches to help reduce incidence, high cost and the need for high coverage rates mean that a vaccine or vaccine-like intervention still remains the most likely scenario to produce a population-level impact on HIV incidence, especially in countries with generalised epidemics. Current global efforts are not sufficient to meet 2030 HIV epidemic goals; acknowledgment of this issue is required to ensure persistent advocacy for population-based control of the ongoing HIV pandemic.
Topics: Humans; HIV Infections; Epidemics; Pre-Exposure Prophylaxis; Incidence; Global Health
PubMed: 38925732
DOI: 10.1016/S2352-3018(24)00098-5 -
Tropical Medicine and Infectious Disease Jun 2024Kaposi sarcoma (KS) is an AIDS-defining angio-proliferative malignancy, with the Kaposi sarcoma-associated herpes virus (KSHV) as its etiologic agent. Upon treatment...
Kaposi sarcoma (KS) is an AIDS-defining angio-proliferative malignancy, with the Kaposi sarcoma-associated herpes virus (KSHV) as its etiologic agent. Upon treatment with chemotherapy, a proportion of HIV-associated KS patients experience disease recurrence within a few months of completing treatment. We aimed at determining whether KSHV-specific adaptive immune responses were associated with KS recurrence upon complete remission. We conducted a prospective cohort study. The primary outcome was the recurrence of HIV-associated KS. An immunofluorescence assay was used to determine anti-KSHV antibodies, an enzyme-linked immunospot was conducted for T cell responses, PCR was carried out to determine KSHV status, and flow cytometry was used for CD4 counting and immunophenotyping. KSHV detection in PBMCs was high and not associated with KS recurrence-free survival ( = 0.29). Anti-KSHV antibody titers were high and not associated with recurrence-free survival ( = 0.63). KSHV-specific T cell responses dropped from baseline levels among individuals with recurrence, but the drop was not statistically significant. Individuals experiencing KS recurrence had a significantly higher proportion of T cell subsets expressing PD1, while those with sustained remission had a significant increase in CD4 T cell counts from baseline levels during the follow-up period ( = 0.02). Anti-KSHV antibodies are not a good correlate of protection from KS recurrence. T cells in individuals experiencing KS recurrence hadhigh PD1 expression, while an increase in CD4 counts was associated with sustained KS remission.
PubMed: 38922046
DOI: 10.3390/tropicalmed9060134 -
Journal of Acquired Immune Deficiency... Aug 2024An effective vaccine is required to end the HIV pandemic. We evaluated the safety and immunogenicity of a DNA (DNA-HIV-PT123) vaccine with low- or high-dose bivalent... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
An effective vaccine is required to end the HIV pandemic. We evaluated the safety and immunogenicity of a DNA (DNA-HIV-PT123) vaccine with low- or high-dose bivalent (TV1.C and 1086.C glycoprotein 120) subtype C envelope protein combinations, adjuvanted with MF59 or AS01B.
METHODS
HIV Vaccine Trials Network (HVTN)108 was a randomized, placebo-controlled, double-blind, phase 1/2a trial conducted in the United States and South Africa. HIV-negative adults were randomly assigned to 1 of 7 intervention arms or placebo to assess DNA prime with DNA/protein/adjuvant boosts, DNA/protein/adjuvant co-administration, and low-dose protein/adjuvant regimens. HVTN111 trial participants who received an identical regimen were also included. Outcomes included safety and immunogenicity 2 weeks and 6 months after final vaccination.
RESULTS
From June 2016 to July 2018, 400 participants were enrolled (N = 334 HVTN108, N = 66 HVTN111); 370 received vaccine and 30 received placebo. There were 48 grade 3 and 3 grade 4 reactogenicity events among 39/400 (9.8%) participants, and 32 mild/moderate-related adverse events in 23/400 (5.8%) participants. All intervention groups demonstrated high IgG response rates (>89%) and high magnitudes to HIV-1 Env gp120 and gp140 proteins; response rates for AS01B-adjuvanted groups approached 100%. V1V2 IgG magnitude, Fc-mediated functions, IgG3 Env response rates, and CD4+ T-cell response magnitudes and rates were higher in the AS01B-adjuvanted groups. The AS01B-adjuvanted low-dose protein elicited greater IgG responses than the higher protein dose.
CONCLUSIONS
The vaccine regimens were generally well tolerated. Co-administration of DNA with AS01B-adjuvanted bivalent Env gp120 elicited the strongest humoral responses; AS01B-adjuvanted regimens elicited stronger CD4+ T-cell responses, justifying further evaluation.ClinicalTrials.gov registration: NCT02915016, registered 26 September 2016.
Topics: Humans; AIDS Vaccines; Vaccines, DNA; Female; Male; Adult; Squalene; Polysorbates; HIV Envelope Protein gp120; Adjuvants, Immunologic; HIV-1; HIV Infections; HIV Antibodies; Double-Blind Method; Middle Aged; Young Adult; Adjuvants, Vaccine; South Africa; Immunogenicity, Vaccine; Adolescent; United States
PubMed: 38916429
DOI: 10.1097/QAI.0000000000003438 -
Nature Communications Jun 2024Broadly neutralizing antibodies (bNAbs) are promising candidates for the treatment and prevention of HIV-1 infections. Despite their critical importance, automatic...
Broadly neutralizing antibodies (bNAbs) are promising candidates for the treatment and prevention of HIV-1 infections. Despite their critical importance, automatic detection of HIV-1 bNAbs from immune repertoires is still lacking. Here, we develop a straightforward computational method for the Rapid Automatic Identification of bNAbs (RAIN) based on machine learning methods. In contrast to other approaches, which use one-hot encoding amino acid sequences or structural alignment for prediction, RAIN uses a combination of selected sequence-based features for the accurate prediction of HIV-1 bNAbs. We demonstrate the performance of our approach on non-biased, experimentally obtained and sequenced BCR repertoires from HIV-1 immune donors. RAIN processing leads to the successful identification of distinct HIV-1 bNAbs targeting the CD4-binding site of the envelope glycoprotein. In addition, we validate the identified bNAbs using an in vitro neutralization assay and we solve the structure of one of them in complex with the soluble native-like heterotrimeric envelope glycoprotein by single-particle cryo-electron microscopy (cryo-EM). Overall, we propose a method to facilitate and accelerate HIV-1 bNAbs discovery from non-selected immune repertoires.
Topics: HIV-1; Humans; Machine Learning; HIV Antibodies; Cryoelectron Microscopy; Antibodies, Neutralizing; HIV Infections; CD4 Antigens; Amino Acid Sequence; HIV Envelope Protein gp120
PubMed: 38914562
DOI: 10.1038/s41467-024-49676-1 -
Sexually Transmitted Infections Jun 2024Studies showed that men who have sex with men (MSM), including those using pre-exposure prophylaxis (PrEP), are at increased risk of hepatitis C virus (HCV) infection....
OBJECTIVES
Studies showed that men who have sex with men (MSM), including those using pre-exposure prophylaxis (PrEP), are at increased risk of hepatitis C virus (HCV) infection. We evaluated HCV prevalence and incidence, along with their associated determinants, in a cohort of PrEP-using individuals in the Netherlands.
METHODS
In 2019, the Netherlands launched a 5-year national programme that offers subsidised PrEP to eligible individuals. We used prospectively collected data from individuals registered in this programme between 2019 and 2022. Individuals underwent annual testing for HCV antibodies and additional HCV-RNA testing when antibodies were present. We calculated the prevalence of past/current HCV infection at first visit and overall incidence rate (IR) during follow-up. Univariable logistic and Poisson regression models were used to identify determinants associated with past/current prevalent or incident HCV infection, respectively. Behavioural factors referred to those occurring in the previous 6 months.
RESULTS
A total of 10 563 (n=10 319, 97.7% MSM) were included. At first visit, 66 of 10 563 (0.6%) had a past/current HCV infection, which was associated with older age [odds ratio (OR) per 10 years=1.57, 95% confidence interval (CI)=1.31 to 1.88], the use of PrEP before first visit (OR=3.03, 95% CI=1.79 to 5.13), receptive condomless anal sex (CAS) (OR=2.73, 95% CI=1.25 to 5.98), chemsex (OR=2.44, 95% CI=1.49 to 3.99) and injecting drug use (IDU) (OR=6.61, 95% CI=2.35 to 18.61). Among 9851 individuals contributing to 17 150 person-years (PYs) of follow-up, 64 incident HCV infections (IR=0.37 per 100 PYs, 95% CI=0.29 to 0.48) were identified. Factors associated with incident HCV infection were receptive CAS [incidence rate ratio (IRR)=2.59, 95% CI=1.12 to 6.02], chemsex (IRR=1.78, 95% CI=1.06 to 2.98), sexually transmitted infection diagnosis (IRR=2.30, 95% CI=1.23 to 4.31) and IDU (IRR=6.15, 95% CI=2.20 to 17.18).
CONCLUSIONS
Past/current prevalence and incidence of HCV were low among individuals in the Dutch PrEP programme. Infections were associated with behaviour known to be associated with HCV. Instead of annual HCV testing, as stated in most PrEP care guidelines, testing frequency for HCV could be based on behaviours associated with HCV acquisition.
PubMed: 38914472
DOI: 10.1136/sextrans-2024-056169 -
PLoS Medicine Jun 2024Broadly neutralizing antibodies (bnAbs) are a promising approach for HIV-1 prevention. In the Antibody Mediated Prevention (AMP) trials, a CD4-binding site targeting...
BACKGROUND
Broadly neutralizing antibodies (bnAbs) are a promising approach for HIV-1 prevention. In the Antibody Mediated Prevention (AMP) trials, a CD4-binding site targeting bnAb, VRC01, administered intravenously (IV), demonstrated 75% prevention efficacy against highly neutralization-sensitive viruses but was ineffective against less sensitive viruses. VRC07-523LS is a next-generation bnAb targeting the CD4-binding site and was engineered for increased neutralization breadth and half-life. We conducted a multicenter, randomized, partially blinded Phase I clinical trial to evaluate the safety and serum concentrations of VRC07-523LS, administered in multiple doses and routes to healthy adults without HIV.
METHODS AND FINDINGS
Participants were recruited between 2 February 2018 and 9 October 2018. A total of 124 participants were randomized to receive 5 VRC07-523LS administrations via IV (T1: 2.5 mg/kg, T2: 5 mg/kg, T3: 20 mg/kg), subcutaneous (SC) (T4: 2.5 mg/kg, T5: 5 mg/kg), or intramuscular (IM) (T6: 2.5 mg/kg or P6: placebo) routes at 4-month intervals. Participants and site staff were blinded to VRC07-523LS versus placebo for the IM group, while all other doses and routes were open-label. Safety data were collected for 144 weeks following the first administration. VRC07-523LS serum concentrations were measured by ELISA through Day 112 in all participants and by binding antibody multiplex assay (BAMA) thereafter in 60 participants (10 per treatment group) through Day 784. Compartmental population pharmacokinetic (PK) analyses were conducted to evaluate the VRC07-523LS serum PK. Neutralization activity was measured in a TZM-bl assay and antidrug antibodies (ADAs) were assayed using a tiered bridging assay testing strategy. Injections and infusions were well tolerated, with mild pain or tenderness reported commonly in the SC and IM groups, and mild to moderate erythema or induration reported commonly in the SC groups. Infusion reactions reported in 3 of 20 participants in the 20 mg/kg IV group. Peak geometric mean (GM) concentrations (95% confidence intervals [95% CIs]) following the first administration were 29.0 μg/mL (25.2, 33.4), 58.5 μg/mL (49.4, 69.3), and 257.2 μg/mL (127.5, 518.9) in T1-T3 with IV dosing; 10.8 μg/mL (8.8, 13.3) and 22.8 μg/mL (20.1, 25.9) in T4-T5 with SC dosing; and 16.4 μg/mL (14.7, 18.2) in T6 with IM dosing. Trough GM (95% CIs) concentrations immediately prior to the second administration were 3.4 μg/mL (2.5, 4.6), 6.5 μg/mL (5.6, 7.5), and 27.2 μg/mL (23.9, 31.0) with IV dosing; 0.97 μg/mL (0.65, 1.4) and 3.1 μg/mL (2.2, 4.3) with SC dosing, and 2.6 μg/mL (2.05, 3.31) with IM dosing. Peak VRC07-523LS serum concentrations increased linearly with the administered dose. At a given dose, peak and trough concentrations, as well as serum neutralization titers, were highest in the IV groups, reflecting the lower bioavailability following SC and IM administration. A single participant was found to have low titer ADA at a lone time point. VRC07-523LS has an estimated mean half-life of 42 days across all doses and routes (95% CI: 40.5, 43.5), over twice as long as VRC01 (15 days).
CONCLUSIONS
VRC07-523LS was safe and well tolerated across a range of doses and routes and is a promising long-acting bnAb for inclusion in HIV-1 prevention regimens.
TRIAL REGISTRATION
ClinicalTrials.gov/ NCT03387150 (posted on 21 December 2017).
PubMed: 38913710
DOI: 10.1371/journal.pmed.1004329 -
JCI Insight May 2024Identifying immune correlates of protection is a major challenge in AIDS vaccine development. Anti-Envelope antibodies have been considered critical for protection...
Identifying immune correlates of protection is a major challenge in AIDS vaccine development. Anti-Envelope antibodies have been considered critical for protection against SIV/HIV (SHIV) acquisition. Here, we evaluated the efficacy of an SHIV vaccine against SIVmac251 challenge, where the role of antibody was excluded, as there was no cross-reactivity between SIV and SHIV envelope antibodies. After 8 low-dose intrarectal challenges with SIVmac251, 12 SHIV-vaccinated animals demonstrated efficacy, compared with 6 naive controls, suggesting protection was achieved in the absence of anti-envelope antibodies. Interestingly, CD8+ T cells (and some NK cells) were not essential for preventing viral acquisition, as none of the CD8-depleted macaques were infected by SIVmac251 challenges. Initial investigation of protective innate immunity revealed that protected animals had elevated pathways related to platelet aggregation/activation and reduced pathways related to interferon and responses to virus. Moreover, higher expression of platelet factor 4 on circulating platelet-leukocyte aggregates was associated with reduced viral acquisition. Our data highlighted the importance of innate immunity, identified mechanisms, and may provide opportunities for novel HIV vaccines or therapeutic strategy development.
Topics: Animals; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; SAIDS Vaccines; Macaca mulatta; Immunity, Innate; CD8-Positive T-Lymphocytes; Antibodies, Viral; Male; Vaccines, Attenuated
PubMed: 38912579
DOI: 10.1172/jci.insight.175800 -
Lancet Regional Health. Americas Aug 2024Manitoba saw the highest number of new HIV diagnoses in the province's history in 2021 and is the only Canadian province not meeting any of the previous UNAIDS 90-90-90...
Sex differences in houselessness, injection drug use, and mental health conditions among people newly diagnosed with HIV in Manitoba, Canada from 2018 to 2021: a retrospective cohort study.
BACKGROUND
Manitoba saw the highest number of new HIV diagnoses in the province's history in 2021 and is the only Canadian province not meeting any of the previous UNAIDS 90-90-90 targets. Our goal was to describe sex differences and syndemic conditions within an incident HIV cohort in Manitoba, and the HIV treatment initiation and undetectable viral load outcomes.
METHODS
This was a retrospective cohort study of all people 18 years and older newly diagnosed with HIV in Manitoba, Canada between January 1st, 2018 and December 31st, 2021. Data was collected as follows: : chlamydia, gonorrhoea, syphilis, and/or hepatitis C antibodies. : age, sex, gender, race/ethnicity, sexual orientation. : CD4 counts, viral load, HIV treatment, hospitalizations, and number of visits to HIV care. Main exposures evaluated: methamphetamine use, injection drug use, houselessness, and mental health conditions. Outcomes: started antiretroviral treatment and achieved an undetectable viral load. A descriptive statistical analysis was used.
FINDINGS
There were 404 new HIV diagnoses in Manitoba from 2018 to 2021; 44.8% were female, 55.2% male; 76.% self-identified as Indigenous, 13.4% white/European, 4.7% African/black; 86.6% cis-gender; 60.9% heterosexual, 13.4% gay, bisexual and men who have sex with men, and 1.7% lesbian. Injection drug use was reported by 71.8% and 43.5% of females and males respectively. Methamphetamine was the most frequently injected drug (62.4%). Amongst females, 81.8% experienced at least one of the following: houselessness (43.1%), mental health comorbidities (46.4%), and injection drug use (71.8%). Only 64.9% of all individuals had an undetectable viral load (61.1% females and 67.9% males), 56.5% among people experiencing houselessness, 59% among young people (≤29 years), and 60.1% among people who inject drugs.
INTERPRETATION
People newly diagnosed with HIV in Manitoba are disproportionately experiencing houselessness, mental illness, and injection drug use (mostly methamphetamine). This pattern is more pronounced for female individuals. These findings highlight the need for syndemic and gender-specific approaches, simultaneously addressing social and health conditions, to treat HIV.
FUNDING
This work was supported by the Canadian Institutes of Health Research, The Manitoba Medical Service Foundation, The James Farley Memorial Fund and the Canada Research Chairs Program.
PubMed: 38912328
DOI: 10.1016/j.lana.2024.100805