Showing papers by "Myron S. Cohen published in 2017"

Staged induction of HIV-1 glycan–dependent broadly neutralizing antibodies

Abstract: A preventive HIV-1 vaccine should induce HIV-1-specific broadly neutralizing antibodies (bnAbs). However, bnAbs generally require high levels of somatic hypermutation (SHM) to acquire breadth, and current vaccine strategies have not been successful in inducing bnAbs. Because bnAbs directed against a glycosylated site adjacent to the third variable loop (V3) of the HIV-1 envelope protein require limited SHM, the V3-glycan epitope is an attractive vaccine target. By studying the cooperation among multiple V3-glycan B cell lineages and their coevolution with autologous virus throughout 5 years of infection, we identify key events in the ontogeny of a V3-glycan bnAb. Two autologous neutralizing antibody lineages selected for virus escape mutations and consequently allowed initiation and affinity maturation of a V3-glycan bnAb lineage. The nucleotide substitution required to initiate the bnAb lineage occurred at a low-probability site for activation-induced cytidine deaminase activity. Cooperation of B cell lineages and an improbable mutation critical for bnAb activity defined the necessary events leading to breadth in this V3-glycan bnAb lineage. These findings may, in part, explain why initiation of V3-glycan bnAbs is rare, and suggest an immunization strategy for inducing similar V3-glycan bnAbs.

Clinical and public health implications of acute and early HIV detection and treatment: a scoping review

Abstract: Introduction: The unchanged global HIV incidence may be related to ignoring acute HIV infection (AHI). This scoping review examines diagnostic, clinical, and public health implications of identifying and treating persons with AHI. Methods: We searched PubMed, in addition to hand-review of key journals identifying research pertaining to AHI detection and treatment. We focused on the relative contribution of AHI to transmission and the diagnostic, clinical, and public health implications. We prioritized research from low- and middle-income countries (LMICs) published in the last fifteen years. Results and Discussion: Extensive AHI research and limited routine AHI detection and treatment have begun in LMIC. Diagnostic challenges include ease-of-use, suitability for application and distribution in LMIC, and throughput for high-volume testing. Risk score algorithms have been used in LMIC to screen for AHI among individuals with behavioural and clinical characteristics more often associated with AHI. However, algorithms have not been implemented outside research settings. From a clinical perspective, there are substantial immunological and virological benefits to identifying and treating persons with AHI – evading the irreversible damage to host immune systems and seeding of viral reservoirs that occurs during untreated acute infection. The therapeutic benefits require rapid initiation of antiretrovirals, a logistical challenge in the absence of point-of-care testing. From a public health perspective, AHI diagnosis and treatment is critical to: decrease transmission via viral load reduction and behavioural interventions; improve pre-exposure prophylaxis outcomes by avoiding treatment initiation for HIV-seronegative persons with AHI; and, enhance partner services via notification for persons recently exposed or likely transmitting. Conclusions: There are undeniable clinical and public health benefits to AHI detection and treatment, but also substantial diagnostic and logistical barriers to implementation and scale-up. Effective early ART initiation may be critical for HIV eradication efforts, but widespread use in LMIC requires simple and accurate diagnostic tools. Implementation research is critical to facilitate sustainable integration of AHI detection and treatment into existing health systems and will be essential for prospective evaluation of testing algorithms, point-of-care diagnostics, and efficacious and effective first-line regimens.

Potent and broad HIV-neutralizing antibodies in memory B cells and plasma.

Abstract: Induction of broadly neutralizing antibodies (bnAbs) is a goal of HIV-1 vaccine development. Antibody 10E8, reactive with the distal portion of the membrane-proximal external region (MPER) of HIV-1 gp41, is broadly neutralizing. However, the ontogeny of distal MPER antibodies and the relationship of memory B cell to plasma bnAbs are poorly understood. HIV-1–specific memory B cell flow sorting and proteomic identification of anti-MPER plasma antibodies from an HIV-1–infected individual were used to isolate broadly neutralizing distal MPER bnAbs of the same B cell clonal lineage. Structural analysis demonstrated that antibodies from memory B cells and plasma recognized the envelope gp41 bnAb epitope in a distinct orientation compared with other distal MPER bnAbs. The unmutated common ancestor of this distal MPER bnAb was autoreactive, suggesting lineage immune tolerance control. Construction of chimeric antibodies of memory B cell and plasma antibodies yielded a bnAb that potently neutralized most HIV-1 strains.

Mimicry of an HIV broadly neutralizing antibody epitope with a synthetic glycopeptide.

Abstract: A goal for an HIV-1 vaccine is to overcome virus variability by inducing broadly neutralizing antibodies (bnAbs). One key target of bnAbs is the glycan-polypeptide at the base of the envelope (Env) third variable loop (V3). We have designed and synthesized a homogeneous minimal immunogen with high-mannose glycans reflective of a native Env V3-glycan bnAb epitope (Man9-V3). V3-glycan bnAbs bound to Man9-V3 glycopeptide and native-like gp140 trimers with similar affinities. Fluorophore-labeled Man9-V3 glycopeptides bound to bnAb memory B cells and were able to be used to isolate a V3-glycan bnAb from an HIV-1-infected individual. In rhesus macaques, immunization with Man9-V3 induced V3-glycan-targeted antibodies. Thus, the Man9-V3 glycopeptide closely mimics an HIV-1 V3-glycan bnAb epitope and can be used to isolate V3-glycan bnAbs.

Basis and Statistical Design of the Passive HIV-1 Antibody Mediated Prevention (AMP) Test-of-Concept Efficacy Trials.

Abstract: Background Anti-HIV-1 broadly neutralizing antibodies (bnAbs) have been developed as potential agents for prevention of HIV-1 infection. The HIV Vaccine Trials Network and the HIV Prevention Trials Network are conducting the Antibody Mediated Prevention (AMP) trials to assess whether, and how, intravenous infusion of the anti-CD4 binding site bnAb, VRC01, prevents HIV-1 infection. These are the first test-of-concept studies to assess HIV-1 bnAb prevention efficacy in humans. Methods The AMP trials are two parallel phase 2b HIV-1 prevention efficacy trials conducted in two cohorts: 2700 HIV-uninfected men and transgender persons who have sex with men in the United States, Peru, Brazil, and Switzerland; and 1500 HIV-uninfected sexually active women in seven countries in sub-Saharan Africa. Participants are randomized 1:1:1 to receive an intravenous infusion of 10 mg/kg VRC01, 30 mg/kg VRC01, or a control preparation every 8 weeks for a total of 10 infusions. Each trial is designed (1) to assess overall prevention efficacy (PE) pooled over the two VRC01 dose groups vs. control and (2) to assess VRC01 dose and laboratory markers as correlates of protection (CoPs) against overall and genotype- and phenotype-specific infection. Results Each AMP trial is designed to have 90% power to detect PE > 0% if PE is ≥ 60%. The AMP trials are also designed to identify VRC01 properties (i.e., concentration and effector functions) that correlate with protection and to provide insight into mechanistic CoPs. CoPs are assessed using data from breakthrough HIV-1 infections, including genetic sequences and sensitivities to VRC01-mediated neutralization and Fc effector functions. Conclusions The AMP trials test whether VRC01 can prevent HIV-1 infection in two study populations. If affirmative, they will provide information for estimating the optimal dosage of VRC01 (or subsequent derivatives) and identify threshold levels of neutralization and Fc effector functions associated with high-level protection, setting a benchmark for future vaccine evaluation and constituting a bridge to other bnAb approaches for HIV-1 prevention.

Treatment as Prevention: Characterization of Partner Infections in the HIV Prevention Trials Network 052 Trial.

Abstract: HIV Prevention Trials Network 052 demonstrated that antiretroviral therapy (ART) prevents HIV transmission in serodiscordant couples. HIV from index–partner pairs was analyzed to determine the genetic linkage status of partner infections. Forty-six infections were classified as linked, indicating that the index was the likely source of the partner’s infection. Lack of viral suppression and higher index viral load were associated with linked infection. Eight linked infections were diagnosed after the index started ART: 4 near the time of ART initiation and 4 after ART failure. Linked infections were not observed when the index participant was stably suppressed on ART.

Virion incorporation of integrin α4β7 facilitates HIV-1 infection and intestinal homing

Abstract: The intestinal mucosa is a key anatomical site for HIV-1 replication and CD4+ T cell depletion. Accordingly, in vivo treatment with an antibody to the gut-homing integrin α4β7 was shown to reduce viral transmission, delay disease progression, and induce persistent virus control in macaques challenged with simian immunodeficiency virus (SIV). We show that integrin α4β7 is efficiently incorporated into the envelope of HIV-1 virions. Incorporated α4β7 is functionally active as it binds mucosal addressin cell adhesion molecule-1 (MAdCAM-1), promoting HIV-1 capture by and infection of MAdCAM-expressing cells, which in turn mediate trans-infection of bystander cells. Functional α4β7 is present in circulating virions from HIV-infected patients and SIV-infected macaques, with peak levels during the early stages of infection. In vivo homing experiments documented selective and specific uptake of α4β7+ HIV-1 virions by high endothelial venules in the intestinal mucosa. These results extend the paradigm of tissue homing to a retrovirus and are relevant for the pathogenesis, treatment, and prevention of HIV-1 infection.

Brief Report: Impact of Early Antiretroviral Therapy on the Performance of HIV Rapid Tests and HIV Incidence Assays

Abstract: BACKGROUND Antiretroviral therapy (ART) can downregulate antibody responses to HIV infection. We evaluated the impact of early vs. delayed ART on the performance of HIV diagnostic and incidence assays. METHODS Samples were obtained from 207 participants in the HPTN 052 trial, who were stably suppressed on ART for ≥4 years [Malawi sites; pre-ART CD4 cell count 350-550 cells/mm (early ART arm, N = 180) or <250 cells/mm or an AIDS-defining illness (delayed ART arm, N = 27)]. Samples were tested with 2 HIV rapid tests and 2 HIV incidence assays; selected samples were also tested with two fourth-generation immunoassays and a Western blot (WB) assay. A pre-ART sample was analyzed if the follow-up sample had a false-negative or weakly-reactive rapid test result, or had an incidence assay result indicative of recent infection (false-recent result). RESULTS Ten (4.8%) samples had a nonreactive or weakly-reactive rapid test result (7/180 early ART arm, 3/27 delayed ART arm, P = 0.13); one sample had nonreactive fourth-generation assay results and 3 had indeterminate WBs. Forty (18.9%) samples had a false-recent incidence assay result; 16 (7.8%) had false-recent results with both incidence assays. Baseline samples had stronger rapid test and WB bands, higher fourth-generation assay signal-to-cutoff values, and fewer HIV incidence assay results indicative of recent infection. CONCLUSIONS False-negative/weakly-reactive HIV rapid tests and false-recent HIV incidence assay results were observed in virally-suppressed individuals, regardless of pre-ART CD4 cell count. Downregulation of the antibody response to HIV infection in the setting of ART may impact population-level surveys of HIV prevalence and incidence.

Virologic outcomes in early antiretroviral treatment: HPTN 052.

Abstract: Introduction: The HIV Prevention Trials Network (HPTN) 052 trial demonstrated that early antiretroviral therapy (ART) prevented 93% of HIV transmission events in serodiscordant couples. Some linked...

Comparison of hepatitis b virus infection in HIV-infected and HIV-uninfected participants enrolled in a multinational clinical trial: HPTN 052

Abstract: Data comparing hepatitis B virus (HBV) infection in HIV-infected [HIV(+)], and HIV-uninfected [HIV(-)] individuals recruited into the same study are limited. HBV infection status and chronic hepatitis B (cHB) were characterized in a multinational clinical trial: HIV Prevention Trials Network (HPTN 052).

Broadly neutralizing antibodies to prevent HIV-1.

Abstract: Advances in technology—especially single-cell antibody cloning techniques—have led to the isolation and characterization of antibodies from people with HIV infection that can neutralize many variants ( 1 ). These are referred to as broadly neutralizing antibodies (bnAbs). Such antibodies can be detected in about 25% of persons with untreated HIV-1 infection ( 2 ), reflecting a host immune response to unremitting viral replication, generation of large numbers of viral variants, and shifting antigen exposure ( 3 ). Although bnAbs may exert some selective pressure as they develop, they generally do not reduce viral burden, improve health, or slow the progression of disease ( 4 ). However, they offer considerable opportunities for treatment and prevention of HIV-1 infection in others. At this time, hundreds of bnAbs have been identified; those that have attracted the most attention are bnAbs with the greatest breadth, neutralizing the largest number of HIV-1 strains, including those traditionally most neutralization resistant ( 1 , 5 ); or bnAbs that have the greatest potency, requiring the smallest concentration to neutralize resistant strains of HIV-1 ( 5 – 7 ). A study by Xu et al. ( 5 ) on page 85 of this issue and by Julg et al. ( 7 ) in Science Translational Medicine illustrate advances in the potential use of bnAbs to prevent HIV-1 infection.

HIV Drug Resistance in Adults Receiving Early vs. Delayed Antiretroviral Therapy: HPTN 052.

Abstract: Introduction We evaluated HIV drug resistance in adults who received early vs. delayed antiretroviral therapy (ART) in a multinational trial [HIV Prevention Trials Network (HPTN) 052, enrollment 2005-2010]. In HPTN 052, 1763 index participants were randomized to start ART at a CD4 cell count of 350-550 cells/mm (early ART arm) or Methods Virologic failure was defined as 2 consecutive viral loads >1000 copies/mL >24 weeks after ART initiation. Drug resistance testing was performed for pretreatment (baseline) and failure samples from participants with virologic failure. Results HIV genotyping results were obtained for 211/249 participants (128 early ART arm and 83 delayed ART arm) with virologic failure. Drug resistance was detected in 4.7% of participants at baseline; 35.5% had new resistance at failure. In univariate analysis, the frequency of new resistance at failure was lower among participants in the early ART arm (compared with delayed ART arm, P = 0.06; compared with delayed ART arm with ART initiation before May 2011, P = 0.032). In multivariate analysis, higher baseline viral load (P = 0.0008) and ART regimen (efavirenz/lamivudine/zidovudine compared with other regimens, P = 0.024) were independently associated with higher risk of new resistance at failure. Conclusions In HPTN 052, the frequency of new drug resistance at virologic failure was lower in adults with early ART initiation. The main factor associated with reduced drug resistance with early ART was lower baseline viral load.

Computational analysis of antibody dynamics identifies recent HIV-1 infection.

Abstract: Accurate HIV-1 incidence estimation is critical to the success of HIV-1 prevention strategies. Current assays are limited by high false recent rates (FRRs) in certain populations and a short mean duration of recent infection (MDRI). Dynamic early HIV-1 antibody response kinetics were harnessed to identify biomarkers for improved incidence assays. We conducted retrospective analyses on circulating antibodies from known recent and longstanding infections and evaluated binding and avidity measurements of Env and non-Env antigens and multiple antibody forms (i.e., IgG, IgA, IgG3, IgG4, dIgA, and IgM) in a diverse panel of 164 HIV-1-infected participants (clades A, B, C). Discriminant function analysis identified an optimal set of measurements that were subsequently evaluated in a 324-specimen blinded biomarker validation panel. These biomarkers included clade C gp140 IgG3, transmitted/founder clade C gp140 IgG4 avidity, clade B gp140 IgG4 avidity, and gp41 immunodominant region IgG avidity. MDRI was estimated at 215 day or alternatively, 267 days. FRRs in untreated and treated subjects were 5.0% and 3.6%, respectively. Thus, computational analysis of dynamic HIV-1 antibody isotype and antigen interactions during infection enabled design of a promising HIV-1 recency assay for improved cross-sectional incidence estimation.

Effectiveness and Cost-Effectiveness of Treatment as Prevention for HIV

Abstract: The beneficial effects of antiretroviral therapy (ART) on individual health are well established, and ART is widely used to reduce the morbidity and mortality due to the human immunodeficiency virus (HIV) (WHO 2016). Recent evidence has strengthened the case for initiating ART as early in the disease stage as possible (Danel and others 2015; INSIGHT START Study Group 2015). Similarly, using ART to prevent mother-to-child transmission of HIV is supported with conclusive evidence and has been adopted into clinical policies worldwide, as discussed in chapter 6 of this volume (John-Stewart and others 2017). Years of accumulating biological and observational evidence also suggest that ART may reduce sexual transmission of HIV, although the field lacked conclusive evidence until recently (Donnell and others 2010; Nachega and others 2013).The evidence base and attention to “treatment as/for prevention” strengthened substantially in 2011 with the interim results from HIV Prevention Trials Network (HPTN) 052, a randomized controlled trial of early versus delayed use of ART among serodiscordant couples (Cohen and others 2011). The trial demonstrated a 96 percent reduction in new infections with earlier initiation of ART and provided strong evidence that ART reduces the sexual transmission of HIV. Final results of this trial with nearly 10,000 person-years of follow-up with similar conclusions were published in 2016 (Cohen and others 2016).This emerging evidence stimulated a range of questions regarding the biological mechanisms of HIV treatment as prevention (TasP), variations in efficacy across subgroups, differences in at-risk populations, optimal implementation strategies, and potential implications for public health (Cohen, Holmes, and others 2012; Delva and others 2012). Recognition of the dual benefits of treatment has resulted in the reevaluation of the cost-effectiveness of ART, as well as of the paradigms of HIV prevention (Garnett and others 2017) and has led to policy discussions about how best to value the risks and benefits of treatment for personal and public health.Even as substantial research and evaluation have improved the understanding of these trade-offs, clinical and public health policy and funding decisions are being made at the program, national, and global levels. This chapter examines the concept of HIV TasP, focusing on the underlying biological mechanisms, effectiveness, and cost-effectiveness of various strategies and settings and assessing how these factors may influence resource allocation, policy decisions, and research agendas at the national and global levels.

Recruitment of Female Sex Workers in HIV Prevention Trials: Can Efficacy Endpoints Be Reached More Efficiently?

Abstract: BACKGROUND/SETTING Randomized controlled trials (RCTs) of HIV biomedical prevention interventions often enroll participants with varying levels of HIV exposure, including people never exposed to HIV. We assessed whether enrolling larger proportion of participants with consistently high exposure to HIV, such as female sex workers (FSWs), might reduce trial duration and improve the accuracy of product efficacy estimates in future HIV prevention trials. METHODS We used an individual-based stochastic model to simulate event-driven RCTs of an HIV prevention intervention providing 80% reduction in susceptibility per act under different proportions of FSW enrolled. A 5% annual dropout rate was assumed for both FSW and non-FSW in our main scenario, but rates of up to 50% for FSW were also explored. RESULTS Enrolling 20% and 50% FSW reduced the median-simulated trial duration from 30 months with 0% FSW enrolled to 22 months and 17 months, respectively. Estimated efficacy increased from 71% for RCTs without FSW to 74% and 76% for RCTs with 20% and 50% FSW enrolled, respectively. Increasing the FSW dropout rate to 50% increased the duration of RCTs by 1-2 months on average and preserved the gain in estimated efficacy. CONCLUSIONS Despite the potential logistical challenges of recruiting and retaining FSW, trialists should revisit the idea of enrolling FSW in settings where HIV incidence among FSW is higher than among non-FSW. Our analysis suggests that enrolling FSW would increase HIV incidence, reduce trial duration, and improve efficacy estimates, even if the annual dropout rate among FSW participants is high.

Effects of patient load and travel distance on HIV transmission in rural China: Implications for treatment as prevention.

Abstract: BACKGROUND Sustained viral suppression through ART reduces sexual HIV transmission risk, but may require routine access to reliable and effective medical care which may be difficult to obtain in resource constrained areas We investigated the roles of patient load and travel distance to HIV care clinic on transmission risk in HIV serodiscordant couples in Henan Province, China METHODS Cox proportional hazard models were used to compare HIV transmission events across couples living near, medium, or farther distances from their assigned HIV care clinics, as well as those attending clinics where clinicians bore high versus low patient loads RESULTS Most (84·4%) of the 3695 serodiscordant couples lived within 10 kilometers of their assigned HIV clinic, and most (73·5%) attended clinics with patient-to-provider ratios of at least 100:1 In adjusted Cox models, attending clinics where clinicians bore average patient loads of 100 or more elevated HIV transmission risk (aHR, 1·50, 95% CI, 1·00-4·84), an effect amplified in village tier clinics (aHR = 1·55; 95% CI, 1·23-6·78) Travel distance was associated with HIV transmission only after stratification; traveling medium distances to village clinics (5-10km) increased transmission risk (aHR = 1·83, 95% CI, 1·04-3·21) whereas traveling longer distances to township or county level clinics lowered transmission risk (aHR = 0·10, 95% CI, 0·01-0·75) CONCLUSION Higher patient loads at HIV clinics was associated with risk of HIV transmission in our population, particularly at village level clinics Farther travel distance had divergent effects based on clinic tier, suggesting unique mechanisms operating across levels of resource availability The resource intensity of long-term HIV treatment may place significant strains on small rural clinics, for which investments in additional support staff or time-saving tools such as point-of-care laboratory testing may bring about impactful change in treatment outcomes

Association of HIV diversity and virologic outcomes in early antiretroviral treatment: HPTN 052.

Abstract: Higher HIV diversity has been associated with virologic outcomes in children on antiretroviral treatment (ART). We examined the association of HIV diversity with virologic outcomes in adults from the HPTN 052 trial who initiated ART at CD4 cell counts of 350-550 cells/mm3. A high resolution melting (HRM) assay was used to analyze baseline (pre-treatment) HIV diversity in six regions in the HIV genome (two in gag, one in pol, and three in env) from 95 participants who failed ART. We analyzed the association of HIV diversity in each genomic region with baseline (pre-treatment) factors and three clinical outcomes: time to virologic suppression after ART initiation, time to ART failure, and emergence of HIV drug resistance at ART failure. After correcting for multiple comparisons, we did not find any association of baseline HIV diversity with demographic, laboratory, or clinical characteristics. For the 18 analyses performed for clinical outcomes evaluated, there was only one significant association: higher baseline HIV diversity in one of the three HIV env regions was associated with longer time to ART failure (p = 0.008). The HRM diversity assay may be useful in future studies exploring the relationship between HIV diversity and clinical outcomes in individuals with HIV infection.