Purpose of review
We propose here that the dynamics rather than the structure of cellular and viral networks plays a determining role in chronic immune activation of HIV infected individuals. A number of novel avenues of experimental analysis and modeling strategies is discussed to conclusively address these network dynamics in the future.
Recent insights into the molecular dynamics of immune activation and its control following SIV infection in natural host primates has provided possible alternate interpretations of SIV and HIV pathogenesis. Concomitant with insights gained in other host-pathogen systems, as well as an increased understanding of innate immune activation mechanisms, these observations lead to a new model for the timing of innate HIV immune-responses and a possible primordial role of this timing in programming chronic immune activation.
Chronic immune activation is today considered the leading cause of AIDS in HIV-infected individuals. Systems biology has recently lent arguments for considering chronic immune activation a result of untimely innate immune responses by the host to the infection. Future strategies for the analysis, comprehension, and incorporation of the dynamic component of immune activation into HIV vaccination strategies are discussed.
Human Immunodeficiency Virus (HIV); Simian Immunodeficiency Virus (SIV); Acquired Immune Deficiency Syndrome (AIDS); Systems Biology; Innate and Adaptive Immunity; Natural Host; Non-human primate (NHP); African Green Monkey (AGM); Rhesus Macaque (RM); AGM SIV (SIVagm); RM SIV (SIVmac); Epigenome
Purpose of review
Over the past 2 years a clearer picture has emerged regarding the properties of HIV-specific CD8+ T cells associated with immunologic control of HIV replication. These properties represent a potential mechanism by which rare patients might control HIV replication in the absence of antiretroviral therapy. This review addresses the background and recent findings that have lead to our current understanding of these mechanism(s).
Patients with immunologic control of HIV are not distinguished by targeted specificities, or greater numbers or breadth of their HIV-specific CD8+ T cell response. For this reason, recent work has focused greater attention on qualitative features of this response. The qualitative features most closely associated with immunologic control of HIV are related to the granule-exocytosis mediated elimination of HIV-infected CD4+ T cells. The ability of HIV-specific CD8+ T cells to increase their contents of proteins known to mediate cytotoxicity, such as granzyme B and perforin, appears to be a critical means by which HIV-specific cytotoxic capacity is regulated.
Investigation from multiple groups has now focused upon HIV-specific CD8+ T-cell granule-exocytosis mediated cytotoxicity as a correlate of immunologic control of HIV. In the near future, a more detailed understanding of the qualities associated with immunologic control may provide critical insights regarding the necessary features of a response that should be stimulated by immunotherapies or T-cell based vaccines.
Long-term nonprogressors (LTNP); elite controllers (EC); CD8+ T cells; perforin; cytotoxicity
Purpose of review
To reduce HIV incidence, treatment-as-prevention (TasP) requires high rates of HIV testing, and antiretroviral treatment (ART) uptake, retention, and adherence, which are currently not achieved in general populations in sub-Saharan Africa. We review the experimental evidence on interventions to increase these rates.
In four rapid reviews, we found nine randomized controlled trials (RCTs) on HIV-testing uptake, two on ART uptake, one on ART retention, and 15 on ART adherence in sub-Saharan Africa. Only two RCTs on HIV testing investigated an intervention in general populations; the other examined interventions in selected groups (employees, or individuals attending public-sector facilities for services). One RCT demonstrated that nurse-managed ART led to the same retention rates as physician-managed ART, but failed to show how to increase retention to the rates required for successful TasP. Although the evidence on ART adherence is strongest – several RCTs demonstrate the effectiveness of cognitive and behavioural interventions – contradictory results in different settings suggest that the precise intervention content, or the context, are crucial for effectiveness.
Future studies need to test the effectiveness of interventions to increase testing and treatment uptake, retention, and adherence under TasP, that is, ART for all HIV-infected individuals, independent of disease stage.
adherence; antiretroviral treatment; HIV testing; HIV treatment-as-prevention; randomized controlled trials; retention
Purpose of review
The purpose of this review was to summarize recent studies on the effect of early antiretroviral therapy (ART) in HIV-infected patients on markers of immune activation/inflammation, viral persistence and serious non-AIDS events.
Early ART, initiated within days to months of HIV infection, was associated with marked reduction in T-cell activation often reaching levels observed in HIV-uninfected individuals. However, the impact of early ART on markers of innate immune activation, microbial translocation and inflammation/coagulation was less clear. Early ART has also been associated with a significant reduction in the frequency of latently infected cells, which was greater if ART was initiated within days to weeks rather than months following infection. However, few studies have evaluated the relationship between immune activation and viral reservoirs, specifically following early ART. Early ART may potentially reduce serious non-AIDS events and associated mortality, but most of these studies have extrapolated from changes in surrogate markers, such as CD4 : CD8 ratio.
Early ART was associated with beneficial effects on multiple markers of immune activation, inflammation and viral persistence. Longer term prospective studies are still needed to determine whether early ART translates to a significant reduction in serious non-AIDS events and mortality.
CD4:CD8 ratio; early antiretroviral therapy; immune activation; serious non-AIDS events; viral persistence
Purpose of the review
Here we highlight the latest advances in HIV vaccine concepts that will expand our knowledge on how to elicit effective acquisition-prevention and/or control of SIV replication in the NHP model.
In the context of the promising analyses from the RV144 Thai Trial and the effective control of SIV replication exerted by rhCMV-(SIV) elicited EM CD8 T cells, the HIV field has recently shifted toward vaccine concepts that combine protection from acquisition with effective control of SIV replication. Current studies in the NHP model have demonstrated the efficacy of HIV-neutralizing antibodies via passive transfer, the potential importance of the CD4 Tfh subset, the ability to effectively model the RV144 vaccine trial and the capacity of an Ad26 prime and MVA boost to elicit Env-specific antibody and cellular responses that both limit acquisition and control heterologous SIVmac251 challenge.
The latest work in the NHP model suggests that the next generation HIV-1 vaccines should aim to provoke a comprehensive adaptive immune response for both prevention of SIV acquisition as well as control of replication in break through infection.
NHP model; vaccines; SIV
Purpose of Review
The pulmonary complications of chronic HIV infection have shifted from
infectious complications towards non-infectious pulmonary complications, predominantly chronic obstructive pulmonary disease (COPD). While the best-established COPD risk factor is cigarette smoking, emerging data suggest HIV infection also independently increases COPD risk. The purpose of this article is to review these data and the conflicting data regarding the role of antiretroviral therapy (ART) in modifying COPD risk.
Observational studies favor HIV as an independent risk factor for COPD, particularly when viral load is high. The mechanisms underlying these associations are unclear, but untreated HIV infection is associated with pulmonary inflammatory responses similar to those seen in non-HIV COPD. ART reduces this pulmonary inflammation, but the clinical benefit of such reduction is unknown. Some observational studies suggest that ART users are at lower risk of COPD, while other studies suggest the opposite.
The effect of ART in causing COPD or reducing COPD risk is unknown, but is currently being tested in a randomized trial. Smoking cessation should remain of high priority.
HIV; Pulmonary disease; chronic obstructive; Antiretroviral therapy; highly active
Purpose of review
Serious non-AIDS events or non-infectious complications of HIV infection far outnumber AIDS events in the current combination antiretroviral therapy (ART) era and are attributed to chronic inflammation. Thus, a better understanding of why inflammation persists on ART will assist in developing better therapeutic strategies, including optimal timing of ART initiation.
Markers of inflammation and coagulation, such as D-dimer, IL-6, C-reactive protein, soluble CD14, and soluble CD163, predict end-organ disease and mortality, whereas markers of T cell activation appear more predictive of CD4 T cell decline, AIDS events, or response to therapy. Initiating ART at high CD4 T cell counts can result in less inflammation as supported by studies in acute and early HIV infection, but antiretroviral drugs may differentially affect inflammatory pathways. Decreasing inflammation in HIV-uninfected subjects may decrease morbidity, but long-term outcomes studies in HIV-infected individuals are lacking.
Circulating biomarkers of inflammation are among the strongest predictors of non-AIDS outcomes in treated HIV infection. With additional investigation, they may serve in the future as specific end-organ disease surrogate endpoints and may help identify those patients at highest risk of non-AIDS events who may benefit from either early ART and/or potential adjuvant anti-inflammatory therapies.
biomarkers; T cell activation; monocyte activation; inflammation; morbidity; HIV
Purpose of review
Current antiretroviral therapies have dramatically changed the disease course of HIV infection. While antiretroviral therapy (ART) is effective at decreasing viral replication and preserving CD4+ T cell numbers, low-level immune activation and inflammation persist in virally suppressed HIV-infected patients. This chronic immune activation/inflammation may contribute to an increased risk for venous and arterial thrombosis.
Several markers of coagulation and inflammation are increased in HIV-infected patients. The Strategies for the Management of Antiretroviral Therapy (SMART) study reported that plasma D-dimer levels, a marker of fibrinolysis, independently predicted morbidity in HIV-infected patients. Increased plasma and cell surface levels of the procoagulant tissue factor (TF) have also been reported in patients with HIV disease. Fibrinogen, von Willebrand factor (vWf), and P-selectin are likewise increased in plasma samples of HIV-infected patients; all of these markers suggest HIV-infection results in a pro-coagulant state. Treatment with antiretroviral therapy reduces, but does not always normalize, levels of biomarkers associated with inflammation and coagulation in HIV+ patients.
HIV-infected patients are at greater risk for both venous and arterial thrombosis. Chronic immune activation and inflammation in these patients appears to contribute to coagulation risk. Antiretroviral therapy reduces viral replication, immune activation, and markers of coagulation, but these indices do not always return to normal, even after several years of viremic control.
coagulation; D-dimer; antiretroviral therapy; inflammation
Purpose of review
To critically appraise recent published literature about factors associated with cancer risk likely to be influenced by combination antiretroviral therapy (cART) in HIV-infected individuals, and the potential of earlier cART initiation to reduce this risk.
Factors leading to increased risk of non-AIDS defining malignancies (NADM) in particular remain poorly understood. Immunodeficiency appears to be key, whereas evidence is emerging that a direct pro-oncogenic effect of HIV, activated inflammatory and coagulation pathways, and cART toxicity may also contribute. By reducing HIV replication, improving immune function and limiting chronic inflammation, cART initiation at higher CD4+ cell counts may therefore reduce NADM risk. However, cART only partly normalizes enhanced inflammation and coagulation seen during HIV infection and conflicting laboratory and epidemiological data have been reported as to if (and how) cART affects NADM risk. Furthermore, secondary analyses of randomized controlled trials comparing early versus delayed cART initiation were inconclusive.
Continuous epidemiological surveillance is warranted to monitor trends in cancer incidence among HIV-infected individuals and to better understand the impact of earlier cART on NADM risk. The role of adjuvant anti-inflammatory or anti-thrombotic therapies to reduce cancer risk deserves further investigation.
HIV; cancer; antiretroviral therapy; inflammation
Purpose of review
Inflammation and immune activation associated with untreated HIV infection may increase the risk for cardiovascular disease (CVD) and are not entirely reversed by antiretroviral therapy (ART). While older ART regimens were associated with drug-specific risks for CVD, this may not be true for modern ART. Thus, with regard to CVD risk, the net benefit of initiating antiretroviral therapy at higher CD4+ T-cell counts remains unclear.
In addition to the well-established risk of coronary heart disease, emerging evidence now suggests that chronic HIV infection is associated with higher risk of ischemic stroke, heart failure, and arrhythmias. These epidemiologic studies have associated immunodeficiency and active viral replication with higher CVD risk. Novel methods of imaging subclinical vascular disease continue to implicate inflammation and immune activation as likely mediators of CVD among patients with HIV. Newer generation protease inhibitors, CCR5 antagonists, and integrase inhibitors do not appear to be associated with the adverse cardiometabolic risks of older drugs.
Recent evidence suggests that treating HIV infection with ART may reduce the risk of CVD, even at higher CD4 T-cell counts; however, the definitive answer to this question will come from clinical trials and long-term observational studies.
Cardiovascular disease; Heart Failure; Sudden cardiac death; Immune activation; Antiretroviral therapy
Purpose of review
The long-lived viral reservoir is a major obstacle to achieving a cure for HIV. Therapeutic strategies, such as early antiretroviral therapy (ART), may be a prerequisite to achieving long-term control of viral replication upon ART withdrawal.
HIV persistence is established early in acute HIV infection (AHI) with infection in long-lived memory CD4+ T cells. Studies conducted in nonhuman primates have suggested that this could occur as early as 3 days postinfection; however, the timing in humans is uncertain. ART during AHI significantly restricts the HIV reservoirs as compared with later treatment. Early ART, particularly prior to the detection of HIV immunoglobulin M, may also reduce the contribution of the long-lived central memory CD4+ T cells to the total HIV reservoir, a profile observed in individuals who naturally control HIV without ART.
It is clear that early ART has a greater impact in limiting the HIV reservoirs than later treatment. However, latently infected long-lived memory CD4+ T cells persist in most early treated individuals. Therefore, additional interventions will likely be required to eliminate all cells capable of producing replication-competent virus but treatment in AHI may be the critical first step in containing the HIV reservoirs.
acute HIV infection; early antiretroviral therapy; HIV DNA; HIV reservoir; replication-competent virus
Purpose of review
We review literature concerning the epidemiology of HIV-associated tuberculosis (HIV-TB), focussing on articles published between 2007-2008.
An estimated 1.37 million new cases of HIV-TB occurred in 2007, representing 15% of the total global burden of TB. In addition, an estimated 456,000 HIV-TB deaths accounted for 23% of global HIV/AIDS mortality. Sub-Saharan Africa is the worst affected region with 79% of the disease burden. The epicentre of the co-epidemic lies in the south of the continent, with South Africa alone accounting for over one quarter of all cases. A critical overlap between HIV and the global multi-drug resistant TB (MDR-TB) epidemics is emerging. Although it is as yet unclear whether HIV is driving a disproportionate increase in MDR-TB cases at a population level, HIV has nevertheless been a potent risk factor for institutional outbreaks, especially in South Africa and Eastern Europe. Increasing data have highlighted the risk of TB among HIV-infected health-care workers in resource-limited settings. However, many studies also show the major benefits to be derived from antiretroviral therapy in high- and low-income countries.
HIV-TB remains a major challenge to global health that requires substantial increases in resource allocation and concerted international action.
HIV; tuberculosis; antiretroviral; epidemiology
Purpose of review
A key factor driving AIDS-associated immunopathogenesis is chronic immune activation. SIV infection of African natural host species leads to high viremia, but low immune activation and absence of disease. Considerable progress in our understanding of pathological immune activation have come from comparative studies of SIV infection in pathogenic Asian macaque species and natural hosts. The focus of this review is to highlight recent work on the natural host model using high throughput genomics.
Several groups have independently conducted microarray gene expression profiling comparing in vivo SIV infection in natural and non-natural hosts. A consistent finding between these studies is that both pathogenic SIV infection of macaques and nonpathogenic infections of natural hosts have strong induction of interferon-stimulated genes (ISGs) early on, but a key difference was that natural hosts downmodulated the interferon response rapidly after acute infection. The development of new genome-based resources for further study of the natural host model is discussed.
Initial efforts using high throughput biology to study SIV infection of natural hosts have effectively identified the ability of natural hosts to resolve interferon responses and immune activation. Further application of ‘omic’-based technologies coupled with integrative systems-based analysis should continue to yield progress.
Simian Immunodeficiency Virus; Microarray; Interferon; ISG; interferon stimulated genes; Genome; Sooty Mangabey; Cercocebus Atys; African green monkey; vervet; Chlorocebus pygerythrus; grivet; Chlorocebus aethiops; sabaeus; Chlorocebus sabaeus; tantalus; Chlorocebus tantalus; Natural host; Rhesus; Macaca mulatta; Systems biology
Purpose of review
Recent clinical research suggests that an HIV-infected patient with
lymphoma who was transplanted with bone marrow homozygous for a disrupted
mutant CCR5 allele has no remaining HIV replication and is effectively cured
of HIV. Here we discuss approaches of disrupting host and viral genes
involved in HIV replication and pathogenesis with the aim of curing patients
Data from the ‘Berlin patient’ suggests that targeted
gene disruption can lead to an HIV cure. This review discusses recent
advances in the field of gene disruption towards the development of an
anti-HIV therapy. We will introduce strategies to disrupt host and viral
genes using precise disruptions, imprecise disruptions, or site-specific
recombination. Furthermore, the production of engineered rare cutting
endonucleases (zinc finger nucleases, TAL effector nucleases, and homing
endonucleases) and recombinases that can recognize specific DNA target
sequences and facilitate gene disruption will be discussed.
The discovery of a gene disruption approach that would cure or
efficiently confine HIV infection could have broad implications for the
treatment of millions of people infected with HIV. An efficient ‘one
shot’ curative therapy would not only give infected patients hope of
a drug- or treatment-free future, but could reduce the huge financial burden
faced by many countries due to widespread administration of HAART.
Homing endonuclease; zinc finger nuclease; TALEN; reservoir; gene targeting
Purpose of Review
Our goal is to summarize recent literature on biomarkers of cardiovascular disease (CVD) in the setting of HIV infection with an emphasis on those associated with clinical events.
Epidemiological data have demonstrated that HIV-infection is associated with increases in well-established markers of inflammation and thrombosis, and levels of hsCRP, IL-6, D-dimer and fibrinogen predict CVD and mortality risk in HIV cohorts. Levels of IL-6, D-dimer and endothelial adhesion molecules increase when antiretroviral therapy is interrupted, suggesting HIV replication may be driving CVD risk in this context. However, data on changes in many CVD biomarkers after starting ART are inconsistent or lacking. Finally, assessment of high-density lipoprotein particle concentration may provide important information specific to HIV-related CVD risk beyond that apparent from traditional measures of serum cholesterol.
Biomarkers of inflammation and thrombosis have the potential to improve CVD risk stratification beyond traditional and HIV-specific factors, and may prove useful for evaluating CVD prevention strategies for individuals with HIV infection.
HIV infection; cardiovascular disease; biomarkers; inflammation; endothelial dysfunction; coagulation; thrombosis; lipoproteins
The nexus of information concerning the CD4-binding site and its recognition by human antibodies capable of effective neutralization has expanded remarkably in the last few years. While barriers are substantial, new insights from donor-serum responses, atomic-level structures of antibody-Env complexes, and next-generation sequencing of B cell transcripts are invigorating vaccine-design efforts to elicit effective CD4-binding-site antibodies.
Antibody template; B cell ontogeny; gp120 envelope glycoprotein; HIV-1 vaccine; Structure-based design
Purpose of Review
Computer simulation models can identify key clinical, operational, and economic interventions that will be needed to achieve the elimination of new pediatric HIV infections. In this review, we summarize recent findings from model-based analyses of strategies for prevention of mother-to-child HIV transmission (MTCT).
In order to achieve elimination of MTCT (eMTCT), model-based studies suggest that scale-up of services will be needed in several domains: uptake of services and retention in care (the PMTCT “cascade”), interventions to prevent HIV infections in women and reduce unintended pregnancies (the “four-pronged approach”), efforts to support medication adherence through long periods of pregnancy and breastfeeding, and strategies to make breastfeeding safer and/or shorter. Models also project the economic resources that will be needed to achieve these goals in the most efficient ways to allocate limited resources for eMTCT. Results suggest that currently recommended PMTCT regimens (WHO Option A, Option B, and Option B+) will be cost-effective in most settings.
Model-based results can guide future implementation science, by highlighting areas in which additional data are needed to make informed decisions and by outlining critical interventions that will be necessary in order to eliminate new pediatric HIV infections.
pediatric HIV; modeling; elimination; PMTCT; cost-effectiveness
Purpose of review
To reach virtual elimination of pediatric HIV, programs for the prevention of mother-to-child HIV transmission (PMTCT) must expand coverage and achieve long-term retention of mothers and infants. While PMTCT have been traditionally aligned with maternal, newborn, and child health (MNCH) services, novel approaches are needed to address the increasing demands of evolving global PMTCT policies.
PMTCT-MNCH integration has improved the uptake and timely initiation of antiretroviral therapy (ART) among treatment-eligible pregnant women in public health settings. Postpartum engagement of HIV-infected mothers and HIV-exposed infants has been insufficient, although alignment of visits to the childhood immunization schedule and establishment of integrated mother-infant clinics may increase retention. Evidence also suggests that the integration of maternal HIV testing into childhood immunization clinics can significantly increase the identification of at-risk HIV-exposed infants previously missed by traditional PMTCT models.
Targeted service integration models can improve PMTCT uptake. However, as global PMTCT policy shifts to universal provision of maternal ART during pregnancy (i.e., Option B/B+), these findings must be reexamined in the context of increased service demand and systems burden. Intensive evaluation is needed to ensure quality clinical care is maintained both for PMTCT and for underpinning MNCH services.
prevention of mother-to-child HIV transmission; PMTCT; HIV; program integration; maternal child health
The development of a preventive HIV vaccine remains an unresolved challenge. Animal models that can predict the results of HIV vaccine efficacy trials and identify the immune mechanisms responsible for vaccine protection would be most useful for HIV vaccine development. The purpose of the current review is to critique recent developments in the use of animal models of HIV infection in preclinical studies of AIDS vaccines and to describe how the use of improved animal models can inform the development of an HIV vaccine.
The results of preclinical experiments with candidate HIV vaccines can vary with the SIV challenge virus used. It is now known that there is considerable variability in the neutralization sensitivity and that the level of viral sequence diversity within the challenge stocks varies. This has allowed more realistic preclinical vaccine studies with heterologous vaccine antigens and challenge viruses. Further, the dose of challenge virus and the route of virus challenge can modify the efficacy of candidate vaccines in preclinical studies.
Recent experiments demonstrate that NHP models of AIDS can reproduce the complex biology of HIV transmission, recapitulate the results of HIV vaccine efficacy trials in humans and be used to identify correlates of protection.
HIV vaccine; animal model; nonhuman primate (NHP); mucosal transmission
Purpose of Review
Describe and compare the diverse organizational structures and funding mechanisms applied to advance HIV preventive vaccine research and development, to help explain and inform evolving infrastructures and collaborative funding models.
Based on models that have been tried, improved or abandoned over three decades, the field seems to have settled into a relatively stable set of diverse initiatives, each with its own organizational signature. At the same time, this set of organizations is forging cross-organizational collaborations, which promise to acquire newly emergent beneficial properties.
Strong motivation to expedite HIV vaccine R&D has driven a diversity of customized and inventive organizational approaches, largely government and foundation funded. While no one approach has proven a panacea, the field has evolved into a constellation of often overlapping organizations that complement or reinforce one another. The Global HIV Vaccine Enterprise, a responsive, rapidly evolving loose infrastructure, is an innovative collaboration to catalyze that evolution.
HIV vaccine; HIV prevention; funding; clinical trials; Global HIV Vaccine Enterprise
Purpose of Review
While a large number of novel broadly neutralizing antibodies has been recently described, the induction of such antibodies via vaccination has proven difficult. By contrast, non-neutralizing antibodies arise early during infection and have been repeatedly associated with both protection from infection and disease progression.
We are beginning to gain new insights into the broader landscape of antiviral mechanisms that non-neutralizing antibodies may harness to fight HIV, providing an unprecedented breadth of approaches by which HIV can be blocked and contained.
In this review we summarize the characteristics of non-neutralizing antibodies, their role in HIV infection, and new paradigm-shifting functions that may be exploited by next generation vaccine approaches aimed at blocking HIV infection.
ADCC; HIV; antibodies
Purpose of review
The genetic characterization of HIV-1 breakthrough infections in vaccine and placebo recipients offers new ways to assess vaccine efficacy trials. Statistical and sequence analysis methods provide opportunities to mine the mechanisms behind the effect of an HIV vaccine.
The release of results from two HIV-1 vaccine efficacy trials, Step/HVTN-502 and RV144, led to numerous studies in the last five years, including efforts to sequence HIV-1 breakthrough infections and compare viral characteristics between the vaccine and placebo groups. Novel genetic and statistical analysis methods uncovered features that distinguished founder viruses isolated from vaccinees from those isolated from placebo recipients, and identified HIV-1 genetic targets of vaccine-induced immune responses.
Studies of HIV-1 breakthrough infections in vaccine efficacy trials can provide an independent confirmation to correlates of risk studies, as they take advantage of vaccine/placebo comparisons while correlates of risk analyses are limited to vaccine recipients. Through the identification of viral determinants impacted by vaccine-mediated host immune responses, sieve analyses can shed light on potential mechanisms of vaccine protection.
HIV-1 breakthrough infections; sieve analysis; viral genetics; vaccine-induced immune responses
Purpose of review
With multiple HIV vaccine candidates suitable for efficacy evaluation in a rapidly changing HIV prevention landscape, innovative HIV vaccine trial design research is much needed to optimally utilize resources by building on lessons learned from past HIV vaccine efficacy trials.
Several recent articles propose new vaccine efficacy trial design strategies tailored to the emerging needs in HIV vaccine evaluation. These include a focus on efficacy evaluation proximal to the vaccination series; more intensive interim monitoring for potential harm, non-efficacy and high efficacy of the vaccine; simultaneous evaluation of multiple vaccine regimens with a shared placebo group; designs that include pilot immunogenicity studies of putative immune correlates to expedite their evaluation; as well as designs tailored to evaluate vaccine efficacy in the context of partially effective non-vaccine prevention modalities.
A more rapid evaluation of multiple vaccine candidates is possible. Weaker vaccines can be weeded out quickly. Pilot studies can be done during the trial to prepare for a timely immune correlates assessment. Evidence that emerges regarding the efficacy of non-vaccine prevention modalities will have important implications for future trial designs.
HIV prevention; multi-arm trial; vaccine efficacy; immune correlates
Purpose of review
We review the broad spectrum of nonreplicating viral vectors which have been studied extensively, from preclinical studies through clinical efficacy trials, and include some of our most promising HIV vaccine candidates.
The success of the RV144 trial, with an ALVAC (canarypox)-based regimen, contrasts with the failures of the Adenovirus 5-based regimens in the Step study, the Phambili study (HVTN 503), and the HVTN 505 study which was recently modified to halt vaccinations due to clinical futility.
The safety profile, immunogenicity, and variety of available candidates make the nonreplicating viral vectors attractive in HIV vaccine development. Building from the success of the RV144 study, further studies of Orthopoxvirus-based vaccines, including Vaccinia-based vaccines, are ongoing and planned for the future. Despite the failures of the Ad5-based vaccines in clinical efficacy trials, other adenovirus serotypes remain promising candidates, especially in prime-boost combination with other products, and with the potential use of mosaic inserts. Other nonreplicating viral vectors such as the rhabdoviruses, alphaviruses and the non-human adenoviruses, provide additional avenues for exploration.
HIV vaccine; nonreplicating vector; Orthopoxvirus; canarypox; Vaccinia; adenovirus
Purpose of review
Briefly describe some of the replication-competent (RC) vectors being investigated for development of candidate HIV vaccines focusing primarily on technologies that have advanced to testing in macaques or have entered clinical trials.
RC viral vectors have advanced to the stage were decisions can be made regarding future development of HIV vaccines. The viruses being used as RC vector platforms vary considerably, and their unique attributes make it possible to test multiple vaccine design concepts and also mimic various aspects of an HIV infection. RC viral vectors encoding SIV or HIV proteins can be used to safely immunize macaques, and in some cases, there is evidence of significant vaccine efficacy in challenge protection studies. Several live HIV vaccine vectors are in clinical trials to evaluate immunogenicity, safety, the effect of mucosal delivery, and potential effects of pre-existing immunity.
A variety of DNA and RNA viruses are being used to develop RC viral vectors for HIV vaccine delivery. Multiple viral vector platforms have proven to be safe and immunogenic with evidence of efficacy in macaques. Some of the more advanced HIV vaccine prototypes based on vesicular stomatitis virus, vaccinia virus, measles virus, and Sendai virus are in clinical trials.
Replication-competent viral vectors; HIV vaccine; SIV challenge model