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1.  Aging and HIV: An Evolving Understanding 
Current opinion in HIV and AIDS  2014;9(4):291-293.
doi:10.1097/COH.0000000000000081
PMCID: PMC4507814  PMID: 24871091
2.  Identifying the Appropriate Comparison Group for HIV-infected Individuals 
Current opinion in HIV and AIDS  2014;9(4):379-385.
Purpose of Review
HIV-infected individuals are living longer as a result of effective treatment. Age-related comorbidities now account for the majority of morbidity and mortality among treated HIV-infected adults. Previous findings regarding the age at, and risk of, these comorbidities have been mixed, sparking debate in the field. Discerning potential differences in the occurrence and burden of age-related comorbidities among treated HIV-infected adults as compared with uninfected adults of the same age requires careful selection of the appropriate uninfected comparison group.
Recent Findings
The validity of comparisons to HIV-uninfected populations is threatened when differences in demographic, clinical, and lifestyle characteristics between HIV-infected and uninfected adults are not considered. Identifying a pool of HIV-uninfected individuals from existing secondary data resources and employing selection methodologies may be a novel approach to reduce threats to internal validity. Issues related to identifying data sources, understanding inclusion criteria, determining measurement error, and threats to inference are discussed.
Summary
The development of clinical interventions targeting age-related comorbidities will rely on deriving valid inferences from appropriate comparison groups. The use of secondary data resources and selection methodology to create the appropriate uninfected comparison group is an attractive approach in the setting of finite resources, but are not without limitations.
doi:10.1097/COH.0000000000000063
PMCID: PMC4105851  PMID: 24840058
HIV-uninfected; HIV infection; aging; harmonization; causal inference
3.  HIV and Ageing: Emerging Research Issues 
Current opinion in HIV and AIDS  2014;9(4):302-308.
Purpose of the review
It is now widely accepted that HIV-infected individuals remain at higher risk for mortality and age-related morbidities than the general population, but several unresolved issues need to be addressed by the research community in the coming years to further improve the health of HIV-infected individuals in the modern treatment era.
Recent findings
While recent studies have helped better define the contribution of HIV to life expectancy and morbidity in the modern ART era, questions remain about the generalizability of these findings to a future HIV-infected population that is expected to be much older. Furthermore, while a consensus has emerged that the persistent inflammatory state contributes to morbidity and mortality in this setting, the relative contributions of this process, health-related behaviors, co-morbidities, and medication toxicities remain incompletely understood. Lastly, significant uncertainty remains over the root causes of the persistent inflammatory state, the specific immunologic pathways to target with interventions, and the most appropriate biomarkers to use for surrogate outcomes in pilot trials of immune-based interventions.
Summary
Each of these issues will be addressed in this review, highlighting recently published and presented studies that inform the discussion, and recommendations will be made for prioritizing the future research agenda.
doi:10.1097/COH.0000000000000072
PMCID: PMC4138123  PMID: 24824891
HIV-1; inflammation; aging; multi-morbidity; mortality; antiretroviral therapy
4.  Patient-centered care for people living with multimorbidity 
Current opinion in HIV and AIDS  2014;9(4):419-427.
Purpose of review
The purpose of this review is to consider a patient-centred approach to the care of people living with HIV (PLWH) who have multimorbidity, irrespective of the specific conditions.
Recent findings
Interdisciplinary care to achieve patient-centred care for people with multimorbidity is recognized as important, but the evaluation of models designed to achieve this goal are needed. Key elements of such approaches include patient preferences, interpretation of the evidence, prognosis as a tool to inform patient-centred care, clinical feasibility and optimization of treatment regimens.
Summary
Developing and evaluating the best models of patient-centred care for PLWH who also have multimorbidity is essential. This challenge represents an opportunity to leverage the lessons learned from the care of people with multimorbidity in general, and vice versa.
doi:10.1097/COH.0000000000000073
PMCID: PMC4144702  PMID: 24871089
HIV; multimorbidity; multiple chronic conditions; patient-centred care
5.  Substance Use in Older HIV-Infected Patients 
Current opinion in HIV and AIDS  2014;9(4):317-324.
Purpose of the Review
Substance use may persist throughout the life course and has a substantial impact on health outcomes globally. As HIV-infected individuals are disproportionately impacted by substance use and living longer, it is critical that providers and researchers alike understand the impact of substance use on older, HIV-infected patients and potential treatment options. To this end, we conducted a review of the literature focusing on the most commonly used substances to outline the epidemiology, health consequences, treatment options and latest research relevant to older, HIV-infected patients.
Recent Findings
Substance use impacts older, HIV-infected patients with regards to HIV-related and non-HIV related outcomes. Counseling strategies are available for marijuana and stimulant use disorders. Brief counseling is useful alongside medications for alcohol, tobacco and opioid use disorders. Many medications for alcohol, tobacco, and opioid use disorders are safe in the setting of antiretroviral therapy. Unfortunately, few interventions targeting substance use in older, HIV-infected patients have been developed and evaluated.
Summary
As older, HIV-infected patients continue to experience substance use and its related health consequences, there will be a growing need for the development of safe and effective interventions which address the complex needs of this population.
doi:10.1097/COH.0000000000000069
PMCID: PMC4175926  PMID: 24824888
HIV; substance-related disorders; older adults
6.  CVD risk in an aging HIV population – not just a question of biology 
Current opinion in HIV and AIDS  2014;9(4):346-354.
Purpose of review
The objective of this review is to 1) appraise recently published literature that describes the relationship between HIV, biologic and environmental risk factors, and CVD risk with particular emphasis on the aging HIV population and 2) to demonstrate that these biologic and environmental factors may interact to increase the risk of CVD in the HIV population.
Recent findings
The mechanisms linking HIV and CVD are multi-factorial and encompass biological and “environmental” modalities including multi-morbid conditions that co-occur with HIV, immunologic alterations associated with HIV, polypharmacy (which affects adherence and increases likelihood of adverse drug-drug interactions) and healthcare disparities in CVD risk reduction by HIV status.
Summary
Data regarding optimal treatment strategies that balance immunological restoration and CVD risk reduction are needed.
doi:10.1097/COH.0000000000000065
PMCID: PMC4321776  PMID: 24824885
Cardiovascular disease; HIV; multimorbidity; polypharmacy; clinical guidelines; healthcare disparities
7.  Th17 cells and Job's syndrome: a model of skin bacterial translocation 
Current opinion in HIV and AIDS  2010;5(2):179-183.
Purpose of review
Patients with HIES share with HIV patients a predisposition to infections, including candidiasis in autosomal dominant HIES (AD-HIES) and molluscum contagiousum in autosomal recessive HIES (AR-HIES). This review highlights the underlying pathogenesis of these diseases and their relevance to HIV infection.
Recent findings
Patients with mutations in STAT3, who lack Th17 cells, develop AD-HIES, while AR-HIES may be caused by mutations in Tyk2 or DOCK8, associated with decreased expansion of CD8 T cells. Recent studies on patients with recurrent mucocutaneous candidiasis have led to the discovery of mutations in CARD9 and DECTIN-1, genes key to the production of the Th17-driving cytokines IL-1β, IL-6, and IL-23. Studies of the peripheral blood of HIV+ patients have shown a decreased Th17:Th1 ratio, and Th17 cells were preferentially depleted from the gastrointestinal tract within weeks of SIV infection of rhesus macaques.
Summary
The consequences of inadequate Th17 production in primary immunodeficiency syndromes illustrate the role of Th17 cells in controlling pathogens to which HIV+ individuals are susceptible. Further understanding of the pathogenesis of opportunistic disease in HIV infection will likely require exploring the role of Th17 cells.
doi:10.1097/COH.0b013e328335ed3e
PMCID: PMC4485419  PMID: 20543597
Hyper IgE syndrome; Job's syndrome; Th17; STAT3; HIV
8.  Antibody engineering for increased potency, breadth and half-life 
Current Opinion in HIV and AIDS  2015;10(3):151-159.
Purpose of review
This review highlights recent developments in HIV-1 antibody engineering and discusses the effects of increased polyreactivity on serum half-lives of engineered antibodies.
Recent findings
Recent studies have uncovered a wealth of information about the relationship between the sequences and efficacies of anti-HIV-1 antibodies through a combination of bioinformatics, structural characterization and in vivo studies. This knowledge has stimulated efforts to enhance antibody breadth and potency for therapeutic use. Although some engineered antibodies have shown increased polyreactivity and short half-lives, promising efforts are circumventing these problems.
Summary
Antibodies are desirable as therapeutics due to their ability to recognize targets with both specificity and high affinity. Furthermore, the ability of antibodies to stimulate Fc-mediated effector functions can increase their utility. Thus, mAbs have become central to strategies for the treatment of various diseases. Using both targeted and library-based approaches, antibodies can be engineered to improve their therapeutic properties. This article will discuss recent antibody engineering efforts to improve the breadth and potency of anti-HIV-1 antibodies. The polyreactivity of engineered HIV-1 bNAbs and the effect on serum half-life will be explored along with strategies to overcome problems introduced by engineering antibodies. Finally, advances in creating bispecific anti-HIV-1 reagents are discussed.
doi:10.1097/COH.0000000000000148
PMCID: PMC4465343  PMID: 25760931
antibody engineering; bispecific reagents; breadth; HIV-1; polyreactivity; potency
9.  Development of Broadly Neutralizing Antibodies from Autologous Neutralizing Antibody Responses 
Current opinion in HIV and AIDS  2014;9(3):210-216.
Purpose of Review
Detailed genetic and structural characterization has revealed that broadly neutralizing antibodies (bnAbs) against HIV-1 have unusually high levels of somatic hypermutation, long CDRH3 domains, and the ability to target one of four sites of vulnerability on the HIV-1 envelope (Env) glycoproteins. A current priority is to understand how bnAbs are generated during natural infection, and translate this information into immunogens that can elicit bnAb following vaccination.
Recent Findings
Strain-specific neutralizing antibodies (nAb) can acquire broad neutralizing capacity when the transmitted/founder Env or a specific Env variant is recognized by an unmutated rearranged germline that has the capacity to develop bnAb like features. This could be a relatively infrequent event, as only certain germlines appear to possess inherent features needed for bnAb activity. Furthermore, the glycosylation pattern and diversity of circulating HIV-1 Envs, as well as the state of the B cell compartment, may influence the activation and maturation of certain antibody lineages.
Summary
Collectively, studies over the last year suggest that the development of HIV-1 Env immunogens that bind and activate bnAb-like germlines is feasible. However, more information about the features of Env variants and the host factors that lead to breadth during natural infection is needed to elicit bnAbs through immunization.
doi:10.1097/COH.0000000000000057
PMCID: PMC4068799  PMID: 24662931
Broadly neutralizing antibodies; affinity maturation; long CDRH3; unmutated common ancestor; HIV-1 envelope evolution
10.  Epitope Target Structures of Fc-mediated Effector Function During HIV-1 Acquisition 
Current opinion in HIV and AIDS  2014;9(3):263-270.
Purpose of review
This review analyzes recent studies suggesting that highly conserved epitopes in the HIV-1 Env trimer are targets of potentially protective non-neutralizing antibodies that mediate antibody-dependent cellular cytotoxicity (ADCC).
Recent findings
Recent studies in both non-human primates and humans, suggest that non-neutralizing antibodies play a role in blocking infection with SHIV/SIV or HIV-1 by Fc-mediated effector function, in particular ADCC. Further, several studies implicate highly conserved epitopes in the C1 region of gp120 as targets of these antibodies. However, these suggestions are controversial, as passive immunization studies do not indicate that such antibodies can block acquisition in non-human primates. Potential reasons for this discrepancy are discussed in the structural context of potent ADCC epitopes on target cells during the narrow window of opportunity when antibodies can block HIV-1 acquisition.
Summary
Cumulative evidence suggests that in addition to virus neutralization, Fc-mediated effector responses to highly conserved epitopes in the HIV-1 trimer play distinct as well as overlapping roles in blocking HIV-1 acquisition. Evidence will be discussed whether non-neutralizing antibodies specific for epitopes on the HIV-1 Env trimer that become exposed during viral entry contribute significantly to blocking HIV-1 acquisition.
doi:10.1097/COH.0000000000000055
PMCID: PMC4104495  PMID: 24670318
Fc-mediated effector function; HIV; antibody; epitope
11.  Adeno-Associated Virus Delivery of Broadly Neutralizing Antibodies 
Current opinion in HIV and AIDS  2014;9(3):250-256.
Purpose of review
In this review, we will discuss the emerging field of vector mediated antibody gene transfer as an alternative HIV vaccine. This approach is an improvement over classical passive immunization strategies that administer antibodies to the host to provide protection from infection. With vector mediated gene transfer, the antibody gene is delivered to the host resulting in long-term endogenous antibody expression from the injected muscle that confers protective immunity.
Recent Findings
A large number of very potent and broadly neutralizing HIV antibodies have recently been isolated and characterized. Vector mediated antibody gene transfer allows one to immediately use these antibodies as a vaccine. Gene transfer studies in both mice and monkeys demonstrate long-term antibody expression in serum from a single injection at concentrations that provide sterilizing immunity.
Summary
Vector mediated antibody gene transfer can rapidly move existing, potent anti-HIV molecules into the clinic. The gene transfer products demonstrate a potency and breadth identical to the original product. This strategy eliminates the need for immunogen design and interaction with the adaptive immune system to generate protection, a strategy that so far has shown little promise.
doi:10.1097/COH.0000000000000056
PMCID: PMC4117238  PMID: 24638019
Antibody gene transfer; Vectored immunoprophylaxis; Adeno associated virus; HIV vaccine
12.  The role of Fc receptors in HIV infection and vaccine efficacy 
Current opinion in HIV and AIDS  2014;9(3):257-262.
Purpose of the review
In this review, the roles of Fc-gamma (Fcγ) receptor polymorphisms are discussed in regards to HIV-1 vaccine efficacy, HIV acquisition, and disease progression. In addition, the significance of the neonatal immunoglobulin G (IgG) Fc receptor and potential effects of the aggregated IgA Fc receptor (FcαR) are addressed.
Recent findings
Fc receptors undoubtedly play an important role in antibody-mediated action in HIV infection and vaccines. Several studies have determined an association between polymorphic variants of FcγRIIA and FcγRIIIA in the acquisition and progression of HIV-1 infection, and in responses to vaccination regimens. A rather complex relationship exists between the relative affinity of these molecules and their impact on HIV disease acquisition and progression and HIV vaccine efficacy.
Summary
The discrepancies between different investigations of the role of Fc receptor polymorphisms appear to derive from the complex nature of the Fc receptor functions including factors like epistatic interactions and the race, gender, age and relative risk behavior of the investigated individuals. Furthermore, Fc receptors in nonhuman primates (NHP), the key model to study an AIDS-like disease in an animal model, appear to be even more diverse than in humans, and the function of these proteins has not been extensively explored. Given the critical role of Fc receptors in antibody-mediated function in humans and NHP, more investigations are needed to fully understand and exploit these functions for vaccine design.
doi:10.1097/COH.0000000000000051
PMCID: PMC4120665  PMID: 24670320
Fc receptors; non-human primate; single nucleotide polymorphism; vaccine efficacy; FcRn
13.  Autoreactivity in HIV-1 broadly neutralizing antibodies: implications for their function & induction by vaccination 
Current opinion in HIV and AIDS  2014;9(3):224-234.
Purpose of Review
This review discusses progress in understanding the impact of immune tolerance on inducing broadly neutralizing antibodies (BnAbs), and how such knowledge can be incorporated into novel immunization approaches.
Recent Findings
Over 120 BnAbs have now been isolated, all of which bear unusual features associated with host tolerance controls, but paradoxically, may also be required for their function. Evidence that poly-/autoreactivity of MPER+ BnAbs can invoke such controls has been demonstrated by knock-in (KI) technology, highlighting its potential for studying the impact of tolerance in the generation of BnAb lineages to distinct Env targets. The requirement for extensive affinity maturation in developing neutralization breadth/potency during infection is being examined, and similar studies in the setting of immunization will be aided by novel vaccine approaches and KI models that either selectively express reverted V(D)J rearrangements, or unrearranged germline segments, from BnAb lineages.
Summary
It is increasingly apparent that immune tolerance, sometimes invoked by self-reactivity that overlaps with BnAb epitope specificity, adds to a formidable set of roadblocks impeding BnAb induction. The path to an effective HIV-1 vaccine may thus benefit from a deeper understanding of host controls, including categorizing which are unique or common at distinct BnAb targets, and ranking those most feasible to overcome by immunization. Ultimately, such emerging information will be critical to incorporate into new vaccine approaches that can be tested in human trials.
doi:10.1097/COH.0000000000000049
PMCID: PMC4127310  PMID: 24714565
broadly neutralizing antibodies; polyeractivity; autoreactivity; immune tolerance; somatic hypermutation
14.  EDITORIAL: Spectrum of HIV Antibodies in Vaccine and Disease 
Current opinion in HIV and AIDS  2014;9(3):207-209.
doi:10.1097/COH.0000000000000060
PMCID: PMC4321716  PMID: 24670323
15.  A Call to Action for Concentrated HIV Epidemics 
doi:10.1097/COH.0000000000000043
PMCID: PMC4009618  PMID: 24499807
HIV epidemiology; concentrated; hot spots; modeling; molecular epidemiology
16.  Molecular tools for studying HIV transmission in sexual networks 
Current opinion in HIV and AIDS  2014;9(2):126-133.
Purpose of review
Phylogenetics is frequently used for studies of population-based HIV transmission. The purpose of this review is to highlight current utilities and limitations of phylogenetics in HIV epidemiological research from sample collection through data analysis.
Recent findings
Studies of HIV phylogenies can provide critical information about HIV epidemics that are otherwise difficult to obtain trough traditional study design such as transmission of drug resistant virus, mixing between demographic groups, and rapidity of viral spread within populations. However, recent results from empirical and theoretical studies of HIV phylogenies challenge some of the key assumptions and interpretations from phylogenetic studies. Recent findings include lack of transmission bottlenecks in men who have sex with men and injection drug, evidence for preferential transmission of HIV virus in heterosexual epidemics, and limited evidence that tree topologies correlate with underlying network structures. Other challenges include a lack of a standardized definition for a phylogenetic transmission cluster and biased or sparse sampling of HIV transmission networks.
Summary
Phylogenetics is an important tool for HIV research, and offers opportunities to understand critical aspects of the HIV epidemic. Like all epidemiological research, the methods used and interpretation of results from phylogenetic studies should be made cautiously with careful consideration.
doi:10.1097/COH.0000000000000040
PMCID: PMC4109889  PMID: 24384502
HIV; Phylogenetics; Linkage
17.  Drug use as a driver of HIV Risks: Re-emerging and emerging issues 
Current opinion in HIV and AIDS  2014;9(2):150-155.
Purpose of Review
We reviewed papers published in 2012–2013 that focused on re-emerging and emerging injection and non-injection drug use trends driving HIV risk behaviors and transmission in some parts of the world.
Recent Findings
While HIV incidence has declined in many countries, HIV epidemics remain at troubling levels among key drug using populations including females who inject drugs (FWID), FWID who trade sex, sex partners of people who inject drugs (SP-PWID), young PWID, and people who use non-injection drugs in a number of low- and middle- income countries such as in Central Asia, Eastern Europe, Southeast Asia, and parts of Africa.
Summary
HIV epidemics occur within contexts of global economic and political forces, including poverty, human rights violations, discrimination, drug policies, trafficking, and other multi-level risk environments. Trends of injection and non-injection drug use and risk environments driving HIV epidemics in Central Asia, Eastern Europe, Southeast Asia, and parts of Africa call for political will to improve HIV and substance use service delivery, access to combination HIV prevention, and harm reduction programs.
doi:10.1097/COH.0000000000000035
PMCID: PMC4112554  PMID: 24406532
injection drug use; non-injection drug use; HIV/AIDS
18.  Concentrated HIV sub-epidemics in generalized epidemic settings 
Current opinion in HIV and AIDS  2014;9(2):115-125.
Purpose of review
A relatively neglected topic to date has been the occurrence of concentrated epidemics within generalized epidemic settings and the potential role of targeted interventions in such settings. We review recent studies in high-risk groups as well as findings relating to geographical heterogeneity and the potential for targeting ‘high-transmission zones’ in the ten highest HIV prevalence countries in sub-Saharan Africa and the world.
Recent findings
Recent studies have confirmed earlier findings that, even in the context of generalized epidemics, men who have sex with men (MSM) have a substantially higher prevalence than the general population. Estimates of prevalence of HIV among people who inject drugs (PWID) in sub-Saharan countries are rarely available and, when they are, often outdated. We identified recent studies of sex workers (SW) in Kenya and Uganda. In all three cases – MSM, PWID and SW – HIV prevalence estimates are mostly based on convenience. Moreover, good estimates of the total size of these populations are not available. Our review of recent studies of high-risk populations defined on the basis of geography showed very high levels of both new and existing infections in Kenya (slums), South Africa (peri-urban communities) and Uganda (fishing villages).
Summary
Recent empirical findings combined with evidence from phylogenetic studies and supported by mathematical models provide a clear rationale for testing the feasibility, acceptability, and effectiveness of targeted HIV prevention approaches in hyper-endemic populations to supplement measures aimed at the general population.
doi:10.1097/COH.0000000000000034
PMCID: PMC4228373  PMID: 24356328
HIV epidemiology; incidence; key populations; spatial analysis; surveillance
19.  HIV INFECTION AMONG FEMALE SEX WORKERS IN CONCENTRATED AND HIGH PREVALENCE EPIDEMICS: WHY A STRUCTURAL DETERMINANTS FRAMEWORK IS NEEDED 
Current opinion in HIV and AIDS  2014;9(2):174-182.
Purpose of review
This article reviews the current state of the epidemiological literature on female sex work and HIV from the past 18 months. We offer a conceptual framework for structural HIV determinants and sex work that unpacks intersecting structural, interpersonal, and individual biological and behavioural factors.
Recent findings
Our review suggests that despite the heavy HIV burden among female sex workers (FSWs) globally, data on the structural determinants shaping HIV transmission dynamics have only begun to emerge. Emerging research suggests that factors operating at macrostructural (e.g., migration, stigma, criminalized laws), community organization (e.g., empowerment) and work environment levels (e.g., violence, policing, access to condoms HIV testing, HAART) act dynamically with interpersonal (e.g., dyad factors, sexual networks) and individual biological and behavioural factors to confer risks or protections for HIV transmission in female sex work.
Summary
Future research should be guided by a Structural HIV Determinants Framework to better elucidate the complex and iterative effects of structural determinants with interpersonal and individual biological and behavioural factors on HIV transmission pathways among FSWs, and meet critical gaps in optimal access to HIV prevention, treatment, and care for FSWs globally.
doi:10.1097/COH.0000000000000042
PMCID: PMC4286412  PMID: 24464089
HIV epidemiology; sex work; structural determinants; theoretical framework
20.  Dynamics of innate immunity are key to chronic immune activation in AIDS 
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 findings
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.
Summary
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.
doi:10.1097/COH.0b013e32834dde31
PMCID: PMC4328998  PMID: 22156845
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
21.  Qualitative Features of the HIV-Specific CD8+ T cell Response Associated with Immunologic Control 
Current opinion in HIV and AIDS  2011;6(3):169-173.
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).
Recent findings
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.
Summary
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.
doi:10.1097/COH.0b013e3283454c39
PMCID: PMC4309378  PMID: 21399496
Long-term nonprogressors (LTNP); elite controllers (EC); CD8+ T cells; perforin; cytotoxicity
22.  Interventions to improve the performance of HIV health systems for treatment-as-prevention in sub-Saharan Africa: the experimental evidence 
Current opinion in HIV and AIDS  2012;7(2):140-150.
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.
Recent findings
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.
Summary
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.
doi:10.1097/COH.0b013e32834fc1df
PMCID: PMC4300338  PMID: 22248917
adherence; antiretroviral treatment; HIV testing; HIV treatment-as-prevention; randomized controlled trials; retention
23.  Impact of antiretroviral therapy (ART) timing on chronic immune activation/inflammation and end-organ damage 
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.
Recent findings
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.
Summary
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.
doi:10.1097/COH.0000000000000118
PMCID: PMC4301839  PMID: 25415420
CD4:CD8 ratio; early antiretroviral therapy; immune activation; serious non-AIDS events; viral persistence
24.  HIV Vaccine Research and Discovery in the NHP model: a unified theory inacquisition prevention and control of SIV infection 
Current opinion in HIV and AIDS  2013;8(4):288-294.
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.
Recent findings
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.
Summary
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.
doi:10.1097/COH.0b013e328361cfe8
PMCID: PMC4288570  PMID: 23666390
NHP model; vaccines; SIV
25.  “Will expanded ART use reduce the burden of HIV-associated chronic lung disease?” 
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.
Recent Findings
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.
Summary
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.
doi:10.1097/COH.0000000000000018
PMCID: PMC4068344  PMID: 24247667
HIV; Pulmonary disease; chronic obstructive; Antiretroviral therapy; highly active

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