Suppression Of Human Immunodeficiency Virus Replication Research Articles

Experiences of Adolescents on Antiretroviral Therapy at Rustenburg Sub-District, Northwest Province, South Africa.

Antiretroviral therapy (ART) is the treatment of people infected with human immunodeficiency virus (HIV) using anti-HIV drugs. The standard treatment consists of a combination of drugs (often called highly active antiretroviral therapy or HAART) that suppress HIV replication. As a result, people who have been infected live longer while on ART, which was initiated in South Africa in 2004. The study aimed to explore the experiences of adolescents on antiretroviral therapy in two primary health care clinics in Rustenburg sub-district Northwest Province. Qualitative, explorative, descriptive, and contextual approaches were adopted. Non-probability purposive sampling was used to select the healthcare facilities, and adolescents were chosen using convenience sampling. In-depth individual interviews were used to collect data from the participants. Only 13 adolescents between the ages of 15 and 19 years were interviewed. Collected data were analyzed using Tesch's eight steps. Qualitative themes identified included a description of the experiences of adolescents living HIV to adulthood and challenges experienced from childhood to adolescence period. Each theme had different sub-themes which included the paradoxical experiences of being diagnosed with HIV and being on antiretroviral treatment. Adolescents experienced poor adherence to ART due to treatment side effects such as drowsiness, change in body image, and headaches. Self-stigma resulted in adolescents not disclosing their status to their peers, closest and sexual partners which also made them not to adhere well in treatment. The study findings revealed that HIV-positive adolescents encounter various experiences while on ART, which causes them not to adhere to treatment. In the study, adolescents also experienced self-stigma which also affected their treatment adherence and brought fear of losing their loved ones.

Pharmacokinetic Drug-Drug Interactions Involving Antiretroviral Agents: An Update.

Antiretroviral therapy is the recognized treatment for human immunodeficiency virus (HIV) infection involving several antiviral agents. Even though highly active antiretroviral therapy has been proven to be very effective in suppressing HIV replication, the antiretroviral drugs, belonging to different pharmacological classes, present quite complex pharmacokinetic properties such as extensive drug metabolism and transport by membrane-associated drug carriers. Moreover, due to uncomplications or complications in HIV-infected populations, an antiretroviralbased multiple-drug coadministration therapy strategy is usually applied for treatment effect, thus raising the possibility of drug-drug interactions between antiretroviral drugs and common drugs such as opioids, stains, and hormonal contraceptives. Herein, thirteen classical antiretroviral drugs approved by US Food and Drug Administration were summarized. Besides, relative drug metabolism enzymes and transporters known to interact with those antiretroviral drugs were detailed and described. Furthermore, one after the summarized antiretroviral drugs, the drug-drug interactions between two antiretroviral drugs or antiretroviral drug - conventional medical drugs of the past decade were discussed and summarized. This review is intended to deepen the pharmacological understanding of antiretroviral drugs and promote more secure clinical applications for antiretroviral drugs to treat HIV.

Impact of Caveolin-Mediated Endocytosis on the Trafficking of HIV within the Colonic Barrier.

ABSTRACTIn the United States, most new cases of human immunodeficiency virus (HIV) belong to the at-risk group of gay and bisexual men. Developing therapies to reverse viral latency and prevent spread is paramount for the HIV cure agenda. In gay and bisexual men, a major, yet poorly characterized, route of HIV entry is via transport across the colonic epithelial barrier. While colonic tears and paracellular transport contribute to infection, we hypothesize that HIV entry through the colonic mucosa proceeds via a process known as transcytosis, involving (i) virion binding to the apical surface of the colonic epithelium, (ii) viral endocytosis, (iii) transport of virions across the cell, and (iv) HIV release from the basolateral membrane. Using Caco-2 colonic epithelial cells plated as a polarized monolayer in transwells, we characterized the mechanism of HIV transport. After exposing the monolayer to HIV apically, reverse transcription quantitative PCR (RT-qPCR) of the viral genome present in the basolateral chamber revealed that transport is dose dependent, cooperative, and inefficient, with released virus first detectable at 12 h. Inefficiency may be associated with >50% decline in detectable intracellular virus that correlates temporally with increased association of the virion with lysosomal-associated membrane protein 1 (LAMP-1+) endosomes. Microscopy revealed green fluorescent protein (GFP)-labeled HIV within the confines of the epithelial monolayer, with no virus detectable between cells, suggesting that viral transport is transcellular. Treatment of the monolayer with endocytosis inhibitors, cholesterol reducing agents, and small interfering RNA (siRNA) to caveolin showed that viral endocytosis is mediated by caveolin-coated endosomes contained in lipid rafts. These results indicate that HIV transport across the intestinal epithelial barrier via transcytosis is a viable mechanism for viral spread and a potential therapeutic target.IMPORTANCE Despite the success of combination antiretroviral therapy in suppressing HIV replication and the emergence and effectiveness of PrEP-based prevention strategies, in 2018, 37,968 people in the United States received a new HIV diagnosis, accompanied by 15,820 deaths. While the annual number of new diagnoses decreased 7% from 2014 to 2018, 14% of people with HIV did not know they were infected. Gay and bisexual men accounted for 69% of all HIV diagnoses and 83% of diagnoses among males. Due to the scope of the HIV epidemic, determining and understanding precise routes of infection and the mechanisms of viral spread are paramount to ending the epidemic. Since transcellular transport of HIV across an intact colonic epithelial barrier is poorly understood, our overall goal is to characterize the molecular events involved in HIV transcytosis across the intestinal epithelial cell.

Negative Regulation and Protective Function of Natural Killer Cells in HIV Infection: Two Sides of a Coin.

Natural killer (NK) cells play an important immunologic role, targeting tumors and virus-infected cells; however, NK cells do not impede the progression of human immunodeficiency virus (HIV) infection. In HIV infection, NK cells exhibit impaired functions and negatively regulate other immune cell responses, although NK cells can kill HIV-infected cells and thereby suppress HIV replication. Considerable recent research has emerged regarding NK cells in the areas of immune checkpoints, negative regulation, antibody-dependent cell-mediated cytotoxicity and HIV reservoirs during HIV infection; however, no overall summary of these factors is available. This review focuses on several important aspects of NK cells in relation to HIV infection, including changes in NK cell count, subpopulations, and immune checkpoints, as well as abnormalities in NK cell functions and NK cell negative regulation. The protective function of NK cells in inhibiting HIV replication to reduce the viral reservoir and approaches for enhancing NK cell functions are also summarized.

The Relationship of Ghrelin Level with Levels of Cluster of Differentiation 4 (CD4) in Human Immunodeficiency Virus (HIV) Patients Receiving Antiretroviral (ARV) Therapy

Background: Ghrelin is primarily involved in the secretion of growth hormone (GH), glucose and lipid metabolism. HIV infection is thought to affect ghrelin levels in HIV patients, especially in patients with lipodystrophy. However, this effect is still unclear because many studies have obtained different results about low or high levels of ghrelin in people with HIV. Suppression of HIV replication with ART rapidly increases CD4 cell count. However, data on the effect of antiretroviral therapy on ghrelin levels is still scant. Aim: To examine the relationship between ghrelin levels and CD4 levels in HIV patients receiving ARV therapy. Method: This research is an observational analysis study, with cross-sectional design, implemented start from April 2020 in Tropical Diseases & Infection Polyclinic, H. Adam Malik Hospital. Blood samples were taken and examined at the Clinical Pathology Laboratory. Primary and secondary data collection from interviews and direct observation. Data will be analyzed with Pearson correlation test if normally distributed or Spearman's test if the data is not normally distributed using SPSS software. Results: A total of 43 the sample consists of 38 patient who received the AFC, 3 patients received Duviral + Efafirens, 1 patient received Tenofovir + Hiviral + Aluvia dan 1 patient received Tenofovir + Hiviral + Neviral. Demographic characteristics based on th highest ages group are 21-30 years and 31-40 years, each of which is 17 people. The correlation of ghrelin level with levels of CD4 on the HIV patient taking ARV shows a significance value of 0.943, it can be concluded that there was no significant relationship between Ghrelin levels and CD4. Conclusion: There was no correlation between ghrelin levels with CD4 levels on HIV patient receiving ARV therapy. Keywords: Ghrelin, HIV, CD4, Antiretrovirals.

Relations of Antiretroviral Combinations to CD4 Levels of HIV TB Patiens in RSUD H.Abdul Manap Jambi

The cases of Human Immunodeficiency Virus (HIV) infection are increasing every year. This case is a disease that is very rapidly transmitted throughout the world. HIV increases the risk of developing tuberculosis (TB) and conversely TB infection increases HIV progression. In 2017, it is estimated that 10 million people have HIV TB. Combination of antiretrovirals is the basis for the management of antiretroviral therapy for HIV / AIDS patients, because it can reduce resistance, suppress HIV replication effectively so that transmission, opportunistic infections and other complications. The purpose of this study was to determine the relationship between antiretroviral combinations and CD4 levels in outpatient HIV TB patients at RSUD H. Abdul Manap Jambi. This study is a retrospective cohort study using medical records of outpatient HIV TB patients at RSUD H. Abdul Manap Jambi based on inclusion and exclusion criteria. Based on research conducted on outpatient HIV TB patients at Abdul Manap Hospital, Jambi, it was found that there was no relationship between antiretroviral combinations and CD4 levels in HIV TB patients, marked by Asimp.Sig 0.778> 0.05.

Stem Cell-Derived Viral Antigen-Specific T Cells Suppress HIV Replication and PD-1 Expression on CD4+ T Cells.

The viral antigen (Ag)-specific CD8+ cytotoxic T lymphocytes (CTLs) derived from pluripotent stem cells (PSCs), i.e., PSC-CTLs, have the ability to suppress the human immunodeficiency virus (HIV) infection. After adoptive transfer, PSC-CTLs can infiltrate into the local tissues to suppress HIV replication. Nevertheless, the mechanisms by which the viral Ag-specific PSC-CTLs elicit the antiviral response remain to be fully elucidated. In this study, we generated the functional HIV-1 Gag epitope SL9-specific CTLs from the induced PSC (iPSCs), i.e., iPSC-CTLs, and investigated the suppression of SL9-specific iPSC-CTLs on viral replication and the protection of CD4+ T cells. A chimeric HIV-1, i.e., EcoHIV, was used to produce HIV replication in mice. We show that adoptive transfer of SL9-specific iPSC-CTLs greatly suppressed EcoHIV replication in the peritoneal macrophages and spleen in the animal model. Furthermore, we demonstrate that the adoptive transfer significantly reduced expression of PD-1 on CD4+ T cells in the spleen and generated persistent anti-HIV memory T cells. These results indicate that stem cell-derived viral Ag-specific CTLs can robustly accumulate in the local tissues to suppress HIV replication and prevent CD4+ T cell exhaustion through reduction of PD-1 expression.

Hypoxic microenvironment shapes HIV-1 replication and latency

Viral replication is defined by the cellular microenvironment and one key factor is local oxygen tension, where hypoxia inducible factors (HIFs) regulate the cellular response to oxygen. Human immunodeficiency virus (HIV) infected cells within secondary lymphoid tissues exist in a low-oxygen or hypoxic environment in vivo. However, the majority of studies on HIV replication and latency are performed under laboratory conditions where HIFs are inactive. We show a role for HIF-2α in restricting HIV transcription via direct binding to the viral promoter. Hypoxia reduced tumor necrosis factor or histone deacetylase inhibitor, Romidepsin, mediated reactivation of HIV and inhibiting HIF signaling-pathways reversed this phenotype. Our data support a model where the low-oxygen environment of the lymph node may suppress HIV replication and promote latency. We identify a mechanism that may contribute to the limited efficacy of latency reversing agents in reactivating HIV and suggest new strategies to control latent HIV-1.

The Role of Metabolizing Enzymes and Transporters in Antiretroviral Therapy.

Patients with human immunodeficiency virus (HIV) receive antiretroviral therapy (ART) through the use of antiretroviral drugs. A combination of at least three drugs that suppress HIV replication is used as standard treatment, and this is often called "highly active antiretroviral therapy" (HAART). Virus resistance is less likely when three or more drugs are used. A complication of anti- HIV drugs has a complex pharmacokinetic profile which is involved with extensive metabolism and transport by drug metabolizing enzymes (e.g., CYPs, SULTs and UGTs) and transporters (e.g., ABC and SLC). Severe drug-drug interactions (DDIs) can occur with combinations of antiretroviral drugs and this can lead to treatment failure or drug-induced toxicities. Previous reviews have focused on the role of CYPs and ABC transporters with use of antiretroviral drugs and their contributions to DDIs. In this review, we systematically and comprehensively explain the roles of enzymes (including CYPs, UGTs and SULTs) and transporters (including ABC and SLC) on all antiretroviral drugs listed on the FDA's website. We also identify the DDIs that have been shown to be clinically important and associated with drug metabolism and transport alterations. Furthermore, we discuss herb-drug interactions that have been shown with long-term HAART when an herb is used to reduce side effects.

Cytokines and T-Cell Homeostasis in HIV Infection.

Untreated human immunodeficiency virus (HIV) infection is characterized by progressive CD4(+) T-cell depletion and CD8(+) T-cell expansion, and CD4(+) T-cell depletion is linked directly to the risk for opportunistic infections and infection-associated mortality. With suppression of HIV replication by antiretroviral therapy, circulating CD4(+) Tcell numbers typically improve while CD8(+) T-cell expansion persists, and both CD4(+) T-cell cytopenia and CD8(+) T-cell expansion are associated with morbidity and mortality. In this brief review, we report on the role that selected homeostatic and inflammatory cytokines may play both in the failure of CD4(+) T-cell restoration and the CD8(+) T-cell expansion that characterize HIV infection.

Proteins, peptides, polysaccharides, and nucleotides with inhibitory activity on human immunodeficiency virus and its enzymes.

Human immunodeficiency virus (HIV), the causative agent of acquired immune deficiency syndrome, has claimed innumerable lives in the past. Many biomolecules which suppress HIV replication and also other biomolecules that inhibit enzymes essential to HIV replication have been reported. Proteins including a variety of milk proteins, ribosome-inactivating proteins, ribonucleases, antifungal proteins, and trypsin inhibitors; peptides comprising cathelicidins, defensins, synthetic peptides, and others; polysaccharides and polysaccharopeptides; nucleosides, nucleotides, and ribozymes, demonstrated anti-HIV activity. In many cases, the mechanism of anti-HIV action has been elucidated. Strategies have been devised to augment the anti-HIV potency of these compounds.

HIV-specific Immunity Derived From Chimeric Antigen Receptor-engineered Stem Cells

The human immunodeficiency virus (HIV)-specific cytotoxic T lymphocyte (CTL) response is critical in controlling HIV infection. Since the immune response does not eliminate HIV, it would be beneficial to develop ways to enhance the HIV-specific CTL response to allow long-term viral suppression or clearance. Here, we report the use of a protective chimeric antigen receptor (CAR) in a hematopoietic stem/progenitor cell (HSPC)-based approach to engineer HIV immunity. We determined that CAR-modified HSPCs differentiate into functional T cells as well as natural killer (NK) cells in vivo in humanized mice and these cells are resistant to HIV infection and suppress HIV replication. These results strongly suggest that stem cell-based gene therapy with a CAR may be feasible and effective in treating chronic HIV infection and other morbidities.

Can HIV Be Cured and Should We Try?

An estimated 35.0 million persons live with HIV; 2.1 million new infections occurred and 1.5 million persons died of HIV in 2013 (World Health Organization, http://www.who.int/hiv/data/epi_core_dec2014.png?ua=1). Despite effective combination antiretroviral therapy (cART), less than one-quarter of patients can access these life-prolonging medications; and despite its effectiveness, cART does not normalize life expectancy, as premature aging, metabolic complications and chronic inflammation complicate HIV therapy. HIV is incurable due to the presence of a latent viral reservoir. During the life cycle of the virus, HIV integrates into the host DNA. A subset of integrated HIV provirus remains transcriptionally silent, producing neither viral proteins nor viral progeny, until reactivation by various physiologic stimuli. This latency of HIV allows some infected cells to escape immune detection and elimination, and these latently infected cells constitute the viral reservoir. The latent viral reservoir allows viral rebound within weeks of interruption of cART, 1,2 where the magnitude of viral replication approaches that present pre-therapy. Although it was once thought that viral rebound occurred universally following therapy interruption, several recent reports challenge that paradigm. The “Berlin patient” successfully cleared HIV after two allogeneic transplants from a donor with homozygous CCR5Δ32 mutation,3 and he has not rebounded HIV after nearly seven years. This case likely represents a cure from HIV; yet other cases have been described where HIV rebound has been attenuated, or delayed. The “Mississippi” baby was a perinatally HIV-infected infant who initiated cART within hours of birth, and when interrupted eighteen months later, viremia remained undetectable for nearly two years.4 The Harvard BMT cases underwent allogeneic BMT, developed undetectable HIV DNA, yet rebounded viremia within only eight months after cART discontinuation.5 Together these cases demonstrate that control of viremia in the absence of cART is possible, if not durable.4 The VISCONTI cohort of 14 HIV-infected adults who initiated antiretroviral therapy during acute infection, and in whom high level rebound viremia had not occurred several years after cessation of therapy,6 similarly demonstrated that viral rebound following cART interruption can be attenuated. These cases have reinvigorated research toward finding a cure for HIV, which certainly will require an exceptional investment of time, talent and resources. Thus it is prudent to question whether such resources would be better devoted to more proximate needs with proven results (such as supplying cART to those without access to it, or supplying pre/post exposure prophylaxis to reduce the rate of new infections).

Adherence to Anti Retroviral Therapy of People Living with HIV/AIDS: a Cross Sectional Survey

Anti Retroviral Therapy (ART) is the drug of choice in the treatment of Human Immunodeficiency Virus (HIV)/Acquired Immune Deficiency Syndrome (AIDS). More than 95% adherence to ART is necessary to achieve suppression of HIV replication. Therefore, a cross sectional study was undertaken to assess the adherence of patients with HIV/Acquired Immune Deficiency Syndrome (AIDS) to ART. The study also intended to identify the relationship of adherence with the socio-demographic and clinical variables. The study was conducted at the ART clinic of a tertiary care hospital, with a sample size of 100. The study participants were chosen using systematic random sampling technique. Morisky Medication Adherence Scale (MMAS) was used to measure the adherence behavior of People Living with Human Immunodeficiency Virus (PLHIV) and Patient recall and Pill count method to assess their actual drug intake.

Monocyte-activation phenotypes are associated with biomarkers of inflammation and coagulation in chronic HIV infection.

Soluble biomarkers of inflammation predict non-AIDS related morbidity and mortality among human immunodeficiency virus (HIV)-infected persons. Exploring associations between plasma biomarkers and cellular phenotypes may identify sources of excess inflammation. Plasma biomarkers (interleukin 6 [IL-6] level, D-dimer level, high-sensitivity C-reactive protein [hsCRP] level, soluble CD14 [sCD14] level, and soluble CD163 [sCD163] level) were measured from cryopreserved samples from the Study to Understand the Natural History of HIV/AIDS in the Era of Effective Therapy (SUN Study). We performed immunophenotyping of peripheral blood mononuclear cells for markers of T-cell and monocyte activation, maturation, and migration. We evaluated associations between cellular phenotypes and soluble biomarkers by Spearman rank correlation and multivariate linear regression. Participants' (n = 670) median age was 41 years, 88% were prescribed antiretroviral therapy, 72% had a plasma HIV RNA load of <400 copies/mL, and the median CD4(+) T-lymphocyte count was 471 cells/µL. After adjustment, CD14(++)CD16(+) monocytes were associated with higher levels of IL-6, hsCRP, and sCD163; associations with IL-6 and hsCRP persisted in persons with suppressed HIV replication. While CCR5(+) monocytes positively associated with D-dimer levels, CCR2(+) monocytes were inversely associated with hsCRP levels. Plasma inflammatory biomarkers that predict morbidity and mortality were strongly associated with monocyte activation and migration, modestly associated with T-cell maturation, and not associated with CD8(+) T-cell activation phenotypes. These findings suggest that strategies to control monocyte activation warrant further investigation.

Tenofovir, Emtricitabine, and Darunavir/Ritonavir Pharmacokinetics in an HIV-Infected Patient After Roux-en-Y Gastric Bypass Surgery

To determine antiretroviral (ARV) pharmacokinetics in a patient who previously underwent Roux-en-Y gastric bypass (RYGB) surgery. We describe a 38-year-old Hispanic man who tested positive for human immunodeficiency virus (HIV) 11 months following RYGB surgery. When the patient presented for care of his HIV, his HIV-1 RNA was 146 138 copies/mL (5.20 log) and his CD4 T cell count was 320 cells/mm(3) (25%). He was initiated on tenofovir disoproxil fumarate (TDF) 300 mg once daily, emtricitabine (FTC) 200 mg once daily, and darunavir/ritonavir (DRV/r) 600/100 mg twice daily. ARV concentrations were similar to historical data. Six months following ARV initiation, HIV-1 RNA was <48 copies/mL and CD4 count had increased to 562 cells/mm(3) (39%). Bariatric surgery has been successfully performed in obese persons infected with the HIV, but data are limited on ARV drug selection and pharmacokinetics in this group. Optimal suppression of HIV replication requires appropriate concentrations of ARV drugs, and in a patient who has undergone RYGB, this can be challenging not only because of a decreased absorptive surface area but also because of an increased intragastric pH. We found that once daily TDF/FTC and twice daily DRV/r produced trough concentrations similar to historic data in a patient who previously underwent RYGB with virologic suppression and immunologic recovery.

Dengue Virus Serotype 1 Non-Structural Protein NS5 Expression Interferes with HIV Replication in a CD4+ T-Cell Line

The NS5 protein expression of certain flaviviruses, such as Dengue virus type 2, West Nile virus, Hepatitis C virus, and GB virus type C, is associated with a reduced in vitro human immunodeficiency virus (HIV) viral load. To evaluate the suppression effect of the dengue virus serotype 1 (DENV1) NS5 protein on HIV replication, a CD4+ T-cell line was transfected with a plasmid that contained the coding sequence of the DENV1 NS5 gene, and later, it was infected with HIV. DENV1 NS5 protein expression suppressed HIV replication by 28.88% (P < 0.005) on the fifth day compared with the control cells. These results confirm the suppression effect on HIV replication when the DENV1 NS5 protein is expressed in CD4+ T cells. Additional studies are needed to understand exactly how the DENV1 NS5 protein participates in the inhibition of HIV in vitro. HIV interaction with other infectious agents, especially in tropical regions, is associated with accelerated HIV/acquired immunodeficiency syndrome (AIDS) disease progression. However, Watt and others1 reported that HIV and dengue interaction was associated with a reduced HIV viral load. In regard to this finding, there are only four reports on HIV and DENV interaction in humans. The first study refers to an HIV patient infected with DENV1, in which a reduction in the viral load was observed during the coinfection.1 The second study describes an HIV patient with dengue hemorrhagic fever in Brazil,2 and the third report is a case series that includes five HIV patients infected with dengue in Singapore.3 Finally, a DENV3 and HIV coinfection in Cuba was described.4 Previous in vitro studies have reported that NS5 protein expression in certain flaviviruses, including DENV2, West Nile virus, Hepatitis C virus, Yellow Fever virus, and GB virus type C(GBV-C), is associated with HIV replication suppression in CD4+ T cells, which is attributed to an increase in the stromal cell-derived factor-1 (SDF-1) cytokine level expression.5 SDF-1 is the principle ligand for the CXCR4 coreceptor, and it blocks HIV fusion and entry into the CD4+ T lymphocytes.6 Despite the fact that these studies have suggested that the NS5 protein expression of DENV2 and other flaviviruses is associated with elevated levels of SDF-1 expression, the participation of the NS5 polyprotein during HIV suppression is not clear. The present study evaluated the effect of DENV1 NS5 protein expression on HIV replication in a CD4+ T-cell line. An in vitro study was carried out, in which Jurkat CD4+ T-cell cultures were infected with HIV. A DENV1 NS5 gene coding sequence was introduced into the experimental group, whereas the control group was only infected with HIV. HIV p24 antigen levels were measured as a viral replication estimator at the end of the experiment.

Interferon Alfa Therapy: Toward an Improved Treatment for HIV Infection

Highly active antiretroviral therapy(HAART) is an expensive, lifelong treat-ment for human immunodeficiencyvirus (HIV) infection that is associatedwith significant toxicity. Despite advanc-es in treatment, there remains a need fornovel therapies for HIV infection. Onestrategy is to achieve a functional cure,in which treatment can be safely stoppeddespite the presence of residual virus, byfinding approaches that enhance the im-mune response to HIV. Such a therapywould require boosting a patient’sim-mune system to suppress viral replicationbelow clinically relevant levels, therebyeliminating the need for HAART. A ster-ilizing cure, by contrast, is one in whichall functional HIV genomes within thebody are eliminated. Latent HIV genomesrepresent a major barrier to a sterilizingcure because these genomes do notproduce viral proteins and thus cannotbe eliminated by the immune system orby current therapies [1].In this issue, Azzoni and colleaguesassessed the potential of pegylated (Peg)interferon alfa-2a to suppress HIV repli-cation [2]. In what could be a first steptowards a functional cure, they foundthat Peg–interferon alfa-2a permitted asubset of subjects to maintain low viralloads for 12–24 weeks in the absence ofHAART. Furthermore, they found thatin patients with a favorable virologic re-sponse to Peg interferon alfa-2a, levelsof HIV provirus in peripheral bloodmononuclear cells (PBMCs) werereduced. This finding suggests that Peg–interferon alfa-2a may eliminate latentHIV genomes, a possibility that wouldshed light on the search for a sterilizingas well as a functional cure for HIV.Interferon alfa is used clinically forthe treatment of hepatitis B and C virusinfections, and several studies have as-sessed the capacity of this cytokine tolimit HIV replication in vivo [3–9].Mul-tiple studies confirm that interferon alfacan reduce viral load and delay diseaseprogression in viremic patients [3,5–11].However, interferon alfa’s potential tosuppress viremia in patients with well-controlled viral loads is less clear.Recently, one study subjected HAART-treated patients with a viral load of<400 copies/mL forat least 6 months anda CD4

British HIV Association guidelines for the management ofHIVinfection in pregnant women 2012

British HIV Association guidelines for the management of<scp>HIV</scp>infection in pregnant women 2012

Inflammation, Immune Activation, and CVD Risk in Individuals With HIV Infection

ANTIRETROVIRAL THERAPY (ART) PROLONGS LIFE, BUT individuals infected with human immunodeficiency virus (HIV) have a shorter life span than their uninfected counterparts and a greater than expected risk of cardiovascular disease (CVD). Part of the increased CVD risk associated with HIV infection can be attributed to an increased burden of traditional risk factors such as cigarette smoking, as well as the effects of ART on lipids, insulin resistance, and body composition. However, increasing evidence suggests that chronic inflammation and immune activation may play key roles in HIV-associated CVD. In individuals without HIV infection, markers of inflammation such as high-sensitivity C-reactive protein (CRP) and interleukin-6 predict CVD events and mortality. Similar although less robust findings have been described in individuals infected with HIV. In an observational study of 70 357 patients from Partners HealthCare, increased CRP levels and presence of HIV were independently associated with risk of acute myocardial infarction. Compared with patients who had normal CRP levels and without HIV infection, the odds ratio for acute myocardial infarction was greater than 4-fold higher among patients with HIV and increased CRP levels. In the Strategies for Management of Antiretroviral Therapy (SMART) study, interruption of ART was associated with greater mortality and CVD events compared with continuous ART, and higher levels of interleukin-6 and D-dimers were associated with all-cause mortality, suggesting that improvements in mortality in the setting of continuous ART may be mediated by a reduction in inflammation. Furthermore, among treatment-naive individuals infected with HIV, initiation of ART improved endothelial function within 4 weeks of treatment despite worsening lipids and the degree of improvement was associated with lower HIV RNA-1 levels. Taken together, these findings suggest that immediately after initiation, ART reduces CVD risk by decreasing inflammation and viral replication, despite having adverse effects on traditional CVD risk factors. However, individuals receiving treatment who have suppression of HIV replication have higher levels of inflammatory markers than uninfected individuals and persistent inflammation while taking ART appears to increase long-term CVD risk. The factors that contribute to ongoing inflammation and immune activation in the setting of chronic, treated HIV infection are incompletely understood and likely are different than in individuals without HIV in whom inflammation is driven, in large part, by visceral adiposity and its associated metabolic abnormalities. Depletion of CD4 cells in gut mucosal lymphoid tissue occurs early in HIV infection and may contribute to ongoing microbial translocation. This process is not completely reversed with ART, even when HIV replication appears to be suppressed. Increased levels of lipopolysaccharide and soluble CD14 (sCD14) persist in some individuals with treated HIV infection, suggesting that intestinal microbial translocation may contribute to persistent immune activation. Furthermore, increased levels of sCD14 are associated with increased all-cause mortality and HIV disease progression, as well as more rapid progression of carotid atherosclerosis. Other putative drivers of cellular activation and associated cytokine secretion include indirect effects of HIV gene products, direct infection of macrophages by HIV, and antigenic stimulation by latent viruses that are common in patients with HIV. Immunological abnormalities that are affected directly by HIV infection such as current and nadir CD4 cell count have been independently associated with CVD risk, as have markers of immune activation and senescence. In this issue of JAMA, Subramanian et al describe for the first time imaging of arterial wall inflammation using fluorine-2-deoxy-D-glucose positron emission tomography (FFDG-PET) in individuals with HIV. In a small crosssectional study, the authors demonstrated that individuals with HIV but without known coronary artery disease have higher aortic uptake of FDG (expressed as the target-tobackground ratio [TBR]) than risk factor–matched individuals without HIV, and have a level of aortic TBR similar to that of individuals without HIV with coronary artery disease. Patients with HIV infection had higher aortic TBR than controls even after adjusting for traditional CVD risk fac-